Abstracts of Poster Presentations

259

31.01.01 PHARMACOTHERAPY, PSYCHOTHERAPY, AND P S Y C H O E D U C A T I O N A L INTERVENTIONS: EF F I CA CY IN RECURRENT DEPRESSION E. Frank, and D. J. Kupfer

POSTER PRESENTATION 31.01

We are currently engaged in a study of maintenance treatments for recurrent unipolar depression which compares the efficacy of psychotherapy, pharmacotherapy and their combination. Rather than focusing exclusively on the number of recurrences in each of the experimental conditions, we have also been concerned with the quality of patients' lives between episodes and with the !ength of the symptom-free interval. The three-year maintenance phase of our study is still in progress; therefore, final results will not be available for another 18 months to 2 years. We can, however, discuss the information available on those 62 patients who have already experienced a recurrence of illness and for whom the blind has been broken. While the majority of recurrences have been e x p e r i e n c e d by patients in the nonme di c a t i on c o n d i t i o n s , it would appear that, with or without medication, psychotherapy has had a significant effect in delaying the onset of a new episode. At this point in time, however, we have little evidence that continued psychotherapy adds to the generally good q u a l i t y of p a t i e n t s ' social f u n c t i o n i n g in s y m p t o m - f r e e interval. A full understanding of the additive and interactive effects of pharmacotherapy and psychotherapy in the treatment of recurrent depression must await the completion of this study ",,,'here analyses which indicate both the recurrences and the survivors will be possible,

Basic and Clinical Aspects of Depression

U n i v e r s i t y of P i t t s b u r g h , School of M e d i c i n e , Department of Psychiatry and Psychology, Western Psychiatric Institute and Clinic, 3811 O'Hara Street, Pittsburgh, PA 15213

31.01.02 CHARACTERISATIOt; BASIS

31.01.03 OF DEPRESSIVE

SUSGROUPS

ON THE

OF P S Y C H O P A T H O L O G I C A L , P S Y C H O P H Y S I O L O G I C A L ,

NEUROENDOCRINOLOGICAL

AND C L I ! ; I C ~ L

PARAMETERS

Marko Munjlza

IN

THE COURSE OF ~EPRESSION E.M.STEINHEYER,A.CZERNIK comparat~an-aqysls Is presented of symptomatological,phychophysiological,neuroendocrinological,diagnosisspecific,and course-specific parameters o f 38 = e m a l e i m p a t i e n t s durina the depressive phase of and after relief from depression.We studied the state or trait dependence of specific reaction patterns of operationalized depressive subgroups.The extent to which the patients can be s u b d i v i d e t into distinguishable groups during the depressive p h a s e and a f t e r recovery from depression,and the specific differences between the possible subgroups are shown. The r e s u l t s of the cluster-,discriminant-,and factor-analyses demonstrate a very high dominance o f b i o c h e m i c a l and n e u r o e n d o c r i n o l o q i c a l narameters for the determination of depressionspecific reaction patterns durin 9 depression.A greater coherence,i.e.,a lower indeeence of the individual psychoautonomic,co9nitive,and psychophysiological s y s t e m s was c o n f i r m e d , w h i c h suggests a narrowina and a reduction of the "degrees of freedom~(HEIMANN) in the depressive phase.After recovery from depression,psycholonic a l and c o g n i t i v e parameters have more relevance and s h o w a h i g h d i s c r i m i n a n t validity between neurotic and e n d o g e n o u s depressive subgroups. Abtl. Psychiatrie der Medizinischen Einrichtungender Rheinisch-Westf~lischen Technischen Hochschule Aachen,Pauwelsstr.,51&~cnen

260

THE THERAPY 3F ORGANIC DEPRESSION

According to the recent reports ]ssued by WHO the prevalencerate of depression is from 3 to 5 per cent for the whole population. The greater incidence of ~3r~ous psychogeriatric disorders with depressivesymptomatology, as well as numerous somatic and neurologic disorders: appears to be the sign o'~ an inCreasingly large number of somatogenic depression and depressive syndrome on the whole. Since the aet~olugy of somatogenic depression has within itself somatic, neurologic, b;olugic, social and other factors, the author explores the application of combined therapy with vasoactive substances and antidepressants. Data were collected prospectively on 190 patients, both genders (86 males and 1C4 females), in age from 45 tO 75 years, over a six weeks period. Throughout the study, the patients received Pentoxyfilin (Trental) and antidepres.~nts according to the form of depressivereaction --inhibited or agitated picture. In addition to tee statistical analysis, particular attention is paid to the clinical evalu~ior of applied therapy inthe most frequent symptoms of somatogenic depression. During the clinical evaluation different scales were used in accordance with symptomatology. The combination of PentoxyfiIin ar=:l antidepressants at all these scales appears to offer more advantages tl-en any other method improving the existing state~ of depressive mood, depressive inhibition, symptoms of fear and SOmatic manifestations. This satisfactory outcome of combined therapy also provides improvement in the sphere of concentration and memory, producing willir~jress for social contacts and interest in work and activity. The satifying effect of combined therapy with regard to the therapy with antidepressants only, especially in depressive, somatic and neurasthenic difficulties, is iliu~rated most obviously by statistical analysis Where the significant difference was obtained already at level below 0.05 for the benefit of Pentoxyfilin in combination with antidepressants. INSTITUTE FOR MENTAL HEALTH, Palmoticeva 37, 11000 Belgrade YUGOSLAVIA Belgrade University Medical ghool

31.01.04

31.01.05

RELATIONAL DEPRESSION RATING SCALE AND CLINICAL ASSESSMENT OF MAPROTILINE Y, Poinso, M. Ohayon Reliable rating scales are needed in multicentric trials of psychoactive drugs. The author presents a new depression rating scale (RDRS) stressing the PsychiatristPatient relationship during a non*directive clinical interview, our basic hypothesis being that the clinician evaluates the severity of the depression more upon this relation than upon the seeking of the classical depressive symptoms. Therefore, RDRS scans the relational elements of the interindividual communication (ie. 1) non-verbal communication tokens: features' and body's mobility, look, clothes, 2) verbal communication: voice, topics, adaptability, 3) emotional display: effective need, anguish during the interview, aggressivity and irritability, selfaggressivity). The 12m item is a global estimation of the quality of the psychiatrist-patient interaction. RDRS performs a reliable estimation of depression, with a perfect correlation with other classical rating scales such as MADRS, as demonstrated by the statistical assessment Its main interests are: 1) easy rating, even by generalists. 2) Monofactorial structure, all the items being closely correlated or:ly with the intensity of depression. 3) steady logarithmic decrement of RDRS sco;es under trealmenL 4) good inter-observer reliability. As an instance, the author presents the results of a mult~=ntric trial of Maprotiline using RDRS together with other rating scales. The scale was welcomed by the clinicians, owing to the fact t~at it needs no change in their own way of interview, Its results are quite similar to those of the other rating scales used, showing no gross discrepancy. This study confirms the value of RDRS as a rating tool for depression. Laboratoire de Traltemant des Connaissances, CHU Sainte-Marguerite, 270, Boulevard de Ste-Marguerite, 13009-Marseille (FRANCE)

PATTERNS OF COGN I T I VE AND PSYCHOMOTOR D I STURBANCES IN DEPRESSED PAT I ENTS UNDER SEDATIVE AND A C T I V A T I N G ANTIDEPRESSIVE THERAPY C . R . V i e i r a , M. Paes de Sousa~ M . L . F i g u e i r a , L.C. P e s t a n a , M. Feio Since previous studies showed that activating ant idepressive therapy improves cognitive and p s y c h o m o t o r p e r f o r m a n c e s of d e p r e s s i v e p a t i e n t s , the q u e s t i o n r e m a i n e d i f t h e same e f f e c t was a c h i e v e d with sedative antideoressive drugs. In m a t c h e d samples of d e p r e s s i v e p a t i e n t s s u b m i t t e d to a c t i v a t i n g (Amineptine) and sedative (Dothiepine and Trazodone) antidepressive t r e a t m e n t s , , t e s t s of central nervous arousal (CFF), attention, Short-term and iconic visual and verbal memory and choice reaction time (CRT), were performed before and after four weeks of t r e a t m e n t . The d a t a o b t a i n e d were s t a t i s t i c a l l y (means, standard deviations and ANOVA) c o m p a r e d a m o n g t h e m s e l v e s a n d a l s o w i t h t h e d a t a o b t a i n e d w i t h t h e same b a t t e r y of test_-- in a sample of n o r m a l subjects. The r e s u l t s were analysed and discussed. D e p t . of P s y c h i a t r y . F a c u l t y of M e d i c i n e of L i s b o n . H o s p i t a l St a M a r i a . Av. Prof. E g a s M o n i z . P-1600 Lisbon. Portugal.

31.01.06

31.01.07

THE INFLUENCE OF SOME PSYCHO-SOC IAL AND PATHOLOGICAL CHARACTERISTICS OF DEPRESSIVE PATIENTS ON THE SYNDROMATIC EVOLUTION UNDER ANTIDEPRESSIVE THERAPY M. Paes de Sousa, M. L . Figueir a 424 depressive patients treated with several antidepressant drugs (Clomipramine, Doxepine, Dibenzepine, Tandamine, Nomifensine, Amineptine, Amitrityline, Nortriptilyne and Minaprine) were d e s c r i b e d a n d assessed b e f o r e a n d a f t e r 1-2 m o n t h s of t r e a t m e n t with t h e AMDP s y s t e m . A principal components analysis on t h e b a s i s of t h e AMDP-4 Scale items, was made before and after the treatment. The f i r s t analysis enabled to isolate three factors (depression/inhibition, anxiety/ agitation and self-distortion) a n d t h e second analysis e n a b l e d to i s o l a t e t w o f a c t o r s ( d e p r e s s i o n / i n h i b i t i o n and anxiety/agitation). Taking into consideration each one of these f a c t o r s , an a n a l y s i s of v a r i a n c e ~sas performed among some psycho-social and psychiatric history variables of t h e s u b j e c t s of t h e sample. The v a r i a b l e s studied were: sex, age, marital status, education, social-economical status, body type D personality, patients psychiatric history, depressive diagnostic, depression modality~ in o r outpatients and antidepressive drug. Significant differences were obtained for some variables. W h e n e v e r t h e r e was more t h e n t w o p o s s i b i l i t i e s for one s i n g l e variable, the Bonferroni t test was a p p l i e d to d i s c r i m i n a t e t h e sens of t h e s i g n i f i c a n c e . The d i f f e r e n c e s c o n s i d e r e d s i g n i f i c a n t were a n a l y s e d and discussed. Dept. of P s y c h i a t r y . F a c u l t y of M e d i c i n e of L i s b o n . H o s p i t a l St -a M a r i a . Av. Prof. Egas Moniz. P-1600 Lisbon. Portugal.

TAIL SUSPENSION TEST : STRAIN DIFFt~RENCES AND THE'EFFECTS OF THREE ANTIDEPRESSANTS A. Len~m'c. I. AvriL L Stdru and R.D. Porsolt Mice when suspended by the tail will alternate between periods of vigorous activity (searching) and immobility (waiting). Immobility, like that measured in the "behavioural despair" test, is reduced by a wide variety of antidepressants. The procedure has been automated (ITEMATIC-TST) and permits the objective measurement of two parameters, immobility and the power of movements. The present experiments compared the behaviour of 5 strains of mice (C57BL10, C57BL6, DBA/2, Balb/C, NMRI) on the two parameters and examined the effects of three antidepressants with different mechanisms of action : imipramine, nomifensine, dtalopram. The resultsshowed dear differencesin base-linebchavlour : Balb/C showed twice as much immobility as NMRI with similar po~ver of movements whereas DBA/2 mice showed similar immobility to NMRI but increased power of movements. The different strains also reacted differently to drugs. NMRI showed clear decreases in immobility with all drags whereas DBA/2 were particularly sensitive to nomifensine and dtalopram. BALB/C responded only to dtalopram..

These results suggest that choice of strain might be a significant factor for dete.cfing antidepressants with particular mechanisms of action.

I.T.E.M.-Labo, 93 Avenue de Fontainebleau, 94270 Kremlin-Bic2tre - France

261

31.01.08

31.01.09

EFFECT OF NIFEDIPINE ON THE SHUTTLEBOX ESCAPE DEFICIT INDUCED BY INESCAPABLE SHOCK IN THE RAT M. Geoffrey, E. Mogilnicka, M. Nielsen and O. J. Rafaelsen The behavioural ~ffeet of subchronic treatment ~ith calcium channel antagonists (nifedipine, verapamil) amd with imipramine ~as assessed in rats subjected to inescapable shock. Furthermore, the effect of subchronic treatment with nifedipine and imipramine on specific 3H-nitrendipine (SH-NDP) binding was investigated in frontal cortex of naive rats and in rats given inescapable shock and later tested in a shuttlebox escape paradigm. The test was carried out in a twe-wa~ shuttlebox and consisted of lO initial trials where changing side in the box once (FRI) terminated shock, and 15 subsequent trials where changing side twice (FR2) was required to terminate shock. After inescapable shock rats show a severe impairment in escape behaviour. Imiprsmine and nifedipine significantly reduced FRI and FR2 escape deficits. Verapamil had no effect. A small but significant increase in the number of 3H-NDP binding sites (Bmax) was seen in rats exposed to the shuttlebox escape test independent of a previous exposure to inescapable shock. Imipramine had no influence on Bmax in any of the groups. Nifedipine did not affect 5H-NDP binding in naive rats, but actually decreased Bmax in rats subjected to inescapable shock and the shuttlebox escape test. The comparable ability of nifedipine and imipramine to reterse the shuttlebox escape deficit induced by inescapable shock speaks in favour of possible antidepressant activity of nifedipine. The biochemical data indieate that cortical }H-NDP binding sites are not correlated to performance in the shuttlebox escape test. Psychopharmacological Research Laboratory, St. Hans Hospital, DK-4000 Roskilde, Denmark

ANTIDE~NT-LI~ ACTION OF8-[]H 0OAT, A D-HTIA ;~I~QIST, IN l)E L ~ ~S~ESS PARADIGM : PFE- OR P O S T - ~ T I C NE[}P.NI~I ? P_z_-F~rtin, Ru ~ [ , O. Maesol, ~ . ~ r t e , S. E1 Mestika~ P. Soubri~, M. Has,n*, A.O. Puesh.

A recent rt~.ie~ suggested the potential indication of buspiroce in anxious patients suffering frcm depression and an qcen trial reported its utility in the treatment of non melaroholie depressed patients. In animal models of depression, the S-HTIA aganists, B-hydroxy-2-(di-npropylamino) tetralin (8-O4-DPAT), bJspirone, gepirone and ips~irone acbCnistered i.p. mimicked the b~havioral effects of antidepressants. For instax~, in the learned helplessness p~c[s theseck'ugareversed the escape deficit ~ by prior i n g l e shocks (60 inescapable ~'~d
21.1 + 1.2

11.9 + 2.6

6.7 + 2.1

18.4 ~ 3.1

12.1 + Z.7

9.4 + 2.7

lhese z~sults indicated that the ability of 8-[}4-CPAT to reverse escape deficit probably involved the stJ~dation of post-syrsptic rather than pre-syrsptic 5-HTIA receptors.

[h~partemont de P ~ l o g i e et Inserm LF/88*, Facult~ de M6declre Plt16-balp~tri~z~, 91 Bd de l'H6~ital, 75015 PARIS, FRANC[.

31.01.10

31.01.11

URINARY 24 HOteLS FREE SULFATE AND GLUCU~ONIDE ~ VALUES fIN ENDOGENOUS %~RSUS NON ENDOGENOUS DEPRESSED PATIENTS :Ph. LESIEUR~ P. PENINQUE, J.P. GARNIER, J.PIRON, J.P. LEPINE and M. PETIT Method : seventeen depressed patients, dru~-free for at least 15 days were hospitalised. All subjects met the DSM3 criteria for r.ajor affective (n=12) or dysthymic(n:5) disor. ders. Severity of depression was assessed usingMADRS (range 28 to 46). The Newcastle Diagnostic Index was used to clas sify the patients as endogenous (n=12) and as nonendogenous (n=5) Before and 30 days after a treatment by metapramine (300 to 600 mg/day), we measured tha 24 hours urinary excretion of free, glucuro and sulfate MHPG. Results : At baseline, the individuals scores on the MADRS are negatively correlated to both total and sulfate MHPG (r= -.516 p<.05 and r = -.611 p<. 01 respectively); the endogenous group havinB the lowest values on this scale : 37.9 + 4.1 vs 31.8 + 3.1 p<.01 . More [nterestingly,-the 24 urinary excretion of total sulfate and glueuro MHPG are significantly lower in tha endogenous group : 5.82 + 2.97 vs 11.72 + 3.84 ~moI/24 H p<.01, 1.08 + .8 vs 3.26 + 1.2 p<.001 and 2.21 + 1.78 vs ~.46 + p <.0[ respectively. Aftar-30 days of treatment the measures were completed in 8 out of 12 endogenous patients, Only the sulfate form increases significantly : 1.04 + 95 vs 3.10 + 2.14 p<.05. Conclusion : These data point-out the relevance of tha Neweastla Diaanostie Index as a clinical tool able to discriminate depressed patients with high and low ~4 urinary MHPG excretion

INTEREST OF IV ADMINISTRATIONOF CLOMIPRAMINEIN RAT FOR THE STUDYOF THE 5-HT PHARMACOLOGICALEFFECTSOF THIS DRUG D.Varoquaux,P.Lesieur,D.Morin,M.Pays,C.Advenier,W.Z.Potter C]omipramine is knownto be a potent and specific serotonir (5-HT) reuptake inhibitor whereas its demethylatedmetabol i t e (DMC) is considered as a noradrenaline reuptake inhiiter (Carlsson and al.,1969;Horn,1976;for review Mass,1979 yttel,1982). The aim of this study was to compare plasma levels of CMI with those of its metabolites after an IV injection of CMI in rat. Two days prior to experiment an indwelling catheter was implanted to the t a i l artery (Chiueh and Kopin,1978). This preparation allowed us a systemic clomipramine (5 mg.kg-l) injection and 10 blood samples collection over a 24 hours period in the sameconscious and unrestrained rat (n=8). Clomipramine (CMI) and its 8-hydroxy (8-OHCMI),demethyl (DMC),8-hydroxydemethyl (8-OHDMC) and didemethyle (DDMC) metabolites were determinedon a 100 ~l plasma sample by Bn HPLC-ECmethod (O.Spreux-Varoquauxand a~.,J.of Chromat. 1987,416,311-319). Tmax(h) were I~0.2 for 8-OHCMI and 0.08 +0.02 for DMC. For CMI,B-OHCMI and DMC, Cmax(Bg.l-I) were 27802+3005, 6.5+0.6 and 51+5 respectively, tl/pB(h) ( t i / 2 apparent for metabolites)'were 2.9+0.4, I0.1%~.8 and 3L5+0.5 respectively, AUC (Ng.l'1.h) were 10725-+ 1865,87.5~ 7.2 and 49.9 9 6.5 r~spectively, and MRT (h) were 2.8~0.7,15.1~I.3 and 4.2,0.5 ~espectively. The plasmaAUC CMI/metabolite ratio is 214.9 for DMCand 122.5 for 8-OHCMI. The 8-OHDMCand DDMCwere mever detectable below 200 pg and 10 pg in 100 ul plasma

Centre Hospitaiier du Rouvray - 4 rue Paul Eluard B.P.A5 76301SOTTEVILLE LES ROUEN - FRANCE

262

l

~ample r e s p e c t i y e l y . Because o f the very few a~ounts o f CMI m e t a b o l i t e s and since CMI i s known t o be a s e l e c t i v e 5-HT reuptake i n h i b i %or, these data suggest IV a d m i n i s t r a t i o n o f CMI to be a ~ e l i a b l e t o o l t o study the pharmacological e f f e c t o f CMI on 5-HT system. D~partement de Biochimie e t Pharmacologie,Centre H o s p i t a l i e r de V e r s a i l l e s , H B p i t a l A.Mignot,F-78 157 Le Chesnay.

31.01.12

31.01.13

PLASMA SEROTONIN LEVELS IN RELATION TO HYPOTHALAMIC-PITUITARY-ADRENAL FUNCTION IN DEPRESSION C. Rupprecht, A. Barocka, M. Rupprecht, G. Beck, IM. Noder and R. Rupprecht {There is evidence that serotonin precursors and !reuptake inhibitors may exert a stimulatory !effect on the hypothalamic-pituitary-adrenai sys'tam. 5-hydroxytryptophan has been shown to proiduce a greater increase in cortisol levels in depressed patients when compared with normal controls. As no data are available on the response of plasma serotonin during the dexamethasone suppression test we studied 7 am and 4 pm preand postdexamethasone cortisol and serotonin levels of 16 patients during depression and after recovery and of 28 healthy controls receiving an oral dose of 1 mg dexamethasone at 11 pm. Dexamethasone had a significant suppressive effect (p
STIMULATION WITH DL-FENFLURAMINE IN ACUTE AND REMITTED PATIENTS WITH M A J O R DEPRESSION A.Vieira. S.KasDer. R.Schmidt G.VoI1. P Richter. H.Kich Ch Mundt Abnormalities in central serotonergic function in depression are suggested by CSF, neuroendocrine and postmortem brain studies. Using dl-fenfluramine (FEN) as a serotonin probe (fenfluramine stimulation test, FFT) we investigated 31 drug-free inpatients (26 female, 5 male; mean age: 55 + 11 years) with major depression by DSM-KI criteria. At baseline and after administration of 60 mg dl-fenfluramine (FEN) p.o. at 9 a.m. hourly blood samples were obtained until 1 p.m and subsequently prolactin, cortisol, TSH, hGH and the plasma levels of dl-fenfluramine and its major metabolite di-norfenfluramine were measured. The test procedure (FFF) was performed in the same indi~Sduals (intraindividual comparison) in the acute stage of the illness with and without application of FEN and after remission. The peak plasma levels of dl-fenfluramine and its main rnetabolite dl-norfenfluramine could be detected in most patients 3 hours after FEN application. These levels did not differ in acutely depressed and remitted patients. A significantly lower increase of dl-fenfluramine stimulated prolactin and hGH values (group x time interaction: prolactin: F = 4.4, p < 0.01; hGH: F = 2.7, p < 0.05) was found in remitted depressed patients. There was no significant difference in FEN stimulated Cortisol and TSH values. Mean peak delta prolactin response to FEN in acutely depressed was significantly (p < 0.05) correlated to that of r e m i n d patients. Hormonal responses were not correlated to the severity of illness but there was a negative correlation (p < 0.05) between mean peak delta prolactin response and hostility. Our findings suggest that remitted depressed patients have a different serotonergic function compared to the acute state of the illness. The data provide further evidence for the FEN stimulated prolactin response to be related to both the state and also to state independent characteristics in patients with major depression. Psychiatric Department of the University of Heidelberg, D-6900 HEIDELBERG, Vo/~strage.4, FRG

31.01.14 DST AND THE BLOCKATORS OF NORADRENERGIC SEROTONERGIC TRANSMISSION IN DEPRESSIVE PATIENTS I. Timoti~ evi6

31.01.15 AND

The integrative model of affective disorders considers depression to be the ending of discrders on psychological, biological and empirical level. The basic indicators in the dia~nose and treatment of depression are the biological disorders entering the scope of functioning of hypothalamic-hypophysicaladrenaline axis, and disorders in functioning of transmitters. LST is used as a measure of functioning for patients who by precise clinical evaluation have been diagnosed as great depressive disorders (DSM III)? or endogenous, unipolar depressions (IC9), and on the basis of these data treated with a~tidepressants of serotonergic reuptake. The sample consisted of two groups (eight patients in each), of both sexes, age range, 25 to 56 years. The A group patients were treated with blockators of noradremergic transmission and those of B group with serotonergic antidepressants. DST was carried out in both groups before the treatment and 28 days after medication. Depression is measured by the score hight on the Hamilton Scale. The results show that all improvements have been achieved disregarding the selective use of antidepressants while DST did not demonstrate sensitivity to the sort of antidepressant. DST singled out the patients with clinical improvement, but not those with biochemical homeostasis which discovers patients in risk of possible decompensation in the case of breaking the continuity of medication.

PsTchopharmacologlcal Aspects of Pineal Function -V. Srinivasan Institute of Physiology, }ladurai ~ledical College ~[adurai India. The possibility of Pineal gland involvement as a part of neuroendocrine dysfunction in some of the psychiatric diseases has received attention in recent years. The significant effects of many psychoactive drugs on the synthesis and secretion of melatonin and the discovery of many receptor sites in the pineal gland, beta adrenergic, alpha 1 adrenergic, D2-dopaminergic S2-serotonergic, muscarinic-cholinergic, GABA ergic, glutamatergic, benzodiazepinergic and peptidergic receptors (Ebadi & Govitrapon$ 1986) have all suggested that the study of pineal function and melatonin secretion provides a valuable model system for psychopharmacological investigations. Murphy et 1986). Many psychoactive drugs, namely chlorpromazine, imipramine, lithium, haloperidol, diazepam, nootropil when administered to animals produces significant increases in pineal melatonin and protein concentrations (Srinivasan et a! !985). Administration of monoamlnc oxidase inhibitor antidepressants and tricyelic antidepressants to animals or to patients suffering from depressive illness causes significant increases i n either CSF, Plasma or Urinary melatonin levels (Golden et al 1987, Murph 7 et al 1986 (a) (b), Srinivasan et al 1984, 1986, 1987, "Thompson et al 1983, 1984). The significant effects of these psychoactive drugs on pineal function and melatonin secretion will be discussed.

263

31.01.16

31.01.17

THE TWENTY FOUR HOUR SECRETORY PROFILES OF PROLACTIN IN MA3OR DEPRESSIVE ILLNESS AND AFTER TREATMENT, P. Linkowski, E. Van Cauter, M. Bal6riaux t M. Kerkhofs, P. Hubain, M. L ' H e r m i t e , J. Mendlewicz. Plasma PRL were measured at 15 rain intervals for 2g hour in 18 male subjects suffering from major endogenous depressive illness and in 7 a g e - m a t c h e d normal men. Eleven of t h e lg depressed patients were restudied during clinical remission following either electroconvulsive therapy or amitriptyline treatment. Durin 8 the acute phase of the illness, the unipolar depressed patients showed an early timing of the nocturnal secretory phase of PRL, which started, on average, two hours earlier than in normal subjects. Moreover, the amplitude of the circadian variation of PRL was reduced in t h e s e patients, with decreased PRL levels during the midsleep period. This latter abnormality was also observed in bipolar patients, who had otherwise normal PRL profiles. These lower midsleep PRL concentrations were associated with a significant increase of the a m o u n t of t i m e spent awake during the same period. Antidepressant t r e a t m e n t did not consistently c o r r e c t t h e abnormalities in the patterns of PRL release observed during t h e a c u t e phase of the illness. These results indicate that early timing of nocturnal PRL secretion and damping of the nighttime PRL elevation m a y be found in patients with endogenous depressive disorders. In c o n t r a s t to disturbances of t h e corticotropic and somatotropic axes, these abnormalities of PRL secretion may be still present during clinical remission following antidepressant t r e a t m e n t . Free University of Brussels, g r a s m e Hospital, Department of Psychiatry, Route de Lennik 808. 5-1070 Brussels.

CINP

XVIth

Congress

Munich,

15th-17th

August

h988

CORTZSOL RESPO~:S~ oF ~ P O L A R

PATiEnTS RECEZVZ~G

AN ANTIGLUCORT!CCID Administration of RU 486, a synthetic antagonist of glucocorticos~eroid at the receptor level, induces in normal subjects a desinhibition of the pituitary adrenal axis and antagonizes the ACTH inhibitory effect of Dexamethasone. When the drug is administred at midnight or I0:00 a.m.. the increase of cortisol, ACTH and Beta-endorphin plasma levels occurs only during the early morning ieak. The response of bipolar patients is an increase of tortisol secretion superior as compared to controls. The best ~ i m e to discriminate patients from controls is 5:00p.m. This m a g n i f ~ d reactivity of the glucorcorticosteroid secretion is consistent wich the abnormalities described using dexamethasone suppression test.

31.01.18

31.01.19

SEASONAL VARIATION OF CORTISOL LEVELS IN DEPRESSIVES A.L.van Bemmel~R.van Diest~ E.H.J.Smeets~P.H.M.van Dongen S i g n i f i c a n t l y lower post-dexamethasone (POST-DEX) c o r t i s o l plasma l e v e l s during the four months November to February compared to the rest of the year have been reported in depressives (1). This f i n d i n g was i n t e r p r e t e d as a seasonal v a r i a t i o n of the dexamethasone suppression t e s t (DST). S i g n i f i c a n t l y less frequent DST nonsuppression in winter than in summer was reported e a r l i e r in depressives (2). Although of unknown o r i g i n , the seasonal v a r i a t i o n of POST-DEX c o r t i s o l l e v e l s is possibly r e l a t e d to a s i m i l a r v a r i a t i o n in PRE-DEX c o r t i s o l l e v e l s . This study is dealing with the question whether a seasonal v a r i a t i o n in PRE- and POST-DEX c o r t i s o l l e v e l s in plasma can be found in depressives. Subjects with major depression were selected from two p s y c h i a t r i c c l i n i c s (n=33 and 54 resp.). They were h o s p i t a l i z e d and tested when depressed. One mg DEX was given at 11 PM and blood samples were c o l l e c t e d at 4 PM on the day before and a f t e r DEX. A POST-DEX c o r t i s o l concentration > 0.14 #mol/1 was defined as nonsuppression. V a r i a t i o n of PRE- and POST-DEX c o r t i s o l levels over a l l seasons was i n v e s t i g a t e d with simple oneway ANOVA and the seasonal d i s t r i b u t i o n of the nonsuppression rate with the Chi-square t e s t . These analyses did not show s i g n i f i c a n t r e s u l t s . Therefore, the consequence for every day p r a c t i c e of the suggested seasonality in the DST, whenever i t e x i s t s , remains doubtful. (1)Swade et a l . J A f f e c t Disord 13, 9-11, 1987 (2)Arat6 et al.Arch.Gen.Psychiatry 43, 813, 1986 Department of C l i n i c a l Psychiatry, State U n i v e r s i t y of Limburg, PO Box 616, 6200 MD Maastricht, The Netherlands.

THE EFFECT OF REPEATED ADMINISTRATION OF ANTIDEPRESSANT DRUGS ON THE THYROTROPHIN RELEASING HORMONE (TRH) CONTENT IN RAT BRAIN STRUCTURES E. Przegali~ski and L. Jaworska

264

Several lines of evidence indicate that some links exist between TRH and depression or antidepressant therapy. For example, repeated treatment with amitriptyline or electroconvulsive shock was shown to increase the TRH concentration in different regions of the central nervous system (Kubek et al., Life Sci., 36, 315, 1985; Lighton et al., Neuropharmacology, 24, 401, 1985). The present study investigated the effect of repeated treatment with the antidepressant drugs: imipramine, amitriptyline, citalopram and mianserin (10 mg/kg p.o., twice daily for 14 days, last dose 4 h before killing) on levels of TRH in several brain structures (cerebral cortex, amygdala + pyriform cortex, hippocampus, nucleus accumbens, striatum and hypothalamus) of the rat. Amitriptyline caused a marked increase in the TRH content in the striatum and nucleus accumbens (by 188 and 126%, respectively). Citalopram and mianserin produced a smaller but significant increase in the peptide content in the striatum only (by 76 and 56%, respectively), while imipramine did not significantly affect the TRB level in any of the examined brain structures. These results speak against the relationship between changes in the brain TRH induced by antidepressant drugs and their therapeutic activity. Institute of Pharmacology, Polish Academy of Sciences, Sm~tna Street 12, 32-343 KrakBw, Poland

31.01.20

31.01.21

PITUITARY-ENDORGAN RESPONSESFOLLOWING COMBINED GROWTH HORMONE-(GHRH), THYROTROPIN- (TRH) AND CORTICOTROPIN-RELEASING HORMONE (CRH) STIMULATION IN DEPRESSEDPATIENTS AND CONTROLS. U. MOller, R. Rupprecht, H.M. Schulte, and K.P. Lesch To explore and to compare hypothalamic-pituitary-somatot r o p i c (HPS), - t h y r o i d (HPT) and-adrenal (HPA) axis funct i o n in depression, 20 subjects (10 patients with a major depressive episode and i n d i v i d u a l l y matched controls) recieved 50 pg GHRH-44 amide at 9:00 h, 200 pg TRH at 9:00 h and lO0 pg human CRH at 18:00 h on consecutive days as an i v bolus dose. Compared t o controls, the depressed pat i e n t s showed blunted GH responses to GHRH (p
NEUROENDOCRINE INTERRELATIONS BETWEEN DEPRESSION AND SEXUAL DYSFUNCTION M. Noder, E. J e c h t , C. R u p p r e c h t , M, R u p p r e c h t and R. R u p p r e c h t While t h e h y p o t h a l a m i c - p i t u i t a r y - g o n a d a l system has found c o n s i d e r a b l e interest in sexual dysfunction, only few data on gonadal hormones are available in depression. In order to investigate possible i n t e r r e l a t i o n s between psychogenic sexual dysfunction and depression we studied 7 am and 4 pm cortisol, t e s t o s t e r o n e and LH levels before and after oral a d m i n i s t r a t i o n of I mg dexamethasone at 11 pm in 20 male subjects with sexual dysfunction, 6 male patients during depression and after recovery and in 20 male healthy controls. Inadequate cortisol suppression occurred in 25% of the impotent patients, in 93% of the depressed patients but in none of the recovered or control subjects. O e x a m e t h a s o n e had no influence on t e s t o s t e r o n e and LH in controls and recovered subjects while there was an increase in testosterone and LH in the morning after de• methasone a d m i n i s t r a t i o n in depressed and imootent patients. In 50% of the depressed, in 45% of the dysfunctional patients but in 16% of the recovered and in 10% of the control subjects only testosterone was increased above 15% of the nighest baseline level. In 50% of the depressed, in 20% of the impotent patients but in none of the recovered and in 5% of the control subjects only p o s t d e x a m e t h e s o n e LH levels exceeded the nighest baseline level by 50%, differences in frequency being significant. These results point to an altered r e a g i b i l i t y of the h y p o t h a l a m i c oituitary-gonadal system to d e x a m e t h a s o n e in deoression and sexual dysfunction as well as to 3ossible n e u r o e n d o c r i n e interrelations. Dermatologische Universit~tsklinik Erlangen, ~artmannstr. 14, D-8520 Erlangen

31.01.22

31.01.23

TYP~IINE CONJL~ATION IN AFFECTIVE DISORDER

TWO CASES OF S E A S O N A L A F F E C T I V E D I S O R D E R -- BIOLOGICAL RHYTHM AND LIGHT THERAPY -M.Okawa, T.Nanami, K. Mishima, T.Shimizu, S. Iijima, Y. H i s h i k a w a S e a s o n a l a f f e c t i v e d i s o r d e r (SAD) is c h a r a c t e r ized by m i l d a f f e c t i v e s y m p t o m s and r e m a r k a b l e t h e r a p u e t i c effects by b r i g h t light. In Japan, SAD has not been r e p o r t e d under the light of b i o l o g i c a l - r h y t h m disorder. A k i t a is l o c a t e d in the n o r t h e r n part of Japan w i t h less sun light in winter. The authors p r e s e n t e d two cases of severe or m i l d SAD w i t h r e s u l t s of i n v e s t i g a t i o n on b i o l o g i c a l r h y t h m s i n c l u d i n g body t e m p e r a t u r e and melatonin. Patient I, a 6 4 - y e a r - o l d man, v i s i t e d our h o s p i tal 15 years ago c o m p l a i n i n g of m e l a n c h o l i a , anorexia, insomnia and fatigue. He h a d a h i s t o r y of r e p e a t e d d e p r e s s i o n in a u t u m n and winter, since he was a h i g h - s c h o o l boy. Recently, he n o t i c e d that m o o d c h a n g e s b e c a m e m i l d w i t h inc r e a s i n g age. This winter, d e p r e s s i v e symptoms were not m a n i f e s t i e d , p r o b a b l y b e c a u s e of frequent o u t - d o o r sun-bathing. D a i l y c h a n g e s of rectal t e m p e r a t u r e in the d e p r e s s i v e state showed a f l a t t e n i n g pattern, w h i l e that in the neutral state showed a c i r c a d i a n r h y t h m w i t h adv a n c e d phase. P a t i e n t 2, a 2 4 - y e a r s - o l d female, v i s i t e d our h o s p i t a l c o m p l a i n i n g of m i l d d e p r e s s i v e symptoms in the last 3 w i n t e r s and her c o n d i t i o n was d i a g n o s e d as SAD. P h o t o t h e r a p y (3000 Lux light e x p o s u r e from 0530 to 0700 hr) was a p p l i e d for 2 weeks. H a m i l t o n scores b e f o r e and after p h o t o therapy were 18 and 7 r e s p e c t i v e l y . C e s s a t i o n of p h o t o - t h e r a p y or e v e n i n g e x p o s u r e of light e x a c e r b a t e d the symptoms. C i r c a d a i n r h y t h m of rectal t e m p e r a t u r e was p r e s e r v e d b o t h b e f o r e and after p h o t o - t h e r a p y . D e p a r t m e n t of N e u r o p s y c h i a t r y , Akita University School of Medicine, Akita, Japan, 010

H. Standish-Barry, me

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P. Hannah, M. A. Sherman,

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There is some evidence that following ingestion of an oral load of Tyramine, depressed patients excrete significantly less tyramine 0 sulphate compared with controls (Lander et al 1975, Harrison et al 1984). Furthermore it seems that this abnormality of Tyramine conjugation perisits even after recovery from the depressive episode, suggesting that it represents a trait marker for depressive illness (BomhsmCarter et sl 1978 s). The mechanism for this abnormality has not yet been fully elicited. (Bonham Carter et al 1978b, 1980, 1981). Harrison et al (1984) have published findings supporting this view. Hale et al (1986) have produced evidence that the Tyramine conjugation test is superior to the dexamethasone suppression test in beth sensitivity to and specificity for endogenous depression. The present study looks at the specificity of the tyram, ine conjugation test in a group of patients suffering from depressive mood disorder. The results provide further evidence that the m)Tamine conjugation test is specific for endogenous depression.

265

31.01.24

31.01.25

PLASMA MELATONIN LEVELS IN AFFECTIVE STATES P.F. M a r r i o t t , I.M. Hc!ntyre, F.K. Oudd, G.D. Burrows, T.R. Norman.

GROWTH HORMONE AS "TRAIT" DISTLqRBANCE IN DEPRESSION S. C. Risch end R. Hauger AbnonTalities of growth hormone secretion have been reported in depressed patients including elevations in daytime p ~ concentrations and attenuated responses to central provocative challenges %ith insulin-induced hypoglycemia, clonidine and the tricyclic antidepressant desmethylimipramine. The recent availability of the hypothalmic peptide human growth releasing factor (hGRF) allows direct testing of pituitary ~ hormone secretory respoP~se in depressed patients, re~nitted depressed patients, and age- and sex-matched nozmals. All subjects received a complete history, physical, laboratory examination and Schedule for Affective Disorder and Schizophrenia (SADS) interview. All subjects received hGRF (I ug/kg) and placebo hGRF intravenously on separate days one week apart in a double-blind, rendcmized, counterbalanced paradigm. Blood samples were obtained every 15 minutes for 30 minutes prior to and for two hours subsequent to the infusions. San~les were subsequently assayed for growd3 hormone and other plasma neurohormones by RIA. Mean ~han~.es in Log_ growth hormone plasma concentrations from baseline to post hGRF timepoints were significantly (p=.001, Diagnostic Group x Drug x Time) attenuated in depressed patients (n=7, RDC Major Depression} end in remitted depressed patients (n=7, RDC Hx of Major Depression, remitted) as conpared with age, weight end sex-(all male) matched normal controls (r~17). These results suggest that many depressed patients have a markedly attenuated growth horr~ne response to hGRF, and, at least in this study, the abnormality may persist for years after recovery from depression. Preliminary results from ongoing studies regarding the diagnostic sensitivity and specificity of this neuroendocrine disturbance will be presented, along with studies of the relationship of this abnormality to other indices of neuroendocrine dysfunction (plasma concentrations of s c ~ a ~ - C , cortisol end prolactin). S. Craig Risch, M.D., Department of Psychiatry, Emory University, Box AF Atlanta, Georgia 30322 USA

Melatonin is a major endocrine product of the pineal gland. I t is produced at night when noradrenaline acts on beta-adrenergic receptors to stimulate enzymes which catalyse the formation of melatonin from serotonin. Some authors believe that nocturnal melatonin levels r e f l e c t beta-receptor function. Because changes in beta-receptor function have been implicated in the mechanism of action of somatic treatments of depression and in the pathophysiology of a f f e c t i v e disorders, investigations of melatonin have been undertaken. We have studied the nocturnal production of melatonin in patients with depression and panic disorder, and in control subjects. Midnight concentrations of melatonin in 22 depressed patients were s i g n i f i c a n t l y lower than 24 control subjects (45.9 • 4.3 pg/ml vs 61.7 • 4 5 pglml; p <0.01). These data support previous reports of reduced melatonYn synthesis in depressive i l l n e s s . In the f i r s t report of panic disorders, we showed s i g n i f i c a n t l y lower midnight levels of melatonin compared with controls (28.4 • 6.4 pg/ml vs. 51.6 • 4.1 pg/ml, p
31.01.26 NERVE,", GENZODIAZEPIHES IN TIIE TRE/.T;.:E::T OF-. ENDOGENOUS E,EP T.ESSIO;,' E. ~ e ~ o v ~ z 3 , ~ve. ~kaf k . N,ihunek Some sucnor~ s,-:pposeo t n a ~ trs::e;iilizer seeh cs T;romazepe.,-., e.nd triszoloUer, zodie.zepi.-:es elpr,rzolP.m ond adinr.zola~ - ecteC as ~nl;idepres sa:;tc, At U n i Q e r s i t v Ps~,chiatric O e p ~ r t z e n t -I in Srno 59 i.~-pts ~,,&re involved ir an open stu-! dy ~vith :;rosszep~m ~nd 65 pts ~,,ith ,'-Ip~ezolaq. ,..ter pl#ee'o Cnterv~l /2 - I0 days/ the (~)ses were individualized, the minimrl ~r,d m~xi::al a v e r a o e d c i l v doses o? b r o ; i a : e o ~ m ' 2 c e l n - s mg and 28 mg ~;:d ~ l p r a z o l e : : , 1 , 3 r e s p . 4 , S~7 m~. D ' : r P : ; i o n r o f the treatment w~-s 23 d+ys i~ ~,,,er~e. The t h e r & p e u t i c effect ~,,as e','al :e~ed ~ c c o r d i . c i:o h[.e F;CD, ~:A;:D, D'/P v,nd .'erc-'sk'-'~ re l e s . i t e 7lid a {! ::,i::D SCFIcs U'rS e - s i ~ : : i fic~,::t decrease o f the ~ l o : . e l ~core as t e l l ~s i:, tl;e ;m ~o ri tv of cy:pto::s Plre~-Ev ~ 2 t e r 7 rT'v$ O ? %reet::~:zt. T'itn ,;romezeons' 2L,II re/..isrio~ v~ns rchieved in 35,~[ of pts / p ~ r t i e l re:;:issio;, i:: 12,7[/, it ~e,~:;s c l i n i c a l l y .~icnlciccnt i~prove:uent i:. Ogr~. ',.ith clprc,:_olFn cli:icelly subste~ti~.l ir3provement was e c h ieved in 71y" oF pts / 5 3 ~ 07 the.n. ~,ere i:-, ?:;II reF,l.~S.O ,/.

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,'ere of Io~,' i:~ter.zity ~ , d f r e r u e ~ c v . ?atiy'ze ~md r ' r o ~ , s i h e s s w a r the most Creouent, l,~ bron~,zep~ .*tudv or.e hslf o? treeted pts ,ere ph~rT::~coresiste.-,t i;~ 2 or even ~ore p r e v i o u s t:-:errp,, c u r e s , v . i t h d i C f e r e n t e n t i d e p r e r s ~ n t e, i'., alprazol,.-~ .~tudy o:~e third of pts,O:-, the bRsis o f o u r p r e l i m i : : ~ rV r e s u l t s ~ve are of the opi:;ion t h a t i o ~ freeuency and d ~ f f e r e - t p r o f i l e of si~;e e f f e c t s h~ve clrs.~ifiefi the.~e ~e-~er b e ~ o d i : z e p i n e s co::siCeri.~q t h e i r a. tide..~rress i r e a c t i o n anong the ar,t i d e p r e s s r . n t s o f the ?-;rther ce'.-.er~tlon. U n i v e r s i t y Psychietric D e p ~ r t u e n t , J i S l a v s k a Ioo " r n o - Pohu-ice G57 15 Czeehoslov~&-{r

266

31.02.01 TREATMENT OF DEPRESSED PATIENTS CLOVOXAMINE FOR UP TO ONE YEAR Richard J Simpson and L DiAnne Bradford*

POSTER PRESENTATION 31.02

Antidepressants (incl. MAO-Inhibitors)

31.02.02 TREATMENT OF ELDERLY DEPRESSED PATIENTS WITH CLOVOXAMINE OR MIANSERIN J Vanderdonckt and L DiAnne Bradford The prevalence of depression worldwide is greater than 10% in people over the age of 65 and even higher if physical illness is present (1). The treatmenI of depression in the elderly compared with the general population iS complicated by more adverse drug reactions due to polypharmacy and/or greater intrinsic susceptibility to adverse reactions, physiological changes such as diminished liver and kidney functions which may increase drug effects. Depressed patients(pts) over the age of 60 yrs who met the DSM-III criteria for major depressive episode, and scored at least 17 on the HAMD prior to treatment were included in the study. 116 pts (94 F.'22 M) participated, with a mean age of 72 yrs. Pts gave informed consent to participate in the study. Pts were randomized to treatment with either clovoxamine(CLO),a new antidepressant which shows no sedative properties or mlanserin(MIA) which has been shown to have sedative properties, and has been claimed to be particularly effective in treating anxiety, associated with depression, as well as anxiety neurosis (2.3). In a week-by-week analysis of the HAMD total scores CLO showed an equivalent effect to MIA throughout the treatment periods, with both groups improving about 55% by wk 8. There was no difference in the treatment groups for any of the four factors of the HAMD. Co-prescriptions of benzodiazepines(BZ) were similar for the two treatment groups. In an analysis of patients who did not receive concurrent BZ (NOCON), CLO performed equally as well as MIA on the anxiety factor (4) and slightly bener on the sleep disturbance factor of the HAMD. The most commonly reported unwanted effects for CLO were nausea, headache and constipation, and for MtA. insomnia and akathisia. CLO was shown to be well-tolerated by elderly pts, and improved the symptoms of depression as effectively as to the sedative antidepressant mianserin. rc'/~" I Gerner 1985 J_ A_f D_~_is(SI1:$23. 2. Russel et al. 1978 Br J Clin Pharm 5:57S: 3. Coati and Pinder 1979,JlntMedRes 7:285: 4. Bradford. Abstr. CINP 1988.

WITH

The long-term safety and efficacy of clovoxamine in depressed patients was studied in an open trial with centres in Austria I Belgium. France, Germany, Sweden, Switzerland, United Kingdom and Yugoslavia. Patients were treated and monitored for up to 12 months, with frequent assessments for efficacy, safely and tolerance, Informed consent was given by the patients for their participation in the study. Two-hundred eighty patients (187 F/93 M, mean age = 52 yrs) entered the study who met the MRC definition for depressive illness and the ICD-9 categories 296.1 or 296.3: pre-treatmenr HAMD was on average 24.7. One-hundred seventy-three (62%) completed one year's treatment: reasons for early termination were: recovery (4.6%). inefficacy (7%), intolerance (9%), suicidetattempt (I.4%) and administrative (non-drug reasons) 1 3 % . O n l y 4 % (I I p a t i e n t s ) r e l a p s e d b e t w e e n m o n t h s 2 a n d 12. T h e r e w a s a s i g n i f i c a n t d e c r e a s e in the total H A M D scores f r o m week 2 onwards (P<0.002): b y m o n t h 2, c o m p a r e d w i t h p r e t r e a t m e n t , p a t i e n t s h a d i m p r o v e d o n a v e r a g e 6 4 % , this r e a c h e d 8 5 % b y m o n t h 12. N a u s e a (1.5%) w a s the m o s t f r e q u e n t l y r e p o r t e d side e f f e c L anlicholinergic effects were minimal, as were adverse c a r d i o v a s c u l a r o r l a b o r a t o D 9 effects, c l o v o x a m i n e w a s n o | associated with weight gain. The data indicate that clovoxamine w a s safe a n d w e l l - t o l e r a t e d d u r i n g l o n g - t e r m t r e a t m e n t . Health Centre. Bridge of Allan, Scotland:*Dept. Clinical Research. Duphar BV, PO Box 900, 1381CP Weesp. Holland

31.02.03 TREATMENT OF ELDERLY DEPRESSED PATIENTS FOR UP TO ONE YEAR WITH CLOVOXA.'v[INE A Rundgren and L DiAnne Bradford* Depression occurs frequently in the elderly, and is even more common in those with concomitant illnesses (1). As the number of people over 65 is steadily increasing worldwide, the treatment of depression in the elderly will provide an increasing burden on the individual, and on social and medical services, Until recently, tricyclic antidepressants(AD) have been the treatment of choice in the elderly. However, the side effects which are most commonly associated with tricyclics, namely cardiovascular, anticholinergic and sedative effects, arc those to which the elderly are most sensitive (l), The long-term safety, and efficacy of clovoxamine (CLO) in 375 depressed patients(pts) has been studied (2,3). The data presented here describes 90 (66 F/24 M) of these pts who were >i 60 years at the beginning of the I yr treatment period. Sixty pts (67%) completed treatment for 1 yr; 3% withdrew fi'om treatment early because of recovery, 8% for inefficacy. 11% for intolerance, 8% for administrative reasons. Only 3% (3 patients) relapsed between mo 2 and 12. The mean total HAMD ~ores indicated a good AD response to CLO, with improvement compared with pretreatment reaching statistical significance (P<0.001) from wk 2 onv.ards. On average, pts improved 68% by wk 8. Frequent safety assessmen~ indicated that there were no significant changes in HR; in the early months of treatment, a very small (
267

31.02.04

31.02.05

CLOVOXAMINE TREATMENT COMPARED WITH MAPROTILINE IN ENDOGENOUS DEPRESSED PATIENTS E Radmayr, Chr Schumann* and L DiAnne Bradford*

LONG-TERM SAFETY OF C1TALOPRAM

Clovoxamine (CLO) comes from a new (non-tricyclic) class of compounds and is equipotent in blocking the re-uptake of both NA and 5-HT, CLO was compared in a double-blind trial with maprotiline (MAP). a "second generation" tetracvlic antidepressant which blocks the reuptake of NA . Patients were entered in six centers in W.Germany. Austria and Yugoslaxia. and had to meet the diagnostic criteria of DSM-III for major depressive disorder. Informed consent was given by the patients for their participation. One hundred fifty-nine patients (117 F/42 M, mean age=49 yrs) entered the study; mean HAMD score at pretreatment was 27.5. 84% of the patients completed the six-weeks trial; 6 CLO and 5 MAP patients stopped treatment early because of recovery; 6 CLO and 4 MAP because of administrative (nondrug) reasons; and 1 patient in each group because of intolerance. The drugs could not be differentiated in reducing symptoms as measured by the HAMD total scores;compared with pretreatment, both groups improved by about 70% at the week 6 assessment. Both compounds had a similar clinical profile on the four factors of the HAMD. Anxiety symptoms were assessed by using the Covi Anxiety Scales in which both dru.gs were shown to equally reduce anxiety associated with depressmn. Few patients complained of side effects. The most frequently reported side effects associated with CLO were nausea and headache while dry mouth and dizziness were most frequently associated with MAP. CLO was associated with little or no effect on cardiovascular measures and anticholinergic effects, nor any adverse effects on laboratory variables. CLO was shown to be safe and well-tolerated, and equally effective as MAP in moderate to severe endogenous depression.

K. Lyby, L. Elsborg, H.E. Hcpfner Petersen and E. Skovlund The selective 5-HT uptake inhibitor CITALOPRAM has been assessed as to long-term safety. This assessment is based on meta-analysis of the results from 325 patients treated for a period varying between 8 and 296 weeks. Safety was monitored by means of a global assessment of side effects, a side effect check list, laboratory investigations of hematological, hepatic and renal function, cardiovascular control, and body weight recordings. Compliance was controlled by plasma level determinations. Results: During long-term treatment (i.e. >8 weeks) the side effect profile was similar to the profile during short-term treatment, and generally the incidence of side effects was low (4% or less). The majority of side effects were mild and caused withdrawal in only 5% of the patients. Most frequent side effects were tiredness, sleep disturbances, headache, and teemor. No adverse effects were observed on the hematological, hepatic or renal function. No body weight gain was recorded. In a few patients with pre-existing low heart rate there was a tendency to sinus bradycardia which was not clinically relevant. Otherwise, no electrophysiological or hemodynamicchanges were observed. Gone3usion Citalopram is a safe and well tolerated drug in long-term treatment of depressive disorders. H. LundbeckA/S, Ottiliavej 7-9, DK-2500 Copenhagen-Valby

Rahnhofplalz, Dornbint. AUT, *Dep! Clinical Research, PO BOX 900, 1381CP 14>esp. NED.

31.02.06

31.02.07

FLUOXETINE (F) AND AMITRIPTYLINE (A) ; SAFETY AND WEIGHT IN THE TREATMENT OF MAJOR DEPRESSIVE DISORDER (MDD).

THE EFFECT OF CITALOPRAM IN DEM~\~IA DISORDERS. A SCANDINAVIAN MLZTI-CENTER STUDY A-L. Nyth, C.G. Gottfries, K. Eizen, K. Engedal, A. Harenko, I. Karlsson, T. Koskinen, L. Larsson, H. Nvgaard, S.M. Samuelsson and A. Yli-Kerttula The present study was undertaken in order to further study the clinical and pharmacological efficacy of citalopram in patients with dementia. Citalopram has been shown to have a specific inhibitory effect on the reuptake of serotonin and it is therefore assumed that the pharmacological effect is an activation of the serotonincontaining neurons. Clinical studies of depressed patients have indicated a good antidepressant effect and fewer secondary effects than tricyclic antidepressant drugs. This is also valid for central anticholinergic as well as cardiovascular secondary effects. The test treatment was carried out during a period of 16 weeks. A double-blind cross-over technique with placebo and citalopram was used. The treatment dose varied between lO and 30 mg r or placebo given daily around four o'clock. Ninety-eight patients with a clinical diagnosis of moderate dementia of Alzheimer type (AD/SDAT) or multi-infarct dementia (MID) were included in the trial while fifty-nine patients completed the whole treatment test. The results of the clinical assessments indicated significant improvements in emotional lability, motivation, confusion, fear-panic, irritation, reduced mood and restlessness. These improvements were not evident during treatment with placebo. Citalopram appeared to have no effect on the motorial and intellectual functions. Cerebrospinal fluid taps taken (n=15) before treatment start and after twelve weeks showed a significant reduction of 5-HIAA. Both in citalopram and placebo treated patients no or few side effects were recorded. The results in the present study are in agreement with the results of earlier studies. Grteborgs universitet, Department of psychiatry and neurochemistry, St. J~rgen's hospital, S-422 03 HisingsBacka, Sweden

M. Czarka, C. Rielaert, , P. Linkowski, M. Kerkhofs, 3. Mendlewicz Thirty-four patients suffering from MDD (RDC) were enrolled randomly in this double blind parallel study. Across the whole study population, there was a moderate weight gain, though not significant (p=0.1) at the end of the study. For the F group, there was no significant weight change, however for A, there was a significant weight gain (p=0.08, mean = 1.33kg.). No significant differences could be observed between males and females in the overall sample. On the whole, F was found to be safer than A, less side effects being reported in the F group (p<0.01). The most frequent side effects reported for Fluoxetine were gastro-intestinal, symptoms (10%) and dry mouth (13%). Free University of Brussels - Erasme Hospital, Dept. of

Psychiatry, route de Lennik Belgium.

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SIDE EFFECT PROFILE AND SAFETY OF CITALOPRAM H.E. H~pfner Petersen, K. Lyby, L. Elsborg, and E. Skovlund A survey of the clinical safety of the selective 5-HT uptake inhibitor citalopram is presented. The assessments of safety are based on meta-analysis of results from more than 1,000 patients. Results: Side effects were generally mild. The most frequently recorded were nausea, sweating, headache, reduced salivation, and tremor. The frequency of side effects - particularly those of anticholinergic type - was significantly lower for citalopram than for trieyclie antidepressants (TCAs), whereas there was no difference compared with placebo. The frequency of recorded side effects in citalopram treated patients was higher in TCA-controlled studies than in placebocontrolled studies. Apart from a slight tendency to sinus bradyeardia in a few patients with pre-existing low heart rate, no adverse effects were observed on the electrophysiological and hemodynamic systems. No adverse effects were observed on the hematological, hepatic or renal systems. Body weight was not changed. Conclusion: The safety profile of citalopram makes it a safe drug of choice in the treatment of depressive disorders. H. Lundbeek A/S, Ottiliavej 7-9, DK-2500 Copenhagen-Valby

KINETICS OF THE INTERACTION OF SERTRALINE WITH THE HUMAN PLATELET PLASMA M E M B R A N E 5-HYDROXYTRYPTAMINE CARRIER O.M. Phillips, K.M. Wood and D.C. Williams Sertraline, a new selective 5-HT uptake inhibitor showed a mixed pattern of inhibition of human platelet 5-HT uptake with a K. value of 2.5nM and K~ value of 25 ruM. i Imipramine and alaproclate were foundlto be fully competitive inhibitors of 5-HT uptake with K. values of 8 emd 13C nM respectively. Sertraline was ~ fully competitive inhibitor of high-affinity [ H]imipramine binding to platelet membranes with a K. value of 1.3nM, as was alaproclate and 5-HT with K. values of 170 and 1 800 nM respectively. Both sertrallne and imipramine, at a concentration o{ 10~M caused a fast monophasic dissociation of [ H]imipramine from platelet membranes in contrast to 5-HT which caused a slow monophasic dissociation. These data are consistant with sertraline binding to the carrier at a physically-distinct site to that for 5-HT and being a potent and specific 5-HT uptake inhibitor. Department of Biochemistry, Trinity College, Dublin 2, Ireland

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DISTRIBUTION AND PHARMACOKINETICS OF THE SELECTIVE 5-HT UPTAKE BLOCKER SERTRALINE IN MAN, RAT AND DOG. R. A. Ronfeld, G. L. Shaw and L. M. Tremaine Sertraline is a highly selective and potent inhibitor of 5-HT uptake (B. Koe et al., J. Pharm. Exp. Ther. 226:686, 1983) under development for the treatment o--~depression. In man, the average terminal elimination half-life is 26 hours, allowing for once daily administration. After a single I00 mg dose, Cmax is about 20 ng/ml and Tmax occurs at 6 to 8 hours. The distribution/elimination is ofen biphasic with the terminal phase attained 12 to 16 hours post-dose. The terminal half-life of 26 hours does not change with multiple dosing or as a function of dose. Dose proportionality and linearity of kinetics were demonstrated in a 3-way crossover study of 50, i00 and 200 mg doses. The serum protein binding of sertraline is 98.6, 98.9 and 97.2% at I00 ng/ml in man, dog and rat, respectively and independent of drug concentration over the range of 20 to 2000 ng/ml. Sertraline binds avidly to both albumin and al-acid glycoprotein. At a concentration exceeding the- usual clinical range, sertraline does not alter the protein binding of warfarin or prepranolol.

TREATMENT

A radiolabel study in rats demonstrated that drug and metabolites distribute extensively into tissues. The volumes of distribution of sertraline in the rat and dog were 23 and 25 i/kg, respectively. In the rat and dog, the elimination half-life of sertraline is about five hours and plasma clearance is high, estimated at 59 and 49 ml/min/kg, respectively. There ls evldenoe of ~irst-pass metabollsm wlth oral admlnlstration. Sertraline is not excreted unchanged in urine or bile. An initial pathway of metabolism is N-demethylation. The elimination half-life of desmethyl-sertraline is 2 to 3 times longer than that of sertraline in man, rat and dog. The metabolite to drug AUC ratio ranged from 0.4 to 3.3 and varied with the species studied, dose and route of sertraline administration. In vitro desmethyl-sertraline is i0 times less actl-ve as an inhibitor of 5-HT uptake than sertraline (B. Koe et al., ibid). The desmethyl metabolite is not thought to contribute to the antidepressant activity in vivo. Pfizer Central Res-earch, Eastern Point Rd., Groton, CT, U.S.A. 06340

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Ilankovie

The autor present latest discoveries of p o s s i b i l i t i e s for t r e a t m e n t and prophylaxis of a f f ective disturbances (above all MD psychosis , schizoaffective episodes, atypical psychotic episodes, behavioural disorders). The prominent antimanic effect and "specific" antipsychotic e f f e c t of t h i s d r u g is s t r e s s e d , its antidepressive characteristic a n d t h e a c t i o n on r e g u l a t i o n of c o n s c i o u s n e s s a n d the a w a k e n e s s - s l e e p c y c l e s . T h e a u t h o r s p r e s e n t t h e i r r e s u l t s in treatment and p r o p h y l a x i s and stress relatively s m a l l r i s k f r o m t o x i c s i d e - e f f e c t s . The psychobiological dimension of s t r e s s is disc u s s e d too: I. the m e c h a n i s m of i n i t i a l O S M O L A R r e a c t i o n ( r o l l e of V A S O P R E S S I N / A D H ) a n d 2. t h e mechanism of d e l a y e d , p r o l o n g e d reaction - "STEROID EXCESS"/hipereortisolemio (Ilankovic,1986)~ Carbamazepin has some vasopressin-like (ADH-rec e p t o r s a g o n i s t ) - the p o s s i b i l e mechanisms of a c t i o n of c a r b a m a z e p i n in a f f e c t i v e and cognitive d i s t u r b a n c e s (psychoses). The neurophysiological m o d e l of " K I N D L I N G " and the a n t i - k i n d l i n g a c t i o n of c a r b a m a z e p i n is a l so d i s c u s s e d - t h e s e m o d e l ~ is o n e of p o s s i b l e mechanism of i n i t i a t i o n , modulation and ecological/behavioural sensibilisation in a f f e c t i v e behaviour and d i s t u r b a n c e s . Psychiatric University Clinic, Center cal N e u r o p h y s i o l o g y & Sleep Disorders, BEOGRAD, Pasterova 2, Y U G O S L A V I A

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31.02.12 BIND;NG OF [3H]SERTRALINETO BRAIN MEMBRANES N G. Bacopoulos, L. A. Lebel , W. M. Welch and B. K. Koe Studies from our laboratories demonstrated that sertraline, a new antidepressant, is a potent and selective inhibitor of the uptake of serotonin in brain (Koe etal., .I. Pharmacol. Exp. Ther. 226, 686, 1983). Serotonin (5-HT) uptake occurs via "transport" sites in neuronal membranes. Several laboratories have reported that non-selective uptake blockers ([3H]imipramine), as well as those more selective for 5-HT ([3H]paroxetine, [3H]indalpine, [3H]citalopram), bind with high affinity to sites associated with S-HT uptake. In these studies, binding affinity of 5-HT uptake blockers was found to correlate with their potency for inhibting 5-HT uptake (Habert etal., Eur. J. Pharmacol. 118, 107, 1985; D'Am,ato et al., J. Pharmacol. Exp. Thor. 242, 364, 1987). Because of the potency and selectivity of sertraline as a 5-HT uptake blocker, [3H]sertratine (23 Curies/retool) was synthesized and investigated as a radioligand for high affinity binding to 5-HT uptake sites in brain membranes. Binding studies with [3H]sertraline were conducted in Tris HCI buffer containing 120 mM NaCi and 5 mM KCI (Mellerup and Plenge, Psychopharmacology 89, 436, 1986). Association experiments with rat brain membranes indicate that binding was complete in 40 min; bound [3H]sertratine was completely dissociated in 20 rain after the addition of 150 nM of unlabeled sertraline. Saturation binding experiments indicated an ap~arent KD of 0.56 nM and Bmax of 885 fmol/mg protein. Similar binding carried out in the presence of either 5-HT (0.5 pM) or paroxetine (1 nM)increased KD by 101% and 223%, respectively, with little change in Br~ax (+7% and + 10%, respectively). These results suggest that paroxetine and 5-HT are competitive inhlbitors of the binding of [3H]sertraline and that the latter is binding to uptake sites for 5-HT. [3H]Sertraline binding to 5-HT uptake sites in homogenates of different regio~ of marmoset brain was also studied. Central Research Division, Pfizer Inc., Groton, CT 06340, USA.

31.02.13 SERTRALINE

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J. A. Nielsen, M. N. Krupp, J. Heym and N. G. BaCODOUlOS A variety of in vitro and in vivo studies demonstrate that sertraline is a highly selective and potent competitive inhibitor of serotonin uptake (Koe et al., J. Pharn.acol. Exp. Ther. 226, 686, 1983). Animal studies have demonstrated that inhibition of serotonin uptake leads to enhanced serotonergic neurotransmission which may have beneficial effects in depression. Indeed, clinical trials have shown sertraline to be an effective antidepressant. An extensive literature, however, also implicates brain serotonin in the regulation of energy balance (Blundell, Neuropharmacology 23, 1537, 1984). Therefore, studies have been carried out to assess the effects of sertraline on feeding and body weight in rodents. Sertraline decreased food intake and body weight in both normal and genetically obese rodent strains (oh/oh mice and fa/fa rats). These effects developed rapidly after initiation of sertraline treatment and were maintained during 5-7 days of continued drug administration. Nonspecific disruption of behavior does not accoD_nt for the observed effects on feeding and body weight since the sertraline treated animals appeared healthy and their locomotor behavior was unaffected. Thus, these results are in accord with a growing body of evidence suggesting that selective serotonin uptake inhibitors may be clinically useful agents for managing some obese patient populations. Pfizer Central Research, Departments of Neuroscience and General Pharmacology, Groton, Connecticut, 06340, U.S.A.

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EFFECTS OF SEROTONERGIC AGENTS ON DOWN-REGULATION OF ~-ADRENOCEPTOR5 BY SERTRALINE B. K. Koe and L A. Lebel Recent studies showed that sertratine, a new 5-HT uptake blocking antidepressant, down-regulates J3-adrenoceptors of cerebral cortex and desensitizes the cAMP generating system of limbic forebrain (Koe etal., Eur. J. Pharmacol., 141, 187, 1987; Byerley et al., Brain Res. 421,377, 1987). Furthermore, these effects of sertraline are facilitated by co-admi nistration of the 5-HT agonist quipazine (Koe, ibid.). We have extended these studies to other serotonergic drugs to ascertain which 5-HT receptors are involved in facilitating sertra.line's down-regulation of ~-adrenoreceptors. Experiments consisted of injecting test drug plus sertraline (17.8 or 32 llmol/kg i.p.) to rats b.id. for 4 days and determining Ko and Bmax of [3H]dihydroalprenolol (DHA) binding in anterior cortex one day after dosing. Test drugs included: 8-hydroxy-2-N,N-dipropylaminotetralin (8-HO-DPAT, 5-HT1A agonist), 3-trifluoromethylphenylpiperazine (TFMPP, 5-HT1B agonist), ritanserin (5-HT2 antagonist), methiothepin (5-HT releaser) and racemic norfenfluramine (5-HT releaser). Dose of all test drugs was 10 Bmol/kg i.p. except for the latter (20 ]Jmol/kg). Scatchard analysis of [3H]DHA binding was determined for each rat brain. The results showed that down-regulation of ~-adrenoceptors by sertraline was neither facilitated nor blocked by co-administered 8-HO-DPAT, TFMPP or ritanserin. In contrast, methiothepin or nonCenfluramine, in combination with 17.Bpmol/kg of sertraline (non-down-regulating dose), elicited a decrease in receptor density (Brnax) without affecting affinity (KD). The latter results are similar to quipazine's facilitation of sertraline (Koe, ibid.) and suggest that quipazine, similar to methiothepin and norfenfluramine, may be also acting to enhance 5-HT release. Our findings indicate that only 5-HT itself seems to be effective in inducing down-regulation of J]-adrenoceptors and that the 5-HT receptors involved in this process may not be the 5-HT1A, 5-HT18 or 5-HT2 type. Central Research Division, Pfizer Inc., Groton, CT. 06340, USA.

SERY~ALINE, AN ANTIDEPRESSA~N~ ~ I C H Ih~IBITS SEROTONIN UPTAKE, SPECIFICALLY DOWN REGLU_ATES BETA. RECEPTORS J.K. Wamsley, R.T. McCabe, E.J. McConnell, F.W. Byerley and B.I. Grosser Chronic exposure to various antidepressant agents has been shown to cause the do~-regulation of both betaadrenergie (beta) and serotenergic (5HT) receptors ~ithin the CXS. ~ n y antidepressant drugs are mixed 5HT and/or noradrenalin uptake inhibitors. Some recently developed compounds, however, appear to have the unique ability to affect only 5HT uptake. The metabolites of these com~ pounds also seem to be specific in this regard. Drug studies in human patients have shown that one of these agents, sertraline, is quite efficacious in its ability to alleviate the symptoms associated with depression in affected individuals. It is still controversial ~ e t h e r beta or 5HT receptor alteration is important in the etiology and treatment of depression. We used the selective 5HT uptake inhibitor sertraline to chronically block u p take in male Sprague-Dawley rats (21 days of treatment). Repeated administration of the non-tricyclic antidepressant caused a down-regulation of beta receptors. These findings occurred in microscopic regions of the brain and were very closely associated with areas that have been shown to have beta-receptor down-regulation after electroconvulsive shock treatment. Moreover, the down regulation induced by sertraline occurred exclusively at the beta I receptor subtype. The irony of these findings is that-we have previously demonstrated that low doses of sertraline do not cause a significant alteration in 5HT receptors following similar treatment. The betal-rece ptor alteration, then, is taking place without a concomitant alteration in 5HT receptor subtypes. These results support the hypothesis that the common denominator of most antidepressant t r e a t ~ n t s is the down-regulation of beta-adrenergic receptors; including those treatments which only directly affect the 5HT system. Department of Psychiatry, University of Utah School of Medicine, Salt Lake City, Utah 84132, U.S.A.

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SERTRALINE IN THE PR~"qENTION OF RELAPSE IN MAJOR DEPRESSION D.P. Doogan and V. Caillard This double-blind placebo-controlled study included 467 patients with major depression. All patients received an open 8-week period of sertraline 5 0 - 2 0 0 m g / d a y titrated according to clinical response. At the end of the 8-week period patients were selected, based on satisfactory clinical response, to receive a further 44 weeks doubleblind therapy of either sertraline or placebo in a randomised design in a 2:1 ratio of sertraline:placebo. The dose range was also 50-200mg/day. The principal efficacy variable was the relapse rate during the 44-week period. Two hundred and ninety five patients received doubleblind therapy (~85 sertraline and 110 placebo). Over the 44-week period the relapse rate on sertraline was 6.5% and on placebo was 39.0%, p < 0.001. This highly significant difference was observed consistently with Hamilton Rating Scale and Clinical Global Impression. ~ne average dose %~s approximately 100n~ daily during t h e long-term period. The number of patients withdrawing during the long-term period due to side-effects was minimal, 4.3% on sertraline and 2.7% on placebo. There were no changes of significance in safety variables - vital signs, ECG, laboratory tests. Pfizer Central Research, Clinical Research Department, Ramsgate Road, Sandwich, Kent. CTI3 9NJ. U.K.

PD-~OXETINE: A SELECTIVE SEROTONINE REUPTAKE INHIBITOR TP~T HAS A WEAKER ANTIDLDRESSANT EFFECT THAN CLOMIPRAMIN~ P. KRAGH-SORENSEN, L.F. GRAM, P. 8ECH, P. VESTERGAARD, O. J..RAFAELSEN, N. REISBY. In total, 147 hospitalized depressed patients were started o n a o n e week sengle blind placebo treatment. 118 patients still fullfilling i n ~ e x c l u s i o n criteria (Hamilton Depression Scale, HDS, 17-item total score X 18) were randomly allocated in a double blind fashion to treatment wi=h either paroxetine 30 mg/day (n=62) or clomipramine !50 mg/day (n=56) (fixed, single evening dose). In total, 56 patients on psroxetine and 46 patients on clomipramine conpleted at least two weeks treatment and were included in analyses of therapeutic effect. The two groups were co=parable in terms of age ~225% < 40 years), sex ~ 7 0 % wo=en) and departmental distribution. The protocolled =rea~ment period was 6 weeks except that non-responders (~S) 16) after 4 weeks were terminated. This occurred =o 27 patients, 23 on paroxetine and 4 on clomipramine. A weekly end-point analysis using response categories showed significantly better effect of clomipramine from 2 weeks treatment and onwards. At 6 weeks t the percentages of complete (HD8 >16) was 57,30 and 13 respectively in the clomipramine treated and 22,30 and 48 respectively in the paroxetine treated patients. Likewise the group average score on the HI)S-total at the end of 6 weeks was ~bo~t 8 in the clomipramine and about 13 in the paroxetine group. Analyses of clusters of items on the HDS showed that the difference on the total scale was due to differences on essentially all items covering the major parts of the depressive syndrome. - More patients on clomipra~ine dropped out due to side effects (orthostatic hypo=ension, palpitations etc.) Paroxetine was virtually devoid of autonomic side effects. The present results are in close agreement with our earlier findings with citalopram, an other serotonin reuptake inhibitor. Danish University Antidepressant Group, - Odense, Hiller ~ , Arhus, Copenhagen, D e ~ a r k .

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CHANGES IN HUMAN WHOLE BLOOD 5HT DURING TRE~TMSNT WITH PAROXETINE - A SELECTIVE 5HT UFTAKE INHIBITOR [, A, Marsden, P, Tyrer, P. Casev and N. Seivewri~ht The effects of the specific 5-hydroxytrypt~ine (5HT) re-uptake i~hib~tor paroxetine on whole blood 5HT and the uptake of [oH]-5HT by platelets was determined in 17 patients with resistant depression. The biochemical p a r ~ e t e r s were measured before paroxetine (30 or 40 mg/day) treatment, during treatment (6 weeks) and after w i t h d r ~ a l of treatment. Two of the 17 subjects failed to complete the trial; of the remaining subjects 12 showed a marked decrease in whole blood SET (~easured using HFLC with electrochemical detection) and [aH]-SHT uptake into platelets. The remaining 3 patients showed a variable response both in terms of whole blood 5HT and platelet during paroxetine treatment. A comparison of the 15 patients completing the trial showed that paroxetine treatment (36.4_+14 pmols/ml) significantly decreased whole blood 5HT compared to the pre-paroxetine value (99.7+_30 pmols/ml). At the end of treatment blood 5HT tended to return towards normal although this was delayed. There was no significant correlation between the change in blood 5HT and Hamilton score during paroxetine treatment although there was a significant improvement in the symptom score (P. Tyrer et al, J. Psyehopharmac., 1988 in press). There was also no correlation between the change in whole blood 5HT and p l a ~ a paroxetine levels. The results confirm that inhibition of 5HT uptake mechanisms are associated with decreased whole blood 5HT (0. Lingjaerde et al, Acta Psyehiatr. Seand. 68, 22-30, 1983) but that changes in whole blood 5HT do not necessarily reflect the clinical efficacy of 5RT uptake blocking drugs in the treatment of depression. Department of Physiology and Pharmacology, Queen's Medical Centre, Nottingham NG7 2UH and Mapperley Hospital, Porchester Road, Nottingham NG3 6AA, U.K.

EFFECTS OF THE ANTIDEPRESSANT PAROXETINE ON PSYCHOMOTOR FUNCTION QUANTITATIVE EgG (QEEG) AND MOOD IN HEALTHY SUBJECTS T.C.G. Tasker~ P. RaDtoDoulos A.M. Johnson, G.R. McClelland Paroxetine (PAR), a selective 5-hydroxytryptar-ine uptake inhibitor (Buss Lassen J. 1978. Psychopharmaeol, 57, 151) is an effective antidepressant (Lund Laursen A. et al 1985. Acta Psychiat. Scand., 7!I, 249-255). As part of the phase I evaluation, the effects of a single oral 30mg dose of paroxetine on the central nervous system of 8 healthy subjects was studied using psychomotor function tests (McClelland G.R. 1987. Human Psychopharmacology, 2, 109-119) visual analo~ae scales (VAS) (Bond and Lader, 1974. Br. J. Med Psychol, 47, 211) and QEEG (McClelland and Raptopoulos, 1985, Psychopharmacol, 85, 327). Whereas amitriptyline (AM/} (75mg) significantly impaired (p<0.05) performance in visual choice reaction time, continuous perfor~nance and tapping rate tasks, pAR did not influence performance (p
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S E L E C T I V E R E D U C T I O N OF 5-HT 2 R E C E P T O R S IN RAT BP~.IN A F T E R R E P E A T E D ~ I I N I S T R A T I O N OF THE ANTIDEPRESSANT, PAROXETI~. A.M. J o h n s o n , . D . R . N e l s o n and D.R. Thomas Paroxetine, an e f f e c t i v e ~ n t i d e p r e s s a n ~ (Lund Laursen et al, A c t a Psy~niat. Scand., 71, 247, 1985), is a p o t e n t ~nd s e l e c t i v e i n h i b i t o r of 5-HT uptake in r o d e n t b r a i n s y n a p t o s o m e s (Ki; l.lnM) w i t h no a f f i n i t y (Ki~ >I~M) for ~i-, ~2 ~, ~ - a d r e n o c e p t o r s , 5 - H T l - l i k e or 5-HT2 receptors in vitro (_"~omas et a ~ P s y c h o pharr~acol., 93, 193, 1987). M a g n u s s e n , et al, 1982, (J. N e u r a l Trans. 55, 217) have shown that 5-HT uptake i n h i b i t i o n in rodent b r a i n by p a r o x e t i n e is m a i n t a i n e d on r e p e a t e d a~mini s t r a t i o n for 21 days. It has now b e e n demons t r a t e d that, w h e n a d m i n i s t e r e d daily for 21 days, paroxetine, 5 m g ~ g i.p. s i @ n i f i c a n t l y (p<0.05) reduces the n u m b e r of [ b H ] - k e t ~ n s e r i n b i n d i n g sites (Bmax) in rat b r a i n c o r t i c a l m e m b r a n e s by 16%, w i ~ h no change in the affinity of the lig~nd (Kd) for the receptor, 24h after the last dose. However, this treatment with p a r o x e t i n e causes no changes (p>0.05) in the b i n d i n q (Kd or Bma x) of [3H]-dihydroalprenolol, [3H]-prazosin, [3H]-clonidine, [3H]-5-HT or [3H]-8-hydrcxy-N-N-dipropylar~inotetralin i n d i c a t i n g that the n u m b e r of, or affinity of ligands for, 6-, ~I-, ~ 2 - a d r e n o cepters or 5 - H T I A r e c e p t o r subtypes is n o t i n f l u e n c e d by p a r o x e t i n e treatment. The above data show t h e r e f o r e that the p r o l o n g e d 5-HT uptake i n h i b i t i o n by r e p e a t e d a d m i n i s t r a t i o n of p a r o x e t i n e leads to the s e l e c t i v e d o w n r e g u l a t i o n of 5-HT 2 r e c e p t o r s in rat brain. This e f f e c t of p a r o x e t i n e may be r e l e v a n t to its action as an a n t i d e p r e s s a n t . Beecha/z P h a r m a c e u t i c a l s , Harlow, U.K. C~!19 bAD.

OPEN-LABEL STUDY OF FLUVOXAMINE IN PATIENTS WITH OBSESSIVE COMPULSIVE DISORDER B.S. Coleman and K.M. Squillace Patients meetin~ diagnostic criteria for obsessive compulsive disorder who had failed to respond to other therapies, were treated with open-label fluvoxamine, a specific serotonin reuptake blocker, under a compassionate use protocol. Psychiatric outpatients of either sex, aged 18 years and over, were treated for up to one year with fluvoxamine. After titration, medication was administered twice daily and maintained at 100-300 m~ per day. The efficacy and safety data collected from this study will Be presented. Kali-Duphar Laboratories, Inc., 20~ Old Wilson BridFe Road, Worthington, Ohio 43085

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ANTIDEPRESSANT AND ANXIETY

LEVOPROTILINE IN COMPARISION TO OTHER ANTIDEPRESSIVE DRUGS N A H U N E K K . . ~ V E S T K A J . , R Y ~ K N E K R . , ~ E ~ K O V A E. U n i v e r s i t y P s y c h i a t r i c Dpt ,Brno, ~SSR

A study of fluvoxamine versus diazepam in anxiousdepressive patients. CHABANNES 3.P.* The authors report an original study conducted in 60 out-patients with anxious and depressive disorders. They compared, under double-blind conditions the efficacy of a molecule known for i t s a n x i o l y t i c spectrum : diazepam, and that of a 5-HT reuptake i n h i b i t o r : fluvoxamine. The results demonstrate : - a much higher efficacy of fluvoxamine in decreasing depressive disorders, - a similar efficacy of both drugs on anxiety. Concerning tolerance, a greater safety of the 5-HT reuptake i n h i b i t o r fluvoxamine can be noted. In fact, this work sets again the question of the true limits between anxiety and depression, therefore between anxiolytics and antidepressants.

* Dr CHABANNES3.P. - Clinique du Nivolet C.H.S. de Bassens - 73011 CHAMBERYCEDEX

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L e v o p r o t i l i n e /CGP 12' 103 A Ciba Geigy/ a R e n a n t i o m e r of Oxyprotiline. which lacks the inhibition of the reuptake of Noradrenaline proved in a m u l t i c l i n i c a l study, on which we participated, good antidepressive and anxio!ytic effect with rapid onset of the therapeutic action in 128 patients with e n d o g e n o u s depression. The t h e r a p e u t i c e f f i G a c y of Levoprotiline was s t u d i e d in an other open study in p a t i e n t s with d e p r e s s i v e phases and its r e l a t i o n s to the changes of cardiovascular parameters in a c o n z r o l e d study c o m p a r i n g the r e s u l t s to those of other a n t i d e p r e s s i v e drugs. ~e tried to include L e v o p r o t i l i n e in o u r classification scheme constructed according to the a n t i d e p r e s s i v e index, which reflects the relation of e f f i c a c y in inhibited, a n x i o u s and atypical forms of depression in 2187 t h e r a p e u t i c cures with 35 a n t i d e p r e s s a n t s and ECT. The influence of the c a r d i o v a s c u l a r s y s t e m was e v a l u a t e d by the c h a n g e s of the parameters of the electromechanical systole /Blumber~'s quotient/ and compared with other antidepressants /using dosulepine as a referential drug/.

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DOb~LE-BLIND, PLACEBO CONTROLLED TRIAL OF MINAPRINE IN MAJOR AFFECTZVE D~SORDER J. Amsterdam~ E. Rickels, L. Goodman, et al. Minaprine (MIN} is a putative antidepressant agent which antagonizes the symptoms of "inhibitory states" in animal models, and in human beings. Prior studies have shown MIN to be as effective as nomifensine and maprotiline in the treatment of endogenous depression. We performed a multicenter trial of three fixed doses of MIN (i00, 200, and 400mg) and placebo in 146 outpatients with major depression to assess the efficacy and safety profile of this compound. There were 87 women and 59 men with an age range from 20 to 69 yrs. After a one week elimination period, subjects were randomly assigned to treatment with MIN or placebo for 4 weeks. Results demonstrated a significantly greater reduction from baseline in the median Montgomery-Asberg Depression Rating Scale (MADRS) scores in the 400mg MIN group compared to placebo (p50% red~ction from the baseline Hamilton Depression Rating (EDR} score, or a final BDR score
PHARMACOLOGICAL PROPERTIES OF MIDALCIPRAN {F 2207), N NOVEL ANTIDEPRESSANT R.MATSUBARA~ T.KOYAMA~ Y.ODNGNKI~ M.NAKNYAMA, T?INOUE, and I. Y A M A S H I T A It is known that lon-g-term treatment with m o s t of a n t i d e p r e s s a n t s decreases b e t a - a d r e n e r g i c and 5-HT~ receptor densities, and the t i m e - l a g of the a n t i d e p r e s s a n t action has been s u g g e s t e d to be due to this phenomenon. Midalcipran (F 2207} is a newly d e v e l o p e d antidepressant in France. An open study i n v o l v i n g 27 cases of major depressive disorders has shown that midalcipran had a significant antidepressant effect w i t h i n 7 days. We i n v e s t i g a t e d the p h a r m a c o l o g i c a l properties of m i d a l c i p r a n , e s p e c i a l l y , t h e effect of c h r o n i c a d m i n i s t r a t i o n on m o n o a m l n e receptors. The in vitro studies in s y n a p t o s o m e s of rat brain showed that m i d a l c i p r a n was an e f f e c t i v e inhibitor of the u p t a k e of both [3H]NE and I~H]5-HT equipotently. Its activity appears to be similar to that of imipramine. Niter chronic t r e a t m e n t with imipramine(20mg/kg, i.p., 2 weeks), t h e densities of [~H]dihydroalprenolol and [3H]ketanserin binding in rat cerebral cortex w e r e s i g n i f i c a n t l y d e c r e a s e d b y 29% and 33%, respectively, whereas m i d a l c i p r a n (20mg/kg, i.p., 3 weeks) caused no s i g n i f i c a n t changes. These results indicate that m i d a l c i o r a n is a novel a n t i d e p r e s s a n t which inhibits the u p t a k e of NE and 5 - H T but does not lead to downregulation of beta-adrenoceptor and 5-HT~ receptor. Therefore, an examination of midalcipran m a y p r o v i d e further clues about the mechanism of d o w n - r e g u l a t i o n and the mode of a n t i d e p r e s s a n t action. Department of P s y c h i a t r y and N e u r o l o g y , H o k k a i d o U n i v e r s i t y School of Medicine, North 15, West 7, Sapporo 060, Japan

31.02.26 D E T E R M I N I N G THE T H E R A P E U T I C DOSE OF M I D A L C I P R A N (F2207) IN THE T R E A T M E N T OF D Y S T H Y M I A S. Bornstein, C. Serre, A. Qu~m~r~, H. Maloux, J.P. C o u z l n i e r M i d a l c i p r a n (M), a n o n - t r i c y c l i c a n t i d e p r e s s a n t w h i c h i n h i b i t s 5-HT and NE r e u p t a k e , has b e e n e v a l u a t e d in o u t p a t i e n t s p r e s e n t i n g signs of d y s t h y m i a c o m p a t i b l e w i t h the DSM III d e f i n i t i o n . The i n v e s t i g a t i v e intent was to c o m p a r e the a n t i d e p r e s s a n t a c t i v i t y of 3 d a i l y d o s e s of M a d m i n i s t e r e d b.i.d, w i t h that e x e r t e d by i00 mg of i m i p r a m i n e (I). The a n t i d e p r e s s a n t a c t i v i t y was a s s e s s e d by means of the H a m i l t o n and the M o n t g o m e r y and A s b e r g scales p e r f o r m e d weekl~, as w e l l as t h r o u g h the use of Beck's i n v e n t o r y w h i c h was c a r r i e d out twice a month. Of 94 p a t i e n t s t r e a t e d d u r i n g 4 w e e k s , 27 r e c e i v e d 20 mg of M daily, 27 r e c e i v e d 50 mg and 23 r e c e i v e d i00 mg; 22 r e c e i v e d I00 mg of I daily. The d e p r e s s i o n scale a n a l y s i s s h o w e d a g o o d c o r r e l a t i o n b e t w e e n M - d o s a g e and a n t i d e p r e s s a n t potency. At d a y 14, the scores for the H a m i l t o n scale w e r e lowered r e l a t i v e l y to initial v a l u e s by 46% w i t h 20 mg of M., 52% w i t h 50 mg, 62% w i t h 100 mg, 54 % w i t h i00 mg of I, r e s p e c t i v e l y . Inasmuch as no s i g n i f i c a n t d i f f e r e n c e was n o t e d at d a y 21 and day 28 b e t w e e n M 50 or I00 and I I00 mg, we p r o p o s e this dose range in the t r e a t m e n t of dysthymia. The 3 M doses w e r e s u f f i c i e n t l y well t o l e r a t e d in all instances, in a w a y little d i f f e r e n t from I with regard to g a s t r o i n t e s t i n a l side effects. The two drugs d i f f e r e d m a r k e d l y , however, w i t h r e s p e c t to a n t i c h o l i n e r g i c - t y p e symptoms, w h i c h only the I-group d e v e l o p e d . In this trial, the t h e r a p e u t i c index for M was s u p e r i o r when c o m p a r e d to I. D ~ p a r t e m e n ~ R e c h e r c h e C i i n i q u e , C e n t r e de P e c h e r c h e Pierre FABRE - 17, Ave. Jean H o u l i n

31.02.27 A DOUBLE-BLIND STUDY COMPARING 2 DOSES OF MIDALC!PRAN {F2207) TO N!ITRIPTYLINE IN MAJOR DEPRESSIVE DISORDERS J.P. Demarez, M. Ansseau, C. Serre, R. Von Frenckell, Ph. Sutet We compared 2 d a i l y doses (50 and lOOmg) of Midalcipran (H) to 150mg Amitrip~vline (A) in hospitalized patients with major depressive disorders compatible with the RDC d e f i n i tion. During this double-blind t r i a l , 42 patients received 150mg d M. and 44 received lOOmg/d, and 45 received 150mg/d A. over a 4-week ~eriod. The population demonstrated a high degree of endo~enicity. Assessment of the antidepressant was carried out by means of the following tests~amilton(we-e~. l~Mont~omerv ~ ~ e r C, plus CGI,I,-2 and 3 (every 2 weeks) A{ dayq4, {he depression scales yielded a noticeably highe~ percentage of lowered scored r e l a t i v e l y to i n i t i a l values in the A-group, as compared to the M:group (Hamilton, p=O,O03; MADRS, ~:0,003), which was e s s e n t i a l l y due to improvment of items such as anxiety and inner tension benefi~ ring from A.'~ sedative e f f e c t . This difference was not ap~ parent with CGI I , 2 and 3. At d.21 and d.2~, the antidepressant a c t i v i t y exerted by' 10Dmg M. did not d i f f e r s i g n i f i c a n t l y from that of 150mgA. Both treatments yielded noticeably better results than 50mgl The s i g n i f i c a n t difference e x i s t i n g according to the assess~ ment scales at d.14 between 100mgM. and 150mgA., although i t was not found in r e l a t i o n to CGI 3 at the same period of ti~e prompted us to consider testing higher dosages (150-200mgM.) in these patients going through an acute, quite endogenomorphic depressive episode ( i n i t i a l score : 36), regardless of the fact that the difference might o r i g i n a t e from delayed impregnation {progressive dosing over 5 days due to poor to< l e r a n c e frequen=l% encountered at onset of treatment with A.~ Nonetheless, we think that the b e n e f i t / s i d e effects r a t i o fe~ lOOmgM, is higher than that obtained f o r A. i f one takes intD consideration t~e anticholinergic-type side effects experienL ced primarily by oatients treated with this t r i c y c l i c a n t i depressant. M. Ansseau - C.~.U. Sart-Tilman - Liege - B 4000

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BEHAVIORAL EFFECTS OF AIIPAHEZOLE, A SELECTIVE ALPHA-2 ANIAGONIST IN RATS R. Lammintausta~ K. Finnes t E. Uyeno, J.G. Csernansky Atipamezole, 4-(2-ethyl-2,3-dihydro-lHinden-2-yl)lH-imidazole is a novel selective alpha-2 antagonist which effectively reverses the alpha-2 agonist sedation in veterinary practice. In rats it has been shown to increase noradrenaline turnover at doses of 0.1 mg/kg and above. In the forced swimming teat of rats atipamezole in acute dosing paradigm (26, 18 and 2 hours before testing) was able to decrease immobility significantly at dose levels of 1.5 and 5.0 mg/kg but not at 0.5 mg/kg i.p. The effect was comparable to that of desipramine. The spontaneous motility of rats is slightly increased at the dose level of 5.0 mg/kg i.p. but not at 1.5 mg/kg. In the approach/avoidance conflict test single doses of atipamezole 0.5-5 mg/kg i.p. did not change either the nonpunished or punished drinking response. Yohimbine 2.5 ig/kg and pentylenetetrazol 15 mg/kg i.p. decreased the punished drinking suggesting an anxiogenic response. We have earlier reported an anxiolytic response for an alpha-2 agonist in this test. After dosing of atipamezole 0.5-5 mg/kg i.p.b.i.d, for 2-3 weeks the response in forced swimming was not significant, neither could any effect be detected in conflict test. A blockade of clonidine sedation could, however, be demonstrated at 5 hours after the last atipamezole dose. Earlier we have shown a persisting forced swimming response after repeated dosing of desipramine. The Bmax values for pindolol and clonidine binding in the cortical brain membranes were not significantly changed after atipamezole treatment. The results suggest an antidepressive but not anxiogenic effect. The behavioral adaptation to repeated dosing needs further clarification. Stanford University, Dept of Psychiatry, and SRI International, Palo Alto, CA, USA. Author present address: Farmos Group Ltd, P 0 Box 425, SF-2OlO1 Turku, Finland

GBR 12909: A CLINICAL PHASE I STUDY OF A SELECTIVE DOP.~INE UPTAKE INHIBITOR U. Segaard I), J. Michalow I), B. Butler I), A. Lund Laursen I), S.H. In@wersen 2), B.E. Skrumsager 3), J.O. Rafaelsen 1,4). GBR 12909 is a phenyl-substituted piperazine derivative, which selectively blocks dopamine uptake. The biochemical and pharmacological profiles of GBR 12909 suggest that it may possess antidepressant activity and/or be of value in the treatment of Parkinson's Disease. The tolerance, the pharmacokinetics and the influence on psychomotor performance of GBR 12909 were investigated in a randomized, placebo-controlled, doubleblind study. Four healthy volunteers were orally administered the single doses of 100, 200 and 300 mg GBR 12909 and placebo, and four other volunteers received 50, 100 and 150 mg GBR 12909 and placebo once daily for seven days. The intermediate and highest single doses resulted in mild-moderate side effects as concentration difficulties, asthenia, feeling of drug influence and palpitations. After multiple dosing side effects were observed during the 100 and 150 mg dosing periods, all being milder than observed in single dose study. A dose related effect on ECG was observed with a slight reduction of the T-wave amplitude. No signs of arrhythmia or incompensation during exercise until exhaustion were observed. T h e p s y c h o m o t o r performance (measured as CRT) and the alertness (measured as CFPF) were not affected. GBR 12909 followed first order kinetics with a terminal elimination half-life of about I-2 days. Steady state serum concentrations of GBR 12909 seemed to be reached within one week. From animal studies the therapeutic daily dose has been estimated to 20-100 mg GBR 12909. Based on results of this study and another human phase I study, the therapeutic doses are expected to be well-tolerated by patients. I) Department of Psychiatry, University of Copenhagen, Rigshospitalet, DK-2100 Copenhagen, Denmark, 2) Pharmacokinetic Laboratory, Novo Industri A/S, 3) Clinical Research, F-R&D, Novo Industri A/S, DK-2880 Bagsvaerd, 4~ Deceased Au0ust 1987.

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E f f e c t of n e w a n t i d e p r e s s a n t s adinazolam and mianserin on intraventricular conduction and cardiac hemodynamics in canine myocardial infarction M. N i s h i m o t o , H. H a s h i m _ o t o , T. O z a k i , $2_. Nagashima, K__~.0 h a r a , M__t. N a k a s h i m a This study was undertaken to examine and compare effects on intraventricular conduction and cardiac function of amitryptyline(AMI), a tricyclic antidepressant, mianserin(MIA), a tetracyclic antidepressant, adinazolam(ADZ), a new benzodiazepine antidepressant, using canine myocardial infarction model. Epicardial bipolar ECGs were recorded from the normal area in the right ventricle and the infarcted area in the left ventricle. Intraventricular conduction was measured the excitation induced by a premature stimulation w i t h v a r y i n g c o u p l i n g i n t e r v a l s in t h e n o r m a l right ventricular area. Left ventricular pressure(LVP), LVPdp/dt, aortic flow, heart rate, coronary artery flow(CAF) and peripheral blood pressure(BP) were measured as parameters of c a r d i a c h e m o d y n a m i c s . 1)Effects on intraventricular conduction:AMI markedly delayed conduction in the infarcted area, whereas MIA and ADZ had little effect on the conduction. 2)Effects on cardiac hemodynamics:AMI i n c r e a s e d in h e a r t r a t e , CAF, BP, b u t d e c r e a s e d in LVPdp/dt. MIA little affected cardiac hemodynamics. ADZ either had little cardiac effect, at clinical doses of 0.5-1.0mg/Kg, but supressed cardiac function a t d o s e l e v e l o f 2 m g / K g o r over. Department of Pharmacology, Hamamatsu U n i v e r s i t y S c h o o l of M e d i c i n e , 3 6 0 0 H a n d a - c h o , Hamamatsu city, Sizuoka, Japan.

WEB 1881, A NOVEL ANTIDEPRESSANT, STIMULATES NORADRENALINE RELEASE IN VIVO AND IN VITRO W.O. Bechtel and 3. Mierau

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WEB 1881 (A-aminomethyl-l-benzylpyrrolidine-2-one) has been shown to have antidepressant-like properties in behavioral animal tests (Lehr et al., preliminary results presented at the Spring Meeting of the DGPH in Mainz, FR Germany, March i988). Studying the mode of action of WEB 1881 concentrations of noradrenaline and dopamine were measured in the rat brain after blockade of catechoiamine synthesis by alpha-methyltyrosine Dretreatment. With high doses of WEB 1881 given subcutaneously noradrenaline concentration was lowered up to ii ~, whereas dopamine concentration was not influenced. The finding led to the conclusion that WEB 1881 stimulates the release and/or ~ncreased the turnover of noradrenalime. The antidepressant imipramine exerts similar effects on noradrenaline concentration in this model. In vitro ~lth rat brain hippocampal slices, WEB 1881 caused an dose-dependent enhancement of electrically evoked no,adrenaline release. Imipramine showed similar effects at about a tenth of WEB 1881 concentration. Adding both drugs simultaneously the WEB 1881 effect was intensified. In contrast, it was attenuated adding WEB 1881 together with clonidine which decreased the electrically evoked noradrenaline release when given alone. However, this action of WEB 1881 can neither be explained by a eiomidine-like alpha-2 receptor affinity nor by any of the numerous receptor affinities and uptake inhibition activities of imipramime, because WEB 1881 could be shown to have none of these properties. Thus, from these studies we conclude a novel mode of action for WEB 1881 compared with that of known antideoressants like imipramine. 5oenringer Ingelheim KG, Department of Biochemistry, D-6507 Ingelheim, FR Germany

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FACILITATION OF SPONTANEOUS ALTERNATION, S I M P L E AND CONCURRENT DISCRIMINATION L E A R N I N G IN MICE BY THE ANTIDEPRESSANT DRUG TIANEPTINE

E F F E C T S OF T I A N E P T I N E ON S L E E P - W A K E F U L N E S S CYCLES AND EEG IN MONKEY

R. Jaffard *, E. Moca~r ,s, D. B~racochSa $1 A. M a r t g h e t t o * and A. Toumane * Antidepressants generally impair memory processes. The present study was designed to i n v e s t i g a t e the effects of t i a n e p t i n e , a new antidepressant, on spatial behaviors involving different types of memory. Sequential (6 trials) spontaneous alternation (S.A.} in a T-muse was used as an index of working memory. (D. B~racoch6a and R. Jaffard, Behav. Neurosc., 1Ol, 167-197, 1987). Reference memory was tested on two appeudvely reinforced tasks differing by their complexity, a left-right (one pair of arms ; T-maze) and a concurrent (six pairs, automated radial maze) discrimination learning task. In all experiments, the drug was administered i.p. 30 minutes before each session. Results showed that at the dose of 10 mg/kg, tianeptine greatly improved S.A. (from 64.0 to 85.0 %, p < 0.001) and facilitated r e t e n t i o n (day 2) of the T-maze discrimination learning task (p = 0.013) without changing the speed of initial acquisition (day 1 : trials to criterion : p > 0,30). Finally, animals treated with tianeptine (10 mg/kg) before each daily session of concurrent discrimination learning were found to learn faster (p < 0.001) and to reach higher discrimination performance than controls at the end of training (day7:80.1 vs 65.1, p < 0.001}, this facilitative effect was weaker with 5 mg/kg and disappeared with 2.5 mg/kg. The present results suggest that tianeptine did not impair this form of memo~" but rather would have facilitating effects on both working and rei'erence memories. The specificity, of these effects are currently being s t u d i e d via a co mp arison of t i a n e p t i n e w i t h o t h e r c l a s s i c a l antidepressants (amitriptyline, desipramine, clomipramine} in our behavioral protocol. * Udiversit~ de Bordeaux I, 33405 TALENCE, France ** I.R.I.S., 27 rue du Pont, 92200 NEUILLY sur SEINE, France

E. Moca~r *. D. Lagarde **, E. Balzamo ***, C. Milhaud ** It has been previously shown that tianeptine an antidepressant which increases serotonin uptake increased active wakefulness during the first hour after acute administration in rat (2.5 - 10 mg.kg-t i.p.). Tianeptine repeated administration did not modify the overall distribution of phases of wakefulness and sleep in the rat. The present study was performed in six adult male Rhesus monkeys (Macaca Mulatta). Tianeptine was administered during 15 days at the dose of 10mg_kg-1 i.m. twice a day at 9a.m. and 6p.m. Placebo was administered one week before and after tianeptine treatment. The animals were running on a 12 h light - 12 h dark (7 p.m. - 7 a.m.) schedule. Sleep-wakefulness cycles were recorded three times during the placebo pre-treatment, on days 1, 8, 12, 15 of tianeptine treatment and 48 h after treatment withdrawal. Continuous EEG and behaviour (video tape recording) were recorded between 6 p.m. and 8 a.m. The effects of tianeptine on sleep-wakefulness cycles and EEG rhythms were analysed during the first hour after administration, during the 12 h of darkness (7 p.m. - 7 a.m.) and between 7 a.m. and 8 a.m. Between 7 p.m. and 8 a.m. there is no s i g n i f i c a n t modification of wakefulness, sleep stages (1 - 2 - 3 - 4) and REM (duration, episode numbers) throughout the treatment. The only modifications induced by tianeptine were observed the first hour after its administration : from day 8 tianeptine induced a significant but moderate increase of wakefulness and a corresponding decrease of sleep stages 2 and 3 and of total sleep duration ; these modifications can persist 48 h after treatment withdrawal. No statistical changes were observed when the whole period of recording was considered. This study coni'Lrms that tianeptine is devoid of sedative effects and does not globally affect sleep-wakefulness pattern and cortical EEG rhythms in monkey. * I.R.I.S., 27 rue du Pont, 92200 NEUILLY sur SEINE, France ** CERMA, 5 bis avenue de la Porte de S~vres, 75731 PARIS cedex 15, France *** Laboratoire de M~decine Expdrimentale, Facult~ de M6decine, 27 boulevard Jean Moulin, 13385 M.A_RSEILLEcedex 5, France

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ACTION OF TL&NEPTINE ON FOCALIZATION" OF ATTENTION IN CAT

M E T A B O L I S M OF T I A N E P T I N E MULTIPLE DOSING IN MAN

P. D e l a g r a n g e * . J.J. Bouyer*,. M-.F. M o n t a r o n * , C. D u r a n d * , E. Moca~r ** and A. Rougeul *

I. Bouver *, R. Farinotti *, P. Gel~ **, L. Grislain **. C. Salvadgri** and G. Mahuzier *

At variance with the effect of other antidepressant drugs that are known to decrease the level of arousal and vigilance, tianeptine was shown to induce a slight arousa' m the rat We have noN" analyzed the changes in attentiveness in the cat, through combined b e h a v i o r a l and e l e c t r o c o r t i e o g r a p h i c m e t h o d s . The development of beta rhythms at 36 Hz over the fronto-parietal cortex had previously been demonstrated to be a reliable index of behavioral focalized attention ~Bouyer et al., Electroeneeph. Clin. Neurophysiol. 51, 244, 1981 ) Tianeptine a d m i n i s t e r e d at 5 m g / k g was shown here to favour attentiveness in our standard paradigm with trains of beta maintained during 90 minutes of recording correlated with the sustained state of attentiveness. At 2 mg/kg, the effects were lighter, and depended upon the sensitivity' of the subjects, but none of the tianeptine treated animals ever developed sleep during the recording sessions. in order to compare the effects with those of a classical antidepressant under the same conditions, the same subjects were administered with amitriptyline. The subjects given similar doses of amitriptyline became drowsy after about 10 minutes and slept all through the recording session (with no REM sleep, though). To sum up, tianeptine increases attentiveness in cat and does not produce drowsiness as other antidepressant substances do. (supported by IRIS grant 375)

Tianeptine is an original antidepressant characterized by a tricyclic structure in which median thiazepin ring is substituted with an amino acid side chain_ Radioisotopically 14C-labelled tianeptine (12.5 mg) was administered orally to 6 healthy volunteers. Tianeptine is rapidly absorbed and e x t e n s i v e l y m e t a b o l i z e d in man. A f t e r 7 d a y s approximately 66 % of the dose was eliminated by renal excretion (55 % during the first 24hoursL Unchanged molecule contributes in urine, 24 hours after administration, for less than 2 % of administered dose. Hydrolysable conjugates represent approximately 20 % of the dose. Chromatographic and mass spectral studies on the urinary metabolites indicate that ~--oxidation is the major route of biotransformation for tianeptine in man. 3 major metabolites accounted for 26 % of urinary radioactivity are products of ~--oxidation. Two of them are tianeptine homologues with C5 and C3 side chain respectively. The third one is a lactam formed by cyclization of C5 metabolite. In plasma, two hours after administration these three metabolites were present but unchang-d tianeptine remained the major compound (300 ng.ml'D. Furthermore, in a separate study, tianeptine was given to 12 healthy subjec~ ; the metabolism profile was examined on the urine collected during the first 24 hours following the first and the last dose of multiple dosing (12.5 mg tid for l 0 days). After 10 days of chronic administration urinary metabolic profile was not modified but some q u a n t i t a t i v e difference appeared. The quantities of tianeptine and C5 derivative conjugates decreased of approximately 50 % while the quantity of the C3 derivative conjugate increased. Thus, the ~-oxidation process seems to be the rate-limiting step for the conjugation of the C3 metabolite following a single dose of tianeptine ; this is no more the case at steady-state.

9 Institut des Neurosciences, CNRS-UPMC, 9 quai Saint Bernard, 75005 PARIS, France 9* I.R.I.S., 27 rue du Pont, 92200 NEUILLY sur SEINE, France

* **

AFTER

S I N G L E AND

Facult~ des Sciences Pharmaceutiques PARIS XI - Avenue JeanBaptiste C16ment - 92290 CHATENAY-MALABRY, France IR.I.S., 27 rue du Pont. 92200 NEUILLY sur SEINE. France

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FLE~OBUTE~OL : A NEWANTIDEPRESSANTDRUGP.~ATED TO BETA ADRENERGIC A G ~ T S . EXPERIMENTAL PROIrILE IN MICE. J. Duteil~ F.A. Rambert t A.M. Pointeau, P. Man~iameli and E. Assous. Putative antidepressant effect was demonstrated in mice with isoprenaline, salbutamol and other beta-agonists. Furthermore, therapeutic improvement was demonstrated with salbutemol in depressive patients. Potential antidepressant effect of FLEROBUTEROL, (fluoro-2 phenyl)-i t-butylamino-2 ethanol, (FLERO), a new drug related to beta-agonists, was studied using classical psychopharmacolo~ical_~ests in mice. I FLERO (-30 min, 0.5-32 mg.kg ~, i.D., 2-16 k~l~

IITrERACTIONS OF FLEROBUTEROL, A NEW A N T I D ~ S A N T

p.o.) completely antaganised apo~r~hine (16 m ~ and partially reversed reserpine- and oxotr~-morineinduced hypothermia and enhanced (16-32 mg.kg , i.p.) the toxic effect of yohimbine. Unlike imipremine (but like other beta agonists), it did not reduce immobility duration in "hehavioural despair" test. FLERO did not enhance 5-HTP-induced head twitches or tremors in MAOI pre-treated mice and did not modify l-DOPA-induced motor activity. As other beta-agonists, FLERO (-30 min, 2-32 mg.kg -~, i.p,) induced a decrease in locomotor activity and did not potentiate the hypnotic effect of barbital. Antagonistic effect of FLERO towards apomorphine-induced hypoth~rmia was prevented by propranolol (-i h, 4-8 mg.kg i' i.D.) but not by alpha m p-tyrosine (-3 h, 75 mg.kg" , i.D.). FLERO did not produce mydriasis and did not prevent oxotremorine-induced tremors or salivary and lacrymal glands hypes-secretion. It did not reduce reserpineinduced palpebral ptosis and did not induce an increase in toxicity in aggregated mice. From these results, FLERO appears to demonstrate potential antidepressant activity in mice. The ratios of the centrally and peripherally active doses of FLERO and salbutemol are to be evaluated. Centre de Recherches du Laboratoire L. LAFON, 19 avenue du Professenr Cadiot. F-94701Maisons-Alfort. France.

31.02.38 AGONIST lq~ROBUTEROL IN RATS : C/IMPARISONWI'r~ S A L B I ~ L ~.J. Puech(1) t M. Henry(2) t P. Martin(1)~ S. Th~venet(2) ~.A. Rembert (2) and J. l)uteil(2). ~otential antidepressant effect ~as demonstrated in mice ith FLEROBUTEROL (fluoro-2 phenyl)-i t-butyl amlno-2 thanol, (FLERO), a new drug related to beta agonists. ~he ratios of the centrally and peripherally active doses of FLERO and salbutemol (SALBU) were evaluated after i.p. I 'administratlon in male Wistar AF rats. in the learned helplessness model, FLERO and SALBU were !daily tested on a 30 avoidance trials session in a ishuttle-box, 48, 72 and 96 h after exposure to 60 ~ncontrollable an~unpredictable electric shocks. FLERO (0.015-0.25 mg.ks -~ b.l.d, for 5 days) stron@ly reduced escape I deficits at the minimlmal dose used of 0.015 mg.kg- (-56Z on day 5, 30 - 45 min after injection). In the same experimental paradigm, SALBU demonstrfted an effect at the minimal effective dose of 12 mg.kg- b.l.d. for 5 days (-50Z on day 5). In conscious rats instrumented with chronic arterial catheter, FLERO was idevoid of positive chronotropic effect at 0.25 mg.kg-* but increas~ heart rate at the minimal effective dose of 0.5 mE.ks- (+ 45 beats/min, at 30 min, lasting 75 min). In the same conditions, SALBU induced a positive chrono~ropic effect at the lowest dose studied of 0.325 mg.kg -~ (+ 70 beats/min at 30 min, lasting more than 120 min). The ratios of the centrally and peri~erally minimal active doses were 33 (0.0~5 vs 0.5 mE.ks ~) for FLERO and 0.03 (12 vs 0.325 mE.ks -~) for SALBU. Hence, this ratio indicates a preferential antidepressant versus cardiac stimulant activity of FLERO as compared to SALBU. These results suggest that cardiac stimulation would be m i n i ~ l in depressed patients treated with FLERO. (i) D~partement de Pharmacologie, CHU Piti~Salp~tri~re, 91, boulevard de l'Hopital. F-75651 PARIS Cedex 13 (2) Centre de Recherches du Laboratoire L. IdLFON, 19, avenue du Professeur Cadiot. F-94701Maisons-Alfort.

~

276

DRUG,

BETA ADR~K~31~TORS IN RAT CNS.

R~. Zini~ D. Morin and J.P. Tillement FLEROBUTEROL (FLERO) has potent antidepressant effects both in animals and man. As it is chemically related to beta-adrenergic agonists and as such a mechanism may be involved in antidepressant effects, its interactions with central beta-adrenoceptors were investiEated. Using radioligand techniques, we determined the inhibition constant (KT) of FLERO and its enantiomers at these receptors. T~eir affinities3were evaluated by the ability to inhibit the binding of [ H]-CGP 12177 (Kn = 0.1 nM) in cerebral cortex (mainly beta-I receptors) and in cerebellum (mainly beta-2), The affinity of (• was very close in both tissues (K T = 926 nM for cortex, K I = 518 nM for cerebellum) which~indicated that the drug was not selective of a beta-adrenergic receptor subtype. In cerebral cortex, binding inhibition of [~H]-CGP 12177 was stereospecific, (-)FLEE0 (KT = 483 nM) being twice more potent than (• and 7~ fold more potent than (+)FLERO (K T = 34 ~M). Moreover (+)FLERO was 7 fold less. active tha~ (+)isoproterenol (KT'-= 140 riM) but 5 fold more active than salbutemol (KI --~4600 riM). In cortical slices from control rats, the addition of i00 ~LM (• resulted in a 135 Z increase in cAMP accumulation over basal level (i00 Z or 6.8 pmoles cAMP/mg protein/10 min at 37~ This increase was similar to that of i00 ~M salbutamol (129 Z) but much lower than the stimulation induced by I00 ~M (• (280 Z) or i00 ~LM (• (402 Z). (• and (• accumulation of cAMP were fully antagonized by i0 mM of (~)atenolol or 10 ~LM of (~)propranolol. These results show that FLERO is a central betaadrenergic agonist with a higher affinity than that of salbutamol. D~partement de Pharmacologic, Universit~ Paris XII, 8 rue du G~n~ral Sarrail. F-94010 Cr~teil, France.

31.02.39 ORAL PHARMACOKINETICS OF A NEW SLOW RELEASE FORMULATION OF VILOXAZINE IN DEPRESSED PATIENTS

5 . 8 o u q u e t ~ S . G u i b e r t r 3.Lavolsy~ 3.B F o u r t 1 1 1 a n . Pnarmacoklnetlc propertzes of v i l o x a z i n e (V), were i n v e s t i g a t e d xn t w e l v e P a t i e n t s w i t h m a 3 o r O e p r e s s i o n (DSM III cr~terla)(lO M,2 F),ages ranged from 35 to 52 y r s , w l t h score h i g h e r than 2B on the r a t l n g s c a l e MADRS . P h a r m a c o k l n e t l o ~ a r a m e t e r s were c a l c u l a t e d f o l l o w l n g the ist and 28th a d m i n i s t r a t i o n s o f a o a l l y 300 mg o r a l

Oose

of v i l o x a z i n e $R. Plasma s a m p l e s were c o l l e c t e d for 24 h at days: I (I) an~ 28 ( s s ) , r e s p e c t l v e l y and at C MIN of days: 7, 14,21. The a e p r e s s l o n rating scales w e r e u n d e r t a k e n at ist, 7th, Idth and,28th days of treatment. Plasma c o n o e n t r a t l o n 5 were d e t e r m i n e d by HPLC and results e x p r e s s e d as (mean~SE). M e a n p l a s m a C MAX of (V)reaohed : 29275 350 ng/ml (i) and 3824 ~ 536 n g / m l ( s s ) respectively. The important values of T M A X : 5 . 3 " 0.5 h(1) and 4.8 t 0.4 n(ss) an~ (MRT): Ii.3 • 0.gh (i), 8.7 : 0.4 h(ss), were in a c c o r d wltn one Oally Oose. E l i m l n a t I o n half-life: T1/2 : 5.6 ~ 0.8 n (1),wa~ higher than the values reported by 8 . V a n d e l (3.4 ~ 0.6 h) and P.F.C 8ayllss (2 to 5 h ) , a f t e r a single a d m l n z s t r a t l o n of 1CO mg s t a n d a r d tablet. The mean v a l u e s of AUC(ss) 0-24h and AUC(1) 0-~. were 3 7 8 0 4 i 5 8 0 5 and 37344 ~ 4795 ng/ml.h, r e s D e c t l v e l v a n d mean Citot reached 163.7 ~ 2 4 . 4 I/h (i) a n d 168.8 Z 21.71/h (Ss)-N~. T h e S e results suggest~ t~at D l o a v a i l a b l l i t y , d l ~ t r l b u t l o n and ellmlnatlon of V w e r ~ f ~ i m l l a r i ~during onron~c d o s l n g altn oral SR farm. H e l g h t p a t i e n t s showed a rapld clinloa~improvement (Tth ~ay) ,with a ratln9 ~cale d e c r e a s e d of 60 9 after 4 weeks of V treatment. NO relatlonshzp was found between plasma levels anO c l i n i c a l response or a d v e r s e effects. N~pital la M i l ~ t r i e , 8P 5 7 7 , 8 6 0 2 1 ~ P o i t i e r s -W.

31,0240

310241

DOSULEPIN (DOTH!EPIN) FOR DEPRESSION. ARE THERE INTERNATIONAL DIFFERENCES? A REVIEW OF CLINICAL USAGE IN OVER 5,000 PATIENTS FROM THE U.K., GERMANY AND FRANCE. S. Donovan Dosulepin (Dothiepin) was administered to 5,386 patients with depressive symptoms ranging between mild and severe, at a dose generally between 75mg/day and 150mg/day for four weeks in an open uncontrolled study in 1,965 U.K. patients (i), 1,866 patients in West Germany (2) and 1,555 French patients (3), by a total of 920 investigators. This is a comparative review of the outcome in the three cohorts. Although the assessment rating scales were different in each country, it was evident that a favourable response occurred in the majority of patients in all three cohorts. Onset of action within one week and maximum rate of improvement during the first two weeks were observed in all three groups, although improvement continued throughout the four week study period. Premature withdrawal due to lack of efficacy was very low in each group and overall, medication was withdrawn in less than 4% of all patients for this reason. Side effects Were common and although they occurred with an apparently variable incidence in each group, the majority were typical anticholinergic effects, most commonly dryness of mouth in up to one-third of patients. Withdrawal due to adverse events was, however, low in all three groups, amounting to 5% of the entire population studied. There were no serious events attributable to study medication. The benefit:risk ratio was high in all three cohorts and despite the differences identified in the populations of depressed patients and variations in study methodology in each country, the overall outcome is reassuringly similar

E ~ C A O Y OF ~IANSERIN IN DIFFERENT DEPRESSIVE

Refs: (1)Rees JA. Marsh BD. Int.Pharmacopsychiat. 1975; 10:54 57. (2)Karrasch KF. Sehulte RM. Zeit T., Med.Welt. 1987;~8:1453-8 (3)Ades J. Synapse. 1987;36:76-80

M.Pijade 25, Yugoslavia

SYNDAO~E S.Loga,

l.Oeri6, E.Rustempa~i6

and V.Dane~

The efficacy and safety of mianserln were compa red with doxepln in 3 independent double-blind controlled studies: (I) in depressive adolescents(5o out-patients), (2) in secondare depression of TBC (30 in-patients) and (3) in alcohol withdrawal syndroms (30 in-patlents). The patients w~re assessed weekly on HDRSeCGI, DTES(only alc oholics),together with a side-effe cts symptoms check-list,physical examination and laboratory assays. During of the 4 week period (alcoholics-2 weeks the patients were treated with mlanserin (30 90 mg) or doxepin(25 - 75mg).The total dayly dosage was given at bedtime. The results of these 3 studies showed that mianserin was as effectiv and as better tolerated than doxepin in milde depression in adolescent9 secondare depression of TB0 patients and in alcohol withdrawal syndrom;morover it seems to have more rapid onset of action than doxepin. UM0 - PsihiJatriJ ska kllnlka,71, ooo SaraJevo,

The Boots Company PLC, NottinGham, NG2 3AA

31.02.42

31.02.43

COt.~ARISON OF CLINICAL EFICACY OF ALPRAZOLAM, MIANSERIN AND IMIPRAMINE IN NEUROTIC DEPRESSION J. S. Relvas, A. S. Vaz-Serra and C. B.'Saraiva

QSAR STUDY OF MAO-A AND MAO-B INHIBITORY ACTIVITY OF SUBSTITUTED PHENYLALKYLAMINES IN-VITRO.

It's a common practice the association of benzodiazepines to antidepressants ~n cl~nical management of neuro=ic depression. Recently, the antidepressant properties of a new family of benzod~azepines has been stud~ed and many clinical trials uncovered a significant and useful clinical effect (Fabre, 1976; Rickels et col., 1982; Feighner et col., 1983; Rush et col., 1985; Overall et col., 1987). The present clinical trial has been conducted in 47 patients diagnosed as neurotic depressives ~n a double-blind, randomized, parallel-groups design. Each group was medicated w~th one of the three drugs during 6 weeks after one week wash-out. Weekly avaliatJons inclued Beck Depression Inventory, Zung Self-Rating Auxiety Scale,Evaluation of three goalsymptoms rated as most disturbing by patients in the first observation, Side-effects Inventory and Laboratory evolution_ Results showed a significant and sustained antJdepressive effect of alprozolamwJth a rapid onset but of a lesser intensity than other two d T u g s Patients medicated with alprazolam presented less side-effects in all parameters. Clfn~ca PsJqui~tr~ea dos Hospitais da UniversJdade de Coimbra. H.U.C. 3049 Coimbra. Portugal.

Massoud Mahmoudian;

Dept. Pharmacology, F i r o o z g a r I n s t i t u t e , Iran, A l i S t . , Tehran 15934, I RAN.

Uinv. Med. Sci.

Q u a n t i t a t i v e s t r u c t u r e a c t i v i t y a n a l y s i s (Hansch a n a l y s i s ) is app]ied t o e l u c i d a t e the s t r u c t u r a l r e q u i r e ments f o r the i n h i b i t i o n o f HAO-A and MAO-8 a c t i v i t y by a series of substituted phenylalkylamines. I t has been found t h a t PL~O-A i n h i b i t o r y a c t i v i t y is achieved best with a compound w i t h a hydrogen a c c e p to r group at para p o s i t i o n o f the pheny] r i n g , a ~ c o n f l g u r a t i o n o f side chain, w i t h a high h y d r o p h o b i c l t y and a high i n d u c t i v e constant ('~). However, the bulky s u b s t i t u e n t s are unfavour to the a c t i v i t y , as can be seen from the negative slope o f the sum o f molar r e f r a c t i v i t y o f s u b s t i t u e n t s on the phenyl r i n g . While, the MAO-B i n h i b i t o r y a c t i v i t y a l s o r e q u i r e s a S c o n f i g u r a t i o n o f the side chain and a high f l e l d Tnduct|ve constant ( ~ , the o t h e r s t r u c t u r a ] requirements are d i f f e r with t h a t o f MAO-A i n h i b i t o r y a c t i v i t y . The I~AO-B i n h i b i t o r y a c t i v i t y is achieved best w i t h a hydrophobic group at para p o s i t i o n o f the phenyl r i n g . A l s o , whi l e a bulky group a t o r t h o p o s i t i o n of the phenyl r i n g is favoured to the MAO-B i n h i b i t o r y a c t i v i t y , a bulky group at meta p o s i t i o n o f the phenyl r i n g w i l l reduce the activity. From these f i n d i n g a model f o r the binding s i t e o f MAO-A and MAO-B iso-enzYmes is p o s t u l a t e d .

277

31.02.44

31.02.45

ANTIDEPRESSANT ACTIVITY OF RU 41 656 AN OXAERGOLINE~ IN BEHAVIOURAL TESTS J.Laurent, M. Guernier~ C. Gieules RU 41 656* a 9-oxaergoline derivative with mixed dopamine (DA) D2 agonist and DI antagonist activities possesses antlanoxic and antiischemic properties together with a beneficial action on learning behaviour. It is under development as a potential therapeutic agent for the treatment of senescence related disorders. DA has been implicated in the mechanism of depression and the DA agonist hromocriptine was found to be clinically effective as an antidepressant (AD). We have therefore looked for a potential AD activity of RU 41 656 in comparison with bromocriptine and two AD compounds : nomifensine~ a catecholamine (DA + NA) uptake inhibitor and amitriptyline a "tricyclic" AD. 3 tests in rats where AD are active were used : immobility induced by forced swimming (FS)j muricidal behaviour (MB) and facilitated acquisition of a passive avoidance in the bulbectomized rat (BR). The EDS0 of RU 41 656 in these tests was : FS = 3 mg/kg p.o. ; MB = 1.5 mg/kg i.p. ; BR = 2.5 mg/kg p.o.. The general order of potency of the compounds tested was : nomifensine~ RU 41 6 5 6 > amitriptyline> hromocriptine. The efficacy of RU 41 656 was independent of any hyperlocomotor activity since unlike most DA agonists it reduces locomotion. These results might be explained by the DAergie activity of RU 41 656 although other mechanisms of action cannot be excluded since it also binds to ~2 and 5HT2 receptors. Nevertheless a potential AD activity is valuable for the therapeutic use of such a compound because depression is often associated with aging. * (86)(~) 6-methyl 8-[(methylthio)methyl] 9-oxaergoline chlorhydrate Centre de Recherches Rouasel Uclaf~ III route de Noisy 93230 Romainville~ France.

ANTIDEPRESSANT ACTIVITY OF RU 41 656 AN OXAERGOLINE~ 14 BEIIAVIOURAL TESTS J.Laurent, H. Guernier~ C. Cieules RU 41 656* a 9-oxaergoline derivative with mixed dopamine (DA) D2 agonist and DI antagonist activities possesses antianoxic and antiiachemic properties together with a beneficial action on learning behaviour. It is under development as a potential therapeutic agent for the treatment of senescence related disorders. DA has been implicated in the mechanism of depression and the D A agenist bromocriptine was found to be clinically effectlve as an antidepressant (AD). We have therefore looked for a potential AD activity of RO 41 656 in compariso= with bromocriptine and two A]) compounds : nomifensine, a catecholamiue (DA + NA) uptake inhibitor and amitriptyline a "tricyclic" AD. 3 tests in rats where AD are active were used : immobility induced by forced swimming (FS), muricidal behaviour (MB) and facilitated acquisition of a passive avoidance in the bulbectomized rat (BR). The ED50 of RU 41 656 in these tests was : FS = 3 mg/kg p.o. ; MB = 1.5 mglkg i.p. ; BR - 2.5 mglkg p.o.. The general order of potency of the compounds tested was : nomifensine~ RU 41 6 5 6 > amitriptyline> bromocriptine. The efficacy of RU 41 656 was independent of any hyperlocomotor activity since unlike most DA agoniats it reduces locomotion. These results might be explained by the DAergic activity of RU 41 656 although other mechanisms of action cannot be excluded siuce it also binds to =2 and 5HT2 receptors. Nevertheless a potential AD activity is valuable for the therapeutic use of such a compound because depression is often associated with aging. * (83)(~) 6-methyl 8-[(methylthio)methyl] 9-oxaergollne chlorhydrate Centre de Recherches Rouasel Uclaf~ III route de Noisy 93230 Romainville, France.

31.02.46

31.02.47

PRECLINICAL CHARACTERISTICS OF MOCLOBEMIDE, A SHORT-ACTING MAO-A INHIBITOR WITH LOW LIABILITY TO ENHANCE THE TYRAMINE PRESSOR EFFECT H.H. Keller~ R. Kettler, W.P. Burkard and M. Da Prada The morpholino-ethyl benzamide moc|obemide (MOCLO) belongs to a new generation of reversible MAO inhibitors which p r e f e rentially inhibits cerebral MAO-A; it lacks hepatotoxicity and only minimally enhances t h e tyramine pressor e f f e c t ("cheese r e a c t i o n " ) (Do Prada et al., J. Neural Transm. Suppl. 26, 33, 1988). Being more active in vivo than in vitro, MOCLO---behaves as a prodrug. Marked MAO-A inhibition ex vivo in the rat occurs within 5 rain a f t e r oral administration in both liver and brain, indicating that the MAO-A inhibiting entity is rapidly formed by biotransformation, possibly occurring at t h e MAO enzyme itself. Accordingly, in vitro MAO-A inhibition is more pronounced and non-competitive if the tissue h o m o g e n a t e is preincubated with MOCLO before adding 5-HT as the substrate, suggesting a m e c h a n i s m - b a s e d type of inhibition. In contrast, even after a high dose (100 l~moles/kg p.o.), m a x i m u m MAO-B inhibition occurs only 1 h and 2 h after administration in liver and brain, resp.. Peripheral MAO-B inhibition is marked in the rat, less pronounced in squirrel monkeys and only moderate in humans (30-50% inhibition in platelets after 200 mg orally). Reversibility of MAO-A inhibition after oral MOCLO to rats has been d e m o n s t r a t e d by dialysis or simple incubation of t h e tissue homogenates at 37 ~ but not at 13~ strongly suggesting a conversion of the inhibiting derivative into inactive products. In comparison with other novel MAO-A inhibitors, t h e a c c u m u lation of the monoamines and the concomitant decrease of their metabolites in rat brain induced by MOCLO is shortlasting (16 h) even a f t e r high doses. More important, MOCLO has a particularly low liability to enhance t y r a m i n e - i n d u c e d pressor e f f e c t s in rats and h u m a n s (Korn et al., J. Neural Transm. Suppl. 26, 57, 1988). The present preclinical data indicate that MOCL--O m e e t s the prerequisites of a safe drug. In man, MOCLO is well tolerated, produces few undesired e f f e c t s of low intensity while being an effective antidepressant (Amrein et at., J. Neural Transm. Suppl. 26, 73, 1988). Pharmaceutical Research D e p a r t m e n t , F. H o f f m a n n - L a Roche & Co., Ltd., CH-4002 Basle, Switzerland

CSF- AND PLASMA CATECHOLAMINES AND METABOLITES UNDER TREATMENT WITH SELECTIVE, REVERSIBLE MAO-A

278

INHIBITORS E. Sofic,

G.

Laux,

P.

Riederer,

H.

Beckmann

R e v e r s i b l e and s e l e c t i v e MAO-A i n h i b i t o r s are t h o u g h t t o be o f t h e r a p e u t i c efficacy in d e p r e s s i o n s y n d r o m e . T h e r e f o r e , m o c l o b e m i d e (MO) (Re 11 1163) has been t e s t e d (no d i e t a r y restriction) vs. m a p r o t i l i n e (MA) i n a 28 day d o u b l e - b l i n d s t u d y i n 20 i n p a t i e n t s matched f o r sex and age. A c c o r d i n g t o DMS I I I f o r m a j o r d e p r e s s i v e d i s o r d e r s 15 (MO-group) and 16 (MAg r o u p ) were u n i p o l a r d e p r e s s i o n s w h i l e t h e o t h e r p a t i e n t s were d i a g n o s e d am o f t h e b i p o l a r t y p e . Ratings (HRSD, MAMA, CGI, SDS, KUSTA) were done on days 0 , 3 , 7 , 1 4 , 2 1 , 2 8 . Compliance was checked by plasma drug l e v e l s of MO. Plasma-(days O, 14,28) and o c c a s i o n a l l y CSF-analyses were performed f o r catecholamines and t h e i r m e t a b o l i t e s by using an HPLC-EC technique. C l i n i c a l r e s u l t s : . p a t i e n t s responded with HRSD< 50% in 73% (MO) and 60% (MA). There were 3 drop outs with MO ( d e l i r i u m j p s y c h o s i s , no e f f e c t ) . Side e f f e c t s : sleep disturbances, p r u r i t u s , a g i t a t i o n (MD); sedation, dry mouth (MA). There were no evidences for h y p e r t e n s i v e r e a c t i o n s w i t h MO. B i o c h e m i c a l r e s u l t s : CSF (MO in 2 p a t i e n t s o n l y ) : inconsistent i n c r e a s e o~-f--NA, A and DA; no c h a n g e s w i t h HVA and 5 - H I A A . P l a s m a : no sign. c h a n g e s in N A , A , D A , HVA and 5 - H I A A with e i t h e r MO or MA. Conclusions: MO shows b e n e f i c i a l t h e r a p e u t i c e f f i c a c y , no c h e e s e e f f e c t and s e e m s to act by i n c r e a s i n g the central catecholaminergic tonus.

Clinical Neurochemistry, Dept. Psychiatry, U n i v e r s i t y o f WOrzburg, WOrzburg, FRG

31.02.48

31.02.49

STIMULATION OF PROLACTIN SECRETION BY THE P~EIrERSIBLE M ~ O - A I N H I B I T O R , M O C L O B F ~ M I D E , I N M ~ N M. K o u l u , M. S c h e i n i n , R. Zin~ner A. K a a r t t i n e n , J. K a l l i o a n d K. P y y k k ~ Three different doses of the reversible preferential MAO-A inhibitor moclobemide (iOO, 200 a n d 3 0 0 m g ) , m a t c h i n g p l a c e b o t a b l e t s , a n d i0 m g o f t h e i r r e v e r s i b l e FL~O-B i n h i b i t o r deprenyl were administered to e i g h t m a l e v o lunteers. MAO-B inhibition after moclobemide was slight (less than 30%). The secretion of prolactin was powerfully and dose-dependently stimulated by moclobemide, as e v i d e n c e d b y i n c r e a s e d p r o l a c t i n l e v e l s i n p l a s m a (an a v e r a g e i n c r e a s e f r o m 6 . 4 + 2 . 7 t o 23.5~7.1 ng/ml at 1 h after intake o~ 300 mg). Prclactin in plasma was slightly reduced after placebo and deprenyl. Plasma growth hormone and cortisol levels were not significantly affected by moclobemide. Serotonergic agonists (e.g. 5 - h y d r o x y t r y p t o phan, t r i c y c l i c a n t i d e p r e s s a n t s , and fenfluramine) a r e k n o w n t o s t i m u l a t e p r o l a c t i n s e c r e t i o n in m a n , I t is s u g g e s t e d t h a t a u g m e n ted p r o l a c t i n r e l e a s e a f t e r s i n g l e d o s e s o f moclobemide may reflect intensified serotonergic neurotransmission in the hypothalamus, due to i n h i b i t i o n o f M A O - A . T h u s , p l a s m a p r o l a c t i n m a y b e a u s e f u l i n d i c a t o r of t h e s e r o t o n e r g i c e f f e c t s o f M~AO-A i n h i b i t o r s . F u r t h e r e x p e r i m e n t s a r e r e q u i r e d t o t e s t t h i s hylmothesis. Depart~nent o f P h a r m a c o l o g y , University of Turku

EFFECTS OF NOCLOBEMIDE AND MAPROTILINE ON HYPOTHALAMIC-PITUITARY-SOMATOTROPIC (HPS) AXIS FUNCTION IN DEPRESSION A. Erb, 6. LBUX, K.P. Lesch The effects of 4 weeks of treatment with the selective MAO-A-inhibitor moclobemide vs. the t e t r a c y c l i c NA re-uptake i n h i b i t o r maprotiline on HPS function were studied by clonidine-evoked growth hormone (6H) release in major depressive disorder. Growth hormone (6H) responses to 2 NO/ kg clonidine were investigated in i0 depressed patients (8 women, 2 men; mean age: 45.8 yrs) before and after treatment with 300 mg/day moclobemide (MOC) and in 13 patients (9 women, 4 men; 48.4 yrs) with a major depressive episode before and after treatment with 150 mg/day maprotiline (MAP). Compared to individually matched controls the depressed patients showed an attenuation of clonidineinduced GH responses before treatment with MOC (392 • 111 vs. 95 • 39 ng.min/ml; p<0.01, Mann-Whitney U test) and with MAP (534 • 190 vs. 124 • 72 ng.min/ml; p ~ 0.001). After treatment the mean 21-item Hamilton Rating Scale scores were significantly improved in both the MOC (26.4 • 2.2 vs. 10.3 • 1.9; p
depressive episode. Department of Psychiatry, University of Wuerzburg, Fuechsleinstrasse 15, 8700 Wuerzburg, FRG

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NIG~ DOSE TRANYLCYPROMINE FOR REFRACTORY DEPRESSION N.J. Berwish and J.D.Amsterdam. AS many as 15% of depressed patients may develop a chronic, refractory illness. Aggressive treatment with various drug conlbinations, unconventional antidepressants, or ECT has met with only partial success. To this end, we initiated an open-label study utilizing high doses of the FL~O inhibitor, tranylcypromine (TCP] at a range of 90mg to 180mg daily, in seven refractory depressives who had failed to respond to at least three prior treatment regimens. All were outpatients with moderate to severe depression. Ages ranged from 27 to 64 yrs, with a mean• illness duration of 12• yrs. The number of previous treatment failures ranged from 3 to 14 with a mean• of 8• Four of 7 subjects (57%) had a complete response, and one had a partial response. The mean• maximum TCP dose for the entire patient group was 129• daily while the mean dose for the "responders" was l12• daily (range 90mg to 130mg). Response was not a function of severity or duration of present episode, nor was it related to the nllmber Of prior treatment failures. Overall, the side effect profile was favorable, and no "cheese reactions" were encountered. Most autonomic side effects occurred at low to moderate TCP doses and diminished at high doses. For example, when compared to pretreatment values there was a significant decrease in the m e a n sitting systolic (p=0.001) and diastolic (p=O.001) blood pressure and the mean standing systolic (p=0.001) and diastolic (p=0.002) blood pressure at moderate TCP doses (67• Interestingly, there were no difference in blood pressure measurements from pretreatment values at the maximum TCP dosing (129• These observations are of clinical significance and suggest the need for further controlled studies using high doses of tranylcypromine in refractory depression. Depression Research unit, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA. 19104, U.S.A.

CLINICAL, KINETIC AND NEUROCHEMICAL FINDINGS WITH THE NEW ANTIDEPRESSANTS BROFAROMINE AND ROLIPRAM T. Becket, K.P. Lesch, G. KOhne, F.v. Baumgarten, P. Riederer, 6. Laux, M. Struck, P. Black Renewed therapeutic interest in MAO inhibitors has followed the advent of selective compounds. Brofaromine is a reversible, selective MAO-A inhibitor, clinical trials have revealed activating and antidepressant properties. Phosphodiesterase inhibition as shown by rolipram enhances second messenger concentration and has been proposed as a new mode of antidepressant action. Rolipram also stimulates noradrenergic transmission presynaptically by increasing noradrenaline synthesis and release. In an open trial n=13 inpatients with a major depressive episode (4 uni-, 3 bipolar, 6 dysthymic) received brofaromine 50 mg t.i.d, for 28 days. 4 patients were withdrawn due to lack of efficacy and adverse effects (restlessness, insomnia). ANOVA showed significant reduction of HRSD (day 28 vs.O, p .005), but nd~ of Bf-S. No cardiovascular effects were observed. CSF and plasma kinetics, catecholamines and metabolites after single dose of 100 mg brofaremine were determined. Furthermore, n=11 inpatients with a major depressive episode (5 uni-, 1 bipolar, 5 dysthymic) were given rolipram 0,75 mg t.i.d.. Four patients dropped out due to lack of efficacy and adverse effects (insomnia, restlessness, nau? sea). HRSD showed significant improvement (day 28 vs. O, p .05) Loss of clinical effect was observed in 3 patients plasma levels varied little within and between patients, increase in urinary MHPS wore off over time. Inter-drug comparison showed no significant difference regarding efficacy. Psychiatrisohe Universit~tsklinik. F0chsleinstra6e 15. 6700 W0rzburg. FR6

279

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THE SELECTIVE AND REVERSIBLEMAO-INHIBITOR BROFAR~-IINE (CGP 11.305 A) IN COMPARISONTO TRANYLCYPROMIN

BROFAROMINE AND TRA.\~LCYPROMINE IN RESISTANT DEPRESSION W.A. Nolen, J. Haffmans and G.S. Jansen Brofaromine (BROF) is a new reversible MAO-inhibitor with a selective effect on MAO-A. In an ongoing doubleblind study BROF (max. 250 mg daily) was compared with tranylcypromine (TRAN) (~ax. i00 mg daily). Until now 12 patients with a major depression (DSM-III), resistant to cyclic antidepressants (given during at least 4 weeks with "therapeutic" plasma levels), have been studied. Clinical effects: One out of 6 patients responded to BROF (i.e. Hamilton score dropped at least 50%). The mean scores dropped from 27.7 to 21.5. Two out of 6 patients responded to TRAN and l patient showed a marked improvement of almost 50%; mean scores 26.5 and 13.8 respectively. Side effects: BROF produced fewer side effects, especially no orthostatic hypotension which was observed in 3 of the patients treated with TRAN. Effects on sleep: REM latency was significantly increased b y BROE while the number ofiREM periods, to=el REM and early morning awakening decreased. TRKN completely suppressed REM sleep and stage 4. Assessing cycli was hardly or nat possible. Sleeplaten6y increased significantly and the number of shifts decreased. Sleepefficiency (SE) was higher in the BRO~ treated patients compared to ~he TRAN group, however, in both groups a significant reduction of SE in comparison to the SE ~btainedbefore treatment. Plasma levels: Until now no clear relation was found between clinical effect, sleep and plasma levels.

M. ZapletAlek, F. Faltus, K. N~hunek, J. Svestka, J. Molcan, U. Binz, G. Wendt Brofaromine is a new selective and reversible MAOi n h i b i t o r type A as demonstrated in animal and human pharmacological studies. In comparison to tranylcypromine i t showed a much (about 3 times) smaller tyraminepotentiating effect and a much shorter pharmacodynamic h a l f l i f e (1.5 days vs. 2 - 3 weeks). Therefore i t is expected to be better tolerated than the classical MAOIs especially regarding hypertensive crises. The results of an open study and a double-blind dose-finding study indicated that brofaromine displays antidepressant a c t i v i t y with few side effects. Remarkable undesired effects were disturbed sleep, weight loss, and nausea. The double-blind study vs. tranylcypromine is running in 4 centres with the aim to present the data of 80 inpatients with therapy-resistent depression. Like in the dose-finding study a l l patients are on s t r i c t d i e t as usually under treatment with classical MAO-inhibitors. Duration of treatment is 6 weeks. Daily doses are 2 x 50 mg brofaromine resp. 2 x 10 mg tranylcypromine. Responders receive maintenance therapy with unchanged d a i l y dosages, non-responders receive increased doses (150 mg resp. 30 mg b . i , d . ) . Parameters f o r evaluation of efficacy and t o l e r a b i l i t y are H~MD, Bf-S, global judgements, onset of action, RR, heart rate and laboratory parameters. Lelarska Fakult~t d. Univ., Psychiatricka Klinika CS Hradec Kralove

Department of Biological Psychiatry, Psychiatric Centre Bloemendaal, Monsterseweg 93, 2553 RT The ~ague, The Netherlands.

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THE SELECTIVE AND REVERSIBLE MAO-INHIBITOR BROFAROMINE (CGP 11.305 A) IN COMPARISONTO IMIPPJ~MINE E. K. Fischer, I . B~rner, M. Heim, H.-J. MSl]er t R. Obelhack, P. Wun~erlich, U. Binz, G. Wendt

EFFECT ON SH-MONOAMINE L~TAKE IN VITRO OF PLASMA OBTAINED FROM HEALTHY MALE VOLUNTEERS TREATED WITH ONE OR MORE DOSES OF THE PUTATIVE ANTIDEPRESSANT SIBUTRAMINE HCL G. P. Luscombe, N. A. Slater, R. D. Wynne, M. B. Lyons and ~. R. Buckett Sfbutramine HCI (BTS 54 524) is a monoamine uptake inhibitor with a pharmacological profile in rodents indicative of potential antidepressant activity (W. R. Buckett et el, Br. J. Pharmac. 90, 94P & 26]P, 1987). We have studied the ability of plasma, obtained from volunteers at regular intervals after one or more doses of sibutramine HCl, to inhibit the in vitro uptake of 3H-noradrenalins (NA) by rat cortical synaptosomes, of 3H-dopamine (DA) by rat striatal synaptosomes, and of 3H-5-hydroxytr)~tamine (5HT) by human platelets from untreated volunteers (R. D. Wynne et el, Acta Pharmacnl. Toxicol. Suppl. 5, 640, ]986). Sibutramine HCI inhibited the uptake of 3H-monoamines in vitro (NA > 5HT > DA) after administration of one or more doses to volunteers. The inhibitory effect was dose-dependent (5-20 mg/day) and increased with the duration of treatment (]4 days), reaching a plateau of approximately 50% inhibition of ~H-NA uptake and 20-30% inhibition of 3H-5NT uptake after sibutramine HCI (20 mg/day). Higher plateaux of SH-NA (60%) and 3H-SHT (40%) uptake inhibition were attained more rapidly by twice daily sibutramine BCI (15 mg). Plasma obtained after either single (50 mg) or repeated (15 mg twice daily) doses of sibutramine HCl had a weak inhibitory effect on mH-DA uptake in vitro. The activity of sihutramine HCI as a monoamine uptake inhibitor in man is similar to its relative activity as a monoamine uptake inhibitor in rodents, and further supports the preclini~al evidence that sibutramine HCI will have an antidepressant effect. Research Department, The Boots Company PLC, Nottingham, NG2 3AA, United Kingdom.

Brofaromine is a new selective and reversible MAO-inhibitor type A as demonstrated in animal and human pharmacological studies. In comparison to tranylcypromine i t showed a much (about 3 times) smaller tyramine-potent i a t i n g effect and a much shorter pharmacodynamic h a l f l i f e [1.5 days vs 2 - 3 weeks). Therefore i t was expected to be better tolerated than the classical MAOIs especially regarding hypertensive crises. In human pharmacological studies brofaromine was administered in combination with tyramine-rich cheese but there was no change in RR and heart rate. The results of a double-blind dose-finding study with in-patients on s t r i c t d i e t on account of tranylcypromine in the control group indicated that brofaromine displays antidepressant a c t i v i t y with good t o l e r a b i l i t y . In an open study, patients receive food with r e l a t i v e l y high tyramine concentration 2 times a week with repeated measurement of RR and heart rate a f t e r the meal. Until now there was no relevant change in circulator), parameters. The double-blind study vs. imipramine is running in 6 centres without d i e t . The aim of the t r i a l is to present the data to 100 in-patients with a f f e c t i v e disorders. Parameters f o r evaluation of efficacy and t o l e r a b i l i t y are HAMD, Bf-S, global judgements, onset of action, RR, heart rate and laboratory parameters. Until now we have got the data of 66 patients. Dr. yon Ehrenwall'sche K l i n i k , 5483 Bad Neuenahr-Ahrweile~

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31.02.56 S-ADENOSYL DEPRESSION: DATA

METHIONINE IN A REVIEW OF THE

3.M. DAVIS, P.G. 3ANICAK, J.F, ~IPINSKI, etal. We report a meta-analysls of ii controlled trials comparing S-adenosyl methionine (SAMe) to either placebo or tricyclie antidepressants (TCA) for the treatment of depression. Using the Mantel-Haenszel, data combined from a number of research centers indicated SAMe's clJncial superiority over placebo: when 37 SAble patients were compared to 25 placebo patients, the Chi Square o~ 30.0 was signilicant at the /4 X 10level. A second anMysis showed a slight superiority for SAMe over TCA's: SAMe (n=i2O) compared to TCA's (n= 112) yielded a Chi Square of 3.93 (p .05). In addition, there were very few side effects with SAMe as compared to TCA's. We also report our preliminary data comparing SAMe to placebo or lmipramine (IMI) under double blind conditions for a two week t r i a l 7 patients received SAMe, /4 received IMI and 5 received placebo. Thus far, SAMe apprears comparable to IMt and signficantly superior to placebo (t = 3.#I, df = I0, p less than .007) based on percent improvement in the HRSD. An ANCOVA using baseline scores as covariates yielded a similar result.

PLASMA LEVELS OF DESMETHYL METABOLITES IN PATIENTS WITH AFFECTIVE DISORDERS TREATED WITH CHLORIMZPRAMINE AND IT~ POSSIBLE CORRELATIONS WITH CLINICAL PARA~TEES AND WITH THE TYPE OF EFFICACY OF TREATMENT M. NARDINI, G.P. SGARAGLI, R. NINCI, L. DELLA CORTE, N. BELARDINELLI, G. BONELLI, M. VALOTI, S. NICOLAU Plasma levels of desmethyl metabolites has been measured in 30 patients with Affective Disorders (DSM III) chronically medicatedwith chlorimipramine. The aim of our work was to verify and suggest an explanation of the observation that a proportion of depressed pa tients do not respond to tricielyc drugs. Plasma levels of metabolites has been measured by a GLC assay method using a NP detector in order to define the N-demethylation pathway (N-monodesmethyl and N-didesmethy] metabolites of chloroimipramine). Our results show that the plasma levels of desmethyl metabolites are higher than those of the parent drug and also correlated with the therapeutic effects. The data observed show that in our case study there is a variability in the capacity to N-desmethylate the chloroimipramine and this fact is suggestive of a polymorphism of this metabolic reaction. A correlation,not significant, is found between N-didesmethyl metabolites' level and the responsivity to the treatment. Further investigations need to investigate the possibility that the clinical response to the treatment with tricyclic drugs depends on the capacity to N-didesmethylate it. References Della Corte L. et al.: Br. J. Psychiatry, 134, 390, 1979 Sgaragli G.P. et al.: Psychopharmacol. Bull., 20,165, 1984 Cattedra di Clinics Psichiatrica e Centro [nterdipartimentale dei Farmaci Psicotropi - Universit~ di Siena (Italy)

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GBR 12909: A SELECTIVE DOPAMINE UPTAKE INHIBITOR AND POTENTIAL ANTIDEPRESSANT. *Erik B. Nielsen, *Peter H. Andersen, **M. Geoffroy and **O.J. Rafaelsen § GBR 12909 is a phenylsubstituted piperazine derivative which selectively blocks dopamine (DA) uptake (IC50=l nM; c o r r e s p o n d i n g values for NE and 5-HT uptake are 440 and 1 7 0 nM, respectively). Ex vivo, in rats, GBR 12909 inhibited DA uptake with an ED50 of 26 m g / k g (ip, 2 h). In b e h a v i o r a l e x p e r i m e n t s , G B R 1 2 9 0 9 caused locomotor activation and, at higher doses, stereotyped behavior. However, the drug failed to substitute for the cueing properties of d - a m p h e t a m i n e (AMPH) in a n i m a l s t r a i n e d to d i s c r i m i n a t e A M P H (I m g / k g ) f r o m s a l i n e . O n t h e converse, AMPH substituted for GBR 12909 in animals trained to d i s c r i m i n a t e G B R 1 2 9 0 9 (i0 mg/kg) from saline. The GBR 12909 cue was blocked by raclopride (D-2 antagonist) and by SCH 23390 (D-I a n t a g o n i s t ) i n d i c a t i n g D A e r g i c m e d i a t i o n of t h i s cue. Furthermore, GBR 12909 was active in a learned helplessness paradigm when given in l o w d o s e s (2 x 3 mg/kg) for 5 days, an effect which may predict antidepressant action. Thus, the behavioral consequences of DA uptake inhibition may be ref l e c t e d in m o t o r a c t i v a t i o n without concurrent stimulant euphoria. Such action may be benefic i a l i n t h e t r e a t m e n t of d e p r e s s i o n . *NOVO Industri A/S, Departments of CNS and Biochemical Pharmacology, DK-2880 Bagsvaerd, Denmark, **Psychochemistry Institute, Rigshospitalet, DK-2100 Copenhagen, Denmark. * Deceased.

MODE OF ACTION AND DOSE FINDING OF SERTRALINE, A NEW ANTIDEPRESSANT BASED ON CEEG-BRAIN MAPPING TECHNOLOGY T u r a n M. Itil*, S u k d e b Mukherjee*, Gulay Dayican**, Gerald Shaw**, and K u r t Z. Itil* Sertraline hydrochloride is a structurally novel compound, s u s p e c t e d of h a v i n g a n t i d e p r e s s a n t potential due to its h i g h l y selective and p o t e n t 5HT u p t a k e blocking properties. Doses wherein 5HT uptake blocking was d e m o n s t r a t e d i n - v i t r o h a v e also b e e n s h o w n not to elicit psychostimulant and/or ~mfieholiner gic a c t i v i t y in animals. This Quantitative Pharmaco-EEG (QPEEG) s t u d y , i n c o r p o r a t i n g c o m p u t e r analyzed E E Q s ( C E E G ) , was conducted with healthy m e n to investigate the Central N e r v o u s System ( C N S ) effects of single doses of 50, 100, 150 and 200rag sertraline in humans. The study was double-blind, single-dose crossover in design and included both placebo and an active d r u g (50rag amitriptyline) as controls. The objectives of the Q P E E G study were to establish the lowest tolerable C N S - effective single dose, determine the m o d e of action and predict the therapeutic ~ n d o w of sertraline. T h e results of this study indicated that sertra]ine has both time and dose-related C N S effects. Comparison of the C E E G changes IIZI Research Center's C E E G D r u g Data Base indieated that sertra]ine has a significant positive correlation with Data Base antidepressants, with 100rag having the highest correlation coefficients. T h e optimum CNS-effective single dose of sertraline wb/ch can be differentiated from placebo at the level of statistical significance was found to be 150mg. It is predicted that this w~ll also be the most

effective therapeutic antidepressant dose. Brain .~lapping of s e r t r a l i n e is similar to o t h e r 511T-blocking antidepressants. Multicenter clinical t r i a l s seem to confirm the CEEG p r e d i c t i o n . *New York Medical College, Div. of Biol. P s y c h i a t r y , !50 White Plains Road, T a r r y t o w n , NY 10591 (USA); **Pfizer, I n c . , G r o t o n , CT 06340 (USA)

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CLOMIPRAMINE AS A SEROTONER~IC PROBE by J.J. L6pez-Ibor Jr., A. Gonz~lez-Pinto and J. Saiz-Ruiz

O f the tricyclic antidepressants clomipramine (CMI)

shows the highest blocking activity on the

reuptake of serotonin, which is purer when it has not yet been metabolized into demethyl-clomipramine. For this reason CMI can be used as a serotonergic probe when administered intravenously, when its effects are measured shortly after its administration and when the concentrations of CMI and its metabolite are measured. The technique consists of the administration of 12.5 mg of CMI in a hundred cc saline solution during 15 minu:es and measuring the prolactin, the cortisol and the growth hormone concentrations basal (30 minutes prior and at the moment of administration)

RITANSERIN IN D Y S T H Y M I C DISORDERS (DSM DOUBLE BLIND STUDY ~ERSUS AMITRIPTILINE G__ t. M e c o r S. ~ i n l , L. M a r i a n i , V. Pasqualoni.

III):

A

Ritanserin is a new selective seroronin 2 receptors antagonist In previous studies Ritanserin showed clinical efficacy in anxiety, tension states and dysthymic disorders (DSM I I I ) . Ritanserin (iO- 20 mg ) and Amitriptiline (25-50) were administered to 30 p a t i e n t s s u f f e r i n g from dysthymic disorders in a double blind study for 8 weeks. The results obtained showed comparable improvement of a n x i e t y (Hamilton Rating Scale for Anxiety, S T A Y Xl) a n d d e p r e s s i o n (Hamilton Rating Scale for Depression). The antidepressant action of Ritanserin was more rapid than amitriptiline; in fact at second week Ritanserin was more efficacious in i statistically significant way ( Mann-Whitney U Test p
and post CMI every 30

minutes for three hours. We have applied this technique to 30 patients suffering from depression {10 major depressions with melancholia, depressions).

10 major depressions a n d 1 0

disthymic

Major depressions in comparison to

disthymias show a blunted prolactin response to the CMI stimulus, suggesting a low activity of the serotonergic system in those patients. Major depressions without melancholia fall in between.

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SLEEP STUDY OF FLUOXETINE (F) AND AMITRYPTILINE (A) IN THE TREATMENT OF MA3OR DEPRESSIVE DISORDERS MDD.

FLUOXETINE (F) AND AMITRYPTILINE (A) : COMPAP,-~,9 TIVE EFF1CACY IN THE TREATMENT OF MA3OR DEPRESSIVE DISORDER (MDD).

M. Kerkhofs, P. Linkowski? C. Rielaert, M. Czarka, 3. Mendlewicz. Thirty-lout patients suffering from MDD (RDC) were enrolled randomly in this double blind parallel study. The study was divided into two periods : a placebo period of I0 days and an active t r e a t m e n t period of ~2 days. Admission procedure included sleep EEG on three consecutive nights (two a c c o m o d a t i o n nights and a third recording night). The termination of the study included sleep EEG (one recording night). Sleep data was analysed using a one way anova with post-hoc Least Significant D i f f e r e n c e tests. The findings c a n be summarized as follows Overall F A Sleep efficiency NS ~,IS I~S Number of Stage p-0.01 p-0.01~" NS Number of awakenings NS p-0.0 I'~ NS Sleep Architecture Awake p-0.0t+ NS NS Stage 1 NS p-O.O04 "~ NS Stage 2 p<0.001 p-0.02 ~" p-0.002~ Stage ~ p<0.001 NS p-0.0 I~, Slow Wave p-0.006 p-0.03~ NS Rem Sleep p-0.O01 p-0.0 i~, I>-0.03~' % S.W.S. NS NS p-O.O3P~ Rem Latency p-0.02 NS p-0.02~ Rem/Non R Ratio p<0.O01 p-0.002~ p-0.01,~ The Sleep results will be discussed in relation to antidepressant response to Fluoxetine and AmitryptiIine. NS : non significant - ~ S i g n i f i c a n t Increase - ~/Significant Decrease.

Free University of Brussels - Erasme Hospital - Dept. of Psychiatry_. route de Lennik $0g, I070 Brussels. Belgium

282

C. Rielaert, P. Linkowski, M. Czarka. M. Kerkhofs1 3. Mendiewicz. ~nirty-four patients suffering from MDD (I~DC) were enrolled randomly in this double-blind parallel study. Logistic regression analysis was used to examine the e f f e ~ s of treatment) gender and age groups on the following parameters : clinical global severity (CGS), patients global impression scale and Covi scale. The scores at visit 2 (baseline) and last visit (endpoint) were In~uded in the analysis. No significant differences in the therapeutic response between F and A were observed, gender and age being controlled. Analysis of variance (.&nova) was performed on baseline, endpoint and endpoint minus baseline differences for Hamilton Depression (HDFLS~ and Montgomery-Asberg (MARDS) scores. No significant e~fect was shown for these parameters in the two groups Further comparison by paired t-test was computed for endpoint to baseline differences only, within each treatsent group and within each sex group. As expected there was a significant decrease in both the HDRS and MADRS for the whole population (p
31.02.64 BRAIN INDICATORS OF THE EFFECTS OF ~AFROTiLINE M. Ih~i~ica~0 Horta t J. Barahona da F0nseca~ Silvia 0uakinin and J. Sim~es da Fonseca Al~hou~h Event Related Potentials of the Brain have been %ridely used as indicators os effects induced by psycho pharmaco, those changes they u~dergo have not yet been taken into account as far as their status as ep!s~emlc correlates of psychological processes is concerned. We have chosen as Brain indicators os the effects of Maprotiiine in acute oral administration both in normal volunteers and in patients suffering From Disthymic Dosorder, the Power Spectrum 0s visual ERPs evoked by distinct but interrelated visual patterns. An interpretation os the effects of M~protiline is pro posed in terms os (a) changes in visual pattern discri ruination; (b) form/tion of classes of equivalence; (c~ coherence values; (d) Reaction Times, establishing a connection between those changes and the characteristics of the Cognitive Set and Mode, is attempted as signi.micant differences were found, concernin s those tour types 0s indicators. Dept. of Medical Psycho~gy, Faculty of Medicine o9 Lisbon, Hospital Sta. Maria, 1600 Lisboa, Portugal.

31.02.65 ~"qIE EFFECTS ON MEMORY OF ANTXDEPR~SSANTS WITH DIFFERING ANTICHOLINERGIC AF~ SEDATIVE PROFILES H. V. Curran, M. Q. Sakulsripon~ and M. H.Lader The effects on memory and psychomotor functions of antidepressants with varyin E sedative and anticholinergic properties were assessed in two studies with healthy volunteers. In the first independent ~roup study, 90 subjects were given a single dose of amitriptyline (37.5, 75 mE) , ~razodone (i00, 200 mg), viloxazine (i00, 200 mg), pz'otriptyline (I0, 20 m E) or placebo. Only the more sedative antidepressants (amitriptyline and trazodone) impaired performance and these compounds had globi~L1 effects on tests of attention, motor speed and primary memory. Although the amitriptyline and trazodone impaired episodic memory, the effect of smitrip~line was significantly greater and this may reflect specific anticholinsrgic action over and above global sedative effects. Tolerance to the effects of amitriptylins and trazodone was assessed in a second study administering these drugs and placebo over a two-'~eek treatment period. Institute of Psychiatry, De Crespigny Park, London SE5 8AF, U.K.

31.02.66

31.02.67

FLUVOXAMINE IN DEPRESSED I N - AND OUTPATIENTS: DIFFERENTIAL EFFECTS, PLASMA LEVELS, RESPONSE PREDICTION M.#eZwaan, P.Hofmann, G.Sch6nbeck, G.KoiniQ, H.Aschauer, P.Parzer. F l u v o x a m i n e (F) is a new antidepressive drug with selective a c t i v i t y in i n h i b i t i n g s e r o t o n i n u p t a k e and is t h e r e f o r e p o s s i b I y d i f f e r e n t f r o m traditional t r i c y c l i c a n t i d e p r e s s a n t s (TCA) in clinical a p p l i c a t i o n . In our investigation we treated depressives, mostly refractory to TCA, with F in t w o settings: i n p a t i e n t c a r e (n=10) and o u t p a t i e n t care (n=23). S t u d y d u r a t i o n was 4 weeks r e s p e c t i v e l y 6 weeks. A f t e r medical c h e c k up, p s y c h i a t r i c d i a g n o s t i c was p e r f o r m e d a c c o r ding to DSM III. F plasma levels, depression r a t i n g s (HRS-D, CGI, l i n e t e s t s ) and side e f f e c t ratings w e r e p e r f o r m e d at r e g u l a r intervals. All patients were s u b m i t t e d to a T R H - T e s t at a d m i s sion a n d at the end of the study. A special c h e c k l i s t of b e h a v i o r or functions putatively related to 5 HT brain a c t i v i t y was f i l l e d o u t (aggression, a p p e t i t e , s e x u a l i t y etc.). The general antidepressive effect was satisfactory in both t r e a t m e n t groups with prominent anxiety reduction. Furthermore the f o l l o w i n g possibly s p e c i f i c e f f e c t s of 5 HT could be found: general a p p e t i t e r e d u c t i o n , significant weight l o s s , no n e g a t i v e i n f l u e n c e on s e x u a l i t y , no increase o f aggressive t r a i t s , no o r t h o s t a t i c dysfunction. Adverse effects were usually mild (most c o m m o n l y g a s t r o i n t e s t i n a l ) and of short duration. In line w i t h p r e v i o u s f i n d i n g s b l u n t e d TSH r e s p o n s e at a d m i s s i o n was r e l a t e d to therap e u t i c response. F plasma levels s h o w e d great v a r i a b i l i t y in relat ion to F dosage; no simple r e l a t i o n could be found between F plasma l e v e l s and c l i n i c a l outcome or s i d e e f f e c t s P s y c h i a t r i s c h e U n i v e r s i t ~ t s k l i n i k Wien. WAhringer Gbrtel 18-20,A-IO90 Wien.

A T T E M P T OF A S S E S S T H E PREDICTIVE VALIDITY OF LABORATORY PERFORMANCE TESTS FROM THE R E S U L T S OF A S U B C H R O N I C S T U D Y OF N E W A N D OLD ANTIDEPRESSANTS (I.E. LEVOPROTILINE AND DOXEPIN, RESPECTIVELY) H. Robbe, E. Schoenmakers and J.F. O'Hanlon In so far as is k n o w n this presentation describes the first study where the attempt was made to correlate drug effects on subjects' performance in a battery of "typical" laboratory tests with those objectively measured in a standardized actual driving test. The purpose was not only to more fully assess the psychomotor effects of an investigational drug (]evoprotiline 25 and 50 m g t.i.d.) versus those of an active drug control (doxepin 25 mE, t.i.d.) and placebo, it was also to determine the validity of laboratory performance measures as predictors of drug effects on

drixdng. Drugs and placebo were administered to 16 healthy male volunteers according to a subchronic (8 day), 4-way, double-blind cross-over design. Performance was assessed on days I, 4 and 8 in each subchronic series in the laboratory and on the first and last days using the driving test. The battery tests induced critical flicker fusion frequency, continuous recall, critical instability tracking, divided attention (subcritical tracking and reaction time to peripheral stimuli), memory search and choice reaction time and sustained attention or %dgilance. The driving test measured road tracking precision (standard deviation of the vehicle's lateral position) during continuous operation over a I00 k m primary highway circuit. Preliminary results show differential d r u g effects on driving performance and some of the laboratory tests. The results will be fully described with respect to the antidepressants' effects and also with regard to the correlations among different measures of these effects. Institute for Drugs, Safety and Behavior, University of Limburg, P.O. Box 616, 6200 M D Maastricht, The Netherlands

283

31.02.68

31.02.69

gibcSemical, ~leurophysiological and Behavioral Effects of Wy-45,233 and Other I d e n t i f i e d Metabolites of the Antidepressant Venlafexine E.' A? Muth, J. A. Moyer, J. T. Haskins, and T. H. Andree Seven metabolites of venlafexine,, i d e n t i f i e d in several species, were examined for CNS pharmacological a c t i v i t y in rodents. The O-des~ethyl compound Wy-45,233, which is {~e major metabolite in man, had the greatest prec l i n i c a l a c t i v i t y . This metabolite exhibited an a n t i depressant p r o f i l e (monoamine uptake blockade, reversal of reserpine hypothermia, induction of pineal ~adrenergic subsensitivity) comparable to the parent drug, venlafexine. This compound also i n h i b i t e d serotonergic and noradrenergic f i r i n g rates l i k e the parent compound, but with less potency. The cyclohexyl ring-hydroxylated metabolite Wy-47,877 and the N-desmethyl m e t a b o l i t e Wy-45,494 were also active in reserpine hypothermia, but Wy-45,494 was a weaker i n h i b i t o r Of serotonin uptake and both metabolites were weaker i n h i b i t o r s of norepinephrine uptake than Wy-45,233. None of the seven m e t a b o l i t e s tested exhibited s i g n i f i c a n t binding at dopamine-2, muscarinic cholinergic, ~-l-adrenergic, histamine-i, or opiate (u) receptors. These results suggest that Wy-45,233 the O-desmethyl metabolite of venlafexine, is an active metabolite which retains the benign side-effect p r o f i l e of venlafexine. Wyeth-Ayerst Research, CN 8000, Princeton, NJ 08543 USA

PHARMACOKINETICS

31.02.70 ~ (IF FOOD C~ ~}]E RHIATIVE BIOAVAIIABIIATY CF ~ I E s A NEW ~ C~mASE-A (MAD-A) n~XBI~rm M.-P. Schoerlin, M. M~ye_rso~, B. }{~=vp_Isand H. ~q~iers MDCI~ (RD 11-1163) is an effective anti-depressant drug which is a rapidly acting, reversible inhibitor of the MAO-A isozyme. ~be drug ~ a relatively large systemic cleaz-ance (ca. 40 L/h) and trdergoes suh~tmutial first p~ss hepatic metabolism. Since food has been shown to influence the oral bioavailabih'ty of drugs hmdnghigh i'mtmtic e x t r a c t i a n ratios, ,,,e emmuined the influs~-e of ameal cn m~lohemide absorption. Twelve healthy male subjects (23-47 yrs) ingested a single oral 100-u~ tablet of moclcb~uide on 2 occasicns. On one study day, the drug was ingested after an overnight fast and food wss withheld for 4 h ~ostdosing. On the other study day, the drug ",.as ingested a f t e r an ove_n~gbt f~-t, b~t 30 rain after eating a standard meal (20% protein, 35% fat, m~d 45% c a ~ t e ) . ~fat meals w~re in~-tsd 4 and i0 h after dosing. Blood s~ples were obtained for up to 12 h and plasma ccrmawtratic*ts of moclobemide and metaholites ~ r e d~.ermined by an HPLC met_hod. ~ue data a-~lyzed by n a n ~ t a l methods and tests of stetistical sipnif~ ~ ~rf~ using Student's p~ired t-test (a = 0.05 cgnsidelx~ signlficmnt). ~ere %~re no significant differences in the mxir~n ~ a s m ox~atr~tion (C~x) ~ d the time of its ~ (Trr~ ) wh~u c c ~ fasting (Coax, 753 rig/el; ~ x , 0.71 h) and n~n-fasting c~diticns (C=sx. 643 rig/el; T~mx, 1.14 h). ~ere ~ r e no significant differ~-~es in total areas l~der the c~-~z~tzatian-time curve (fasting, 1676 rig-h/el; ten-fasting, 1752 ng.h/ml) or in appprent oral c l ~ (fasting, 64.1 L/h; r~n-fasting, 62.9 L/h). q~e r~lative oral hioavailability of moclolmm/de (food/no food) ~ s i.i0 (+- 18% CV). [[here was a carmiste~ ~ in ~ in the ~ of food (L77 h) which, a l t : ' - n , ~ srsll, ~ s signific~Ycly different fram the non-fasting ccrdition (1.60 h). There was no si~ificant diff~ance in AUCs ~ the v-~lues w~re corrected for t1~, b~t the ratio (food/no food) decreased to 0.98 (-+ 14% CV). We cc~cl~rle that food (at least the C~mlpositicn of the meal used in this study) has no influ~-,ce on the rate or campleteness of the gastrointestinal absorption Of noclobemide following a single oral 100-rag dose. Depsrtm~r~ of Clinical l~=~1~cology, F. Hoff.~=~-La Roche & Co. Ltd., Gr~iz~_her~ 124, C~-4002 Basel, Switzerland

284

AND METABOLISM OF LEVOPROTILINE

IN

HEALTHY VOLUNTEERS W. Dieterle, R. Ackermann and G. Kaiser The new antidepressant levoprotiline-HCl is the R-enantiomer of racemic oxaprotiline.HCl. Its pharmacokinetic and metabolic characteristics were evaluated after single or multiple dosing in human subjects. After a single 75-mg p.o. dose (N=6), levoprotiline was completely absorbed, Cma x in blood being reached at 4 h (median). The mean elimination half-life was 21 h. The drug was mainly excreted in conjugated form by the kidney. Urinary excretion (0-96 h) of the sum of free plus conjugated levoprotiline amounted to 69% of dose on an average. After repeated daily dosing with 75 mg (N=6) for 15 days, the kinetics of levoprotiline did not change. The accumulation ratio for the blood levels of levoprotiline was 1.9, which corresponds to a 90% increase of AUC during a dosing interval of 24 h at steadystate when compared to the first 24-h interval. The concentration-time profile after the first dose was described by a sum of 3 exponential functions (=Y). Using Y, the steady-state concentrations during multiple dosins were simulated. Experimental trough levels on day 5, 8, 12 and 15 as well as the concentrations after the last dose were very well comparable to the simulated curve. Levoprotiline was extensively metabolized. Both in blood and urine, the direct O-glucuronide was the predominant metabolite. Thus, levoprotiline may possess considerable advantages over the traditional antidepressants: It can be anticipated that the disposition and kinetics are not significantly influenced by coadministration of enzyme inhibitors or inducers, old age, liver disease and genetic factors. Research and Development, Pharmacokinetics Division, CIBA-GEIGY Ltd., Basle (Switzerland)

31.02.71 ANTIDEPRESSANTS GI~N REPEATEDLY INCREASES TEE BEHAVIOURAL EFFECTS OF KETHOXAMINE AN ~ - A D R E N O C E P T O R AGONIgT K ~edzonv. Z. Ro~oz. S. Skuza and J.MaJ Ye found previously that repeated treatment with antidepressant drugs (~-D) increases the bebavioural affects mediated by ~ - a d r e n o c e p t o r s (e.g. clonidine Induced aggressiveness). In the present paper the influence of AD given repeatedly on the behavloural effects of methoxamlne, an ~ - a d r e n o c e p t o r a~onist, was studied. Following AD were used: imlpramine (noradrenaline and serotonin uptake inhibitor), (+)ozaprotiline (noradrenaline uptake inhibitor), ci~alopram (serotonln uptake inhibitor), mlanserin (without effects on amine uptake). Male u rats (150-2508 ) were used. Methoxamine (25 and 50 ~g) injected into the lateral brain ventricle increased the exploratory activity. The exploratory activity was measured in the open field test (total time of walking, number of sector crossings, rearing + peeping).AD give~ repeatedly (10 m~/kg p.o. twice daily for 14 days) but not acutely enhanced the effects induced by methoxamine (all parameters mentioned above). Acute or repeated treatment with AD did not stimulate the exploratory activity of control rats. The present results support our earlier hypothesis that AD (showing different pharmacological profiles) given repeatedly increase the responses to ~1adrenoceptor agonlst. institute of Pharmacology, Polish Academy 31-345 Krakow Smetna street 12, Poland

of

Sciences,

3102 73

3102 72 ANTIDEPRESSANT DRUGS GIVEN REPEATEDLY THEOCI-ADRENOCEPTOR AGONIST AFFINITY

INCREASE

V. Klimek and J. Ma~ Our previous findings indicated that antidepressant drugs (AD) given repeatedly increase the behavioural effects of phenylephrine, a n ~ 1 - a d renoceptor agonist. In this paper the competition of phenylephrine for 3H-prazosin (an O61-adrenoceptor antagonist) binding sites in the brain of rats treated repeatedly with AD was studied. Male Wistar rats {160-200 g) were used. AD showing different pharmacological profiles in an acute experiment (imipramine, amitriptyline, (+)-oxaprotiline, citalopram, mianserin) were given at a dose of 10 mg/kg ~.o., twice daily for 14 days. The binding of ~H-prazosin was measured in the cortex, thalamus and hippocampus. The results indicate that the repeated treatment with AD used enhances the ability of phenylephrine to inhibit the binding of 3H-prazosin to ~1-adrenoceptors (K~ values were decreased) in the brain regions ss here. The present data suggest that the increase in the affinity o f ~ 1 - a d r e n o c e p t o r s for their agonist is responsible for the f u n c t i o n a l ~ 1 - a d r e n ergic hypersensitivity found after the repeated treatment with different AD. Institute of Pharmacology, Polish Academy of Sciences, Sm~tna Street 12, 31-343 Krak6w, Poland

PARTICIPATION OF~R-ADRENOCEPTORSAND PROTEIN KINASE C IN THE RELEASEOF NORADRENALINEFROMCAT CEREBRALARTERIES M.R. de Sagarra~ G. Balfag6n, S. Arribas, M.T. Barr6s, M.i. Capil~a, and J. Marin F~eld electrical stimulation (2 Hz, 0.3 msec) e l i c i t e d an increase of the t r i t i u m e f f l u x over the basal level from cat cerebral arteries preloaded with t r i t i a t e d noradrenaline (NA). This e f f l u x was reduced by clonidine (I HM) or B-HT 920 (I pM),~p-adrenoceptor agonists, and unaffected by yohimbine (i pM), an~p-adrenoceptor antagonist. The action of clonidine was b?ocked by yohimbine (I #M). Phorbol 12-myristate 13-acetate (PMA) (3 pM), an activator of protein kinase C (PKC), potentiated t r i t i u m release e l i c i t e d by electrical stimulation without modification of spontaneous secretion, whereas 4K-phorbol 12,13 didecanoate (3 #M), an inactive compound, had no effect. Tritium release evoked by tyramine was not modified by PMA. In the presence of PMA, the electrically-evoked tritium secretion was reduced by clonidine (I pM) or by B-HT 920 (0.1 pH). The presence of clonidine, B-HT 920 or yohimbine reduced the action of PMA. The f a c i l i t a t o r y effect of PMA was not increased by the Ca2+ ionophore A23187 (5 #M). These results suggest: (I) The existence of presynaptic autoinhibitory ~2-adrenoceptors in these arteries. (2) The participation of PKC of perivascular adrenergic nerve endings in the exocytotic release of noradrenaline. (3) The p o s s i b i l i t y that P~ acts p a r t i a l l y by interfering with prejunctional autoinhibitory~-adrenoceptors. (4) The effect of PMA is not related wYth Ca2+ i n f l u x produced by A23187. Supported by FISSS, CAYCYT84/327 and CSIC DI/585 Departamento de Farmacolog{a y Fisiolog~a, and Departamento de Bioquimica, Facultad de Medicina, Universidad Aut6noma, 28029 Madrid, Spain

31.02.74

31.02.75

EFFECTS OF CHRONICAND ACUTE TREATMENTWITH DESIPRAMINE AND COCAINEON THE MODULATIONOF NORADRENALINERELEASE FROMCAT CEREBRALARTERIES BY PRESYNAPTIC~-ADRENOCEPTORS S. Arribas, G. Balfag6n, M.R. de Sagarra, M.T. BarrOs, M.I. Capilla, and J / M a r i n Cat cerebral[ arteries preincubated with t r i t i a t e d noradrenaline (NA) increased the t r i t i u m e f f l u x over the basal level upon f i e l d e l e c t r i c a l stimulation (2 Hz, 0.3 msec). The ~-adrenoceptor agonists, clonidine (I HM), NA (lpM) and B-HT 920 (1 pM), reduced this e f f l u x , whereas the ~2-adrenoceptor antagonist yohimbine (I NM) had no effect B-HT 920 was more powerful than the other two agonists in reducing tritium efflux. Methoxamine (1 ~M), an W1-agonist, did not affect the action of clonidine, but'the effect of the l a t e r was blocked by yohimbine. Methoxamine (1 pM) did not s i g n i f i c a n t l y modify the t r i t i u m e f f l u x e l i c i t e d by the stimulation. Yohimbine (I ~M) had no effect, but t r i t i u m e f f l u x was reduced by the drug at 5 pM. Phentolamine ( i pM), and ~-adrenoceptor antagonist, as well as prazosin, anKl-antagonist, plus yohimbine, i~ creased the tritium release. The daily treatment with desipramine (I0 mg/kg i . p . ) or cocaine (10 mg/kg i . p . ) during 12 days (chronic administration) blocked t o t a l l y or p a r t i a l l y the i n h i b i t o r y action of clonidine upon the stimulation-evoked t r i t i u m release, whereas the acute (2 days) treatment did not produce any change. These results suggest: (1) The existence of presynaptic d2-adrenoceptors in these arteries, which modulate the NA release from adrenergic nerve endings. (2) The chronic treatment with neuronal uptake i n h i b i t o r s , such as desipramine (a t r i c y c l i c antidepressant) or cocaine induces a loss of s e n s i t i v i t y of 2-receptors, which f a c i l itates the NA release. The time course of this effect, in the case of the antidepressant, seems to be related with the onset of c l i n i c a l a c t i v i t y of this drug. Supported by FISSS Departamento de FarmacologTa y Fisiologfa and Departamento de BioquTmica, Facultad de Medicina, Universidad Aut6noma, 28029 Madrid, Spain

NEUROPHYSIOLOGIC.J~L EVIDENCE FOR ,~M~TIDEPRES~NT - INDUCED SUPERSENSITIVITY

OF HIPPOGAHPAL

OC I-

ADRENERGIC RECEPTORS M. BIZ&AK The effect of prolonged treatment with antidepressant drugs on neuronal responsiveness to the ~ - a d r e n e r g i c receptor agonist phenylephfine was studied in tne rat hippocampal slice

preparation. In s l i c e s p r e p a r e d from c o n t r o l a n i m a l s ( n o n t r e a t e d or s a l i n e - t r e a t e d rats) phenylephrine ( 0 . 2 and 20 pM) evoked a d o s e - d e p e n d e n t d e c r e a se i n the spontaneous f i r i n g r a t e o f CA1 l a y e r n e u r o n s . An i n h i b i t o r y r e a c t i o n was a l s o i n d u ced by metoxamine ( 1 0 ~M)o The e f f e c t s o f phen y l e p h r i n e and metoxamine were b l o c k e d by p r a z o s i n CO.Ol pM). P r o l o n g e d a d m i n i s t r a t i o n of i m i p r a m i n e , m i a n s e rin and ( + ) - o x a p r o t i l i n e (10 mg/kg p. Oo, twice d a i l y f o r 14 days) r e s u l t e d i n a s i g n i f i c a n t enhancement of the p h e n y l e p h r i n e ( 0 . 2 pM) induced inhibition of neuronal spontaneous d i s c h a r g e s i n s l i c e s p r e p a r e d 48 h a f t e r the l a s t dose of the d r u g . Only a s l i g h t p o t e n t i a t i o n o f the p h e n y l e p h r i n e - e v o k e d r e a c t i o n was o b s e r v e d i n the group t r e a t e d w i t h ( - ) - o x a p r o tiline.

The above d a t a s u p p o r t the h y p o t h e s i s t h a t prolonged treatment with antidepressants enhances the c e n t r a l o~-adrenoceptor function. P o l i s h Academy of S c i e n c e s , I n s t . P h a r m a c o l o g y , 12 Smg~na s t . , Krakaw, P o l a n d

285

31.02.76 FLUOXETIREVERSUS CLOMIPRAMINEIN ENDOGENOUSDEPRESSION AND MELANCHOLIA-MULT!CiNTRIC STUDY P. Moron, G, Besancon, G, Carrier, B. Cordier, A. Desiova~ni,R. Dufour, M. Ferreri, D. Ginestet, L. Leger, J. Pellet, E. Per~vier, L. Singer and G. Ulliac Efficacy and safety of fluoxetinewere studiedon a two-month period, Fiuoxetinewas compared to clomipramiuein the treatmeutof patients suffering from severe endogenous depressive states and melancholia.All these patients were hospitalized. During the first month, patients were visitedtwice the first week, then once the following weeks during the first month and twice during the second month. The do~age wan flexible according to the severity of the depressive symptons: 2~ to 80 mg for fluoxetine,50 to 200 mg for c]omipramine, Oxazepam was allowed as a~ annolytic. Several scales were used to measure drugs efficac?: -Hamzltun scale for depression (21 items), -~DRS, -Cov~ anxiety scale, -Widlocher-retardationscale, -Self-evaluationscales for severity of deprenniou and fur global evaluation. Results: -62 patients were enrolled, - 8 patients were excluded (no respect of inclusioncriteria), -19 patients dropped out (reasons of drop out were similar in the twn groups). Therefore 50 patientswere treatedduring one month, 35 during two months. After two months of treatment,there is no difference~tween fluoxetineand clomipraminein terms ~f efficacy and tolerance, The global improvementis 68 % in the two groups on Hamilton; on MADRS scale, improve~ent is 75 % under fluoxetine and 72 % under clomipramine (this differenceis not significant]. After 4 weeks of treatment, clomipramineimproves slightly retardationand anciety but after 8 weeks the hesults are equivalentunder the two treatments. Although there is no significantdifference in terms of tolerance and side effects, ~ore patients under c]omipramineare sufferingfrom constipation,dry mouth, dizziness and h?potennion. Under fluoxetine, the number of patients who experiencednausea was more important. No biological (hematologyand enzymology) abnormalitywas reported. In conclusion, fluoxetineis as effective and safe as clomipramine in the treatne~t of severe depressive states and mealancholia.

31.03.01 Prophylactic to treatment illness and

POSTER PRESENTATION 31.03

Lithium and Carbamazepine

St. S c h m i d t Seibold / W.

lithium treatment: response and patient attitudes toward therapy / W. L u d w i g Greil

Psychiatric Hospital Munich (Head: Prof.

of Dr.

/ E.SchmSlz

the University H. H i p p i u s )

/ S.

of

Based an the records of 80 patients with affective and schizoaffective disorders that were treated in the lithium clinic of our hospital, the course of illness before and during maintenance lithium treatment was analyzed. We tried to find out whether or not the patients' beliefs about their illness and its treatment are correlated with parameters of treatment response. The patients beliefs were assessed using a compliance self rating scale and an illness concept scale. Our results indicate that there are no correlauions between treatment response and the parameters "reliance on the physician" and "reliance on medication". Patients' beliefs about "susceptibility to illness,, however, were correlated with parameter s indicating low treatment response. Additionally, patients receiving concomitant treatment with neuroleptics emphasized the unpleasant side effects of p h a r m a c o t h e r a p y .

31.03.02

31.03.03

CARBAMAZEPINE: POSSIBLE CLINICAL ADVANTAGES OF A SLOW RELEASE FO~4ULATION IN PSYCHIATRY B. Tettenborn, G. Kr~mer, R. Besser, K. D. Stoll

CARBAMAZEPINE VERSUS LITHIUM IN PROPHYLAXIS OF RECURRENT AFFECTIVE DISORDERS W. Bellaire, K. Demisch, K. D. Stoll

Chronic carbamazepine(CBZ) administration or combined treatment with other anti-epileptic drugs leads to auto- and/or heteroinduction of its metabolism with reduced elimination h a l f - l i f e and marked fluctuations of serum levels in spite of t . i . d , or even q.e.d. prescription.

Recently preliminary results of one-year-prophylaxis in 98 patients with recurrent affective disorders, Eandomly treated with either carbamazepine(CBZ, Tegretal K) or lithium (Li) were reported and lead to the conclusion that both treatments are globally comparablein effect (1,2): CBZ group Li-group number of 'patients 46 52' mean duration of illness 8,4 yrs 10,5 yrs mean numberof episodes per year 1,5 1,1 mean number of episodes in the year before t r i a l 1,76(~I.06) 1,69(~I.02)

The pharmacokinetics of CBZ slow release (Tegretal 400 retard) were investigated in comparison to conventional CBZ (Tegretal 200) in volunteers and epileptic patients. The slow release formulation revealed a pronounced delay of absorption associated with decreased serum peaks, thus resulting in a markedly lower fluctuation index even with a b . i . d , regimen. Clinical effectiveness was equivalent to conventional CBZ. These pharmacokinetic data hint to possible advantages in the clinical use of CBZ in psychiatry with - improved compliance due to - reduced side-effects and - reduced number of daily dosages. Neurologische Universit~tsklinik, Langenbeckstr. I , D-6500 Mainz

mean number of episodes during the year of the study 0,67(~0.54) 0.73(t0.97) success rated at least good 41 pts(89 %) 45 pts(86%) t o l e r a b i l i t y rated at least good 44 pts(96 %) 45 pts(86%) There is data collection for a second year in the majority of patients of this multicentric study. Results of prophylactic treatment for two years w i l l be presented with reference to similar controlled studies with CBZ, Li and/or placebo. Literature: (I) Demisch K., PSYCHO14, 88, 1988 (2) Stoll K.-D. et al. ]-6: New Direction in Affective Disorders (Lerer, D. and Gershon, S. eds.), Springer, in press Psychiatrie der Universit~ts-Nervenklinik D- 6650 Homburg (Saar)

31.03.05

31.03.04 PROPHYLAXIS AFFECTIVE PSYCHOSES.

CARBAMAZEPINE

IN

J.~VESTKA, University

OF

THE

Psychiatric

K.NKHUNEK Department,Brno,

~SSR

Carbamazepine /CBZ/ and Lithium carbonicum /Li/ were intraindividually compared as for a period

prophylactic of 460 days.

drugs in 24 pts. The average d&ily

dose of CBZ was 706 m E /correspondin G serum level 5.2 mikro~/ml/ a n d Li 835 mg /serum level 0.52mval/i/. the occurence of

In c o m p a r i s i o n new phases was

signif, lower. There was the dur@tion of phases and lenghts test/.

of

the

Disapearanoe

hospital of the

with Li on CBZ

no difference in t h e n u m b e r stay

phases

their frequency was achieved o n C B Z a n d 5 0 p e r c e n t o n Li.

or

in and

/Nilooxon lowering

in 6 2

of

percent

In a n o t h e r s t u d y p r o p h y l a c t i c efficiency of CBZ was compared with a combination CBZ+Li in 20 patients for 1 year. The combination CBZ§ was signif, better in shortening the lenghts of the phases and the necessary hospitalization. phases didn't differ. Of c y c l e r s 77 p e r c e n t on the combination

The the

was favourably CBZ§

COMPARATIVE STUDY BETWEEN TWO GROUPS OF PATIENTS WITH MANIC-DEPRESSIVE BIPOLAR DISORDER TREATED BY LITHIUM OR CARBAMAZEPINE. F. Rouillon~ M.B. Durand, T. LEMPERIERE This study compares the quality of therapeutic results obtained with lithium and earbamazepine in 30 patients with manic-depresslve bipolar psychosis (Bipolar disorder, manic or Depressed, in remission according to D.S.M. III criteria). The two groups of patients, sex and age. matched, are comparable as to their soeiodemographie and clinical characteristics and the psychotropes combined with their thymo-regulating treatment. The comparison has been made by one of us among those patients being normothymic since at least three months, and with mean lithium or tegretol plasma levels of 0,72 Z 0,12 meq/l and 7,5 ~ 2,2 ng/l respectively. The evaluation was based on the Comprehensive Psychiatric Rating Scale (C.P.R.S.), a checklist of side effects (C.H.E.S.S.) and a questionnaire on psychological experience of disorders wiewed by patient. The average global score of C.P.R.S. has been improved in the Carbamazepine group and side effects were less frequent with CBZ than with lithium according to the C.H.E.S.S. list. The information from questionnaire also shows trend in favour of Carbamazepine. However none of these differences has reached a level of statistical significance, except for some items(reduced libido and inability to concentrate, diminution of physical capacities and activities, more important in lithidm

group).

number of 9 quick influenced

In t h e ~hird part, prophylactic compared to the combination L+CBZ.

Li

was

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2ROPHYLAXISFOF BIPOLAR DISORDER IN ELEDERLY: A DOUBLE-BLIND STUDY WITH LITHIUM VS CARBAMAZEPINE. A. L e n z i , F. L a z z e r i n i , D. M a r a z z i t i , G. M a s s i m e ~ ti, P. L u c a r e l l i . Several conflicting results have been reporetd on the use of Lithium for the prophylaxis of Bipolax Disorder in the elderly. Fro m a pharmacological p o i n t o f v i e w , L i t h i u m is p o t e n t i a l l y t o x i c i n geriatric age. Furthermore, features of Bipolar Disorder in elderly suggest to utilize Carbamazepine.W~uthus comparedd the effeciacy and tolerability of Lithium and Carbamazepine in a group o f 23 a g e d b i p o l a r p a t i e n t s , i n a d o u b l e - b l i n d 3 year trial. L i t h i u m w a s e f f e c t i v e i n 60% o f t h e p a t i e n t s , with no severe side effects. On the contrary, the group of'patients treated with Carbamazepine showed a high number of drop-outs and more severe side effects. The low effectiveness of Carbamazepine may be due to the high initial dosage, indicating the need for a lower dosage of this drug in geriatric patients. T h e r e f o r e , L i t h i u m s a l t s a p p e a r to b e a n e f f e c t i ve and safe therapeutic tool for the elderly, e v e n if t h e y d o r e q u i r e d r e g u l a r m o n i t o r i n g o f serum levels and thyroid, cardiac and renal function controls. Department of Psychiatry, University of Pisa, V i a R o m a , 67, 5 6 1 0 0 PISA (Italy).

The addition of Carbamazepine to lithium induces changes in Red Blood C e l l (RBC) lithium. C. U d i n a , E. ~ i v a r e z , R. M a r t l n - S a n t o s , J.M. Q u e r a l t 6 , C. C a s t i l l o , J. P 4 r e z - B l a n c o , M. Casas. Carbamazepine (CBZ) p l u s lithium has been s u g g e s t e d as an a l t e r n a t i v e in the c o n t r o l of n o n r e s p o n d e r b i p o l a r or s c h i z o a f f e c t i v e p a t i e n t s A synergistic action between CBZ and lithium r e m a i n s u n k n o w n . In o r d e r to i n v e s t i g a t e p o s s i b l e c h a n g e s in R B C a n d l i t h i u m l e v e l s a f t e r a d d i t i o n of CBZ, 9 p a t i e n t s d i a g n o s e d as b i p o l a r m a x n i a c and s c h i z o a f f e c t i v e d i s o r d e r s a c c o r d i n g to D S M - I I I - R c r i t e r i a w i t h a p a s t h i s t o r y of at l e a s t 1 a d m i s s i o n to P s y c h i a t r y w a r d a n d r e f r a c t o r y to l i t h i u m c a r b o n a t e for t h e l a s t 2 y e a r s were studied. There were 6 males and 3 females a g e d 37+13, w i t h a d u r a t i o n of the d i s e a s e of 9.8+6 years. RBC lithium levels were performed b e f o r e and a f t e r a d d i t i o n of CBZ. Comparison was m a d e u s i n g W i l c o x o n p a i r e d t - t e s t . RBC l i t h i u m l e v e l s a f t e r a d d i t i o n of C B Z dropped f r o m 0 . 3 9 + 0 . 2 m m o l / l to 0 . 2 7 + 0 . 1 m m o l / l (z= -2.04, p<~.02). This difference remained signi f i c a n t d u r i n g the f i r s t 2 m o n t h s (z= - 1 . 9 8 , p < 0 . 0 2 and z= - 1 . 6 6 , p ~ 0 . 0 5 r e s p e c t i v e l y ) , b u t n o t at 5 a n d 10 m o n t h s (z= - 1 : 6 2 , p < 0 . 0 8 and z= -1.38, p < 0 . 0 9 ) . T h e s e r e s u l t s s u g g e s t an i n t e r a c t i o n b e t w e e n C B Z and R B C l i t h i u m levels? A p o s s i b l e m e c h a n i s m of s u c h i n t e r a c t i o n c o u l d i n v o l v e the c o u n t e r t r a n s p o r t of C B Z a c r o s s t h e RBC membrane. D e p a r t m e n t of P s y c h i a t r y and B i o c h e m i s t r y . H o s p i t a l S a n t a C r e u i S a n t Pau, Av. S . A . M . C l a r e t , 167. 08025-Barcelona (SPAIN).

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C O M P A R I S O N OF C A R B A M A Z E P I N E N O R M A L F O R M U L A T I O S (NF) TO T E G R E T O L " D I V I T A B S " (DT). ~R~_N!~dam, A.J.M. Loonen Twenty hospitalfzed psychiatric patients, stabil i z e d on NF, c o m p l e t e d an open, r a n d o m i z e d , c r o s s - o v e r c o m p a r i s o n of the k i n e t i c s , t o l e r a b i l i t y and e f f i c a c y o f NF to the n e w c o n t r o l l e d r e l e a s e f o r m u l a t i o n DT. The i n d i c a t i o n s for e a r b a m a z e p i n e (CBZ) w e r e e p i l e p s y , b e h a v i o u r a l d i s t u r b a n c e s a n d / o r b i p o l a r d i s o r d e r . All but one p a t i e n t s r e c e i v e d c o - m e d i c a t i o n . S e r u m l e v e l s of CBZ and of its m e t a b o l i t e c a r b a m a z e p i n e - l O , l l e p o x i d e (EPO) w e r e a s s e s s e d d u r i n g NF t h e r a p y and 3 w e e k s a f t e r a s w i t c h to DT. S e r u m s a m p l e s were d r a w n j u s t b e f o r e NF or DT i n t a k e and 2, 4, 6 and 8 h o u r s t h e r e a f t e r . F r o m e a c h d a y - c u r v e the f o l l o w i n g p a r a m e t e r s w e r e d e r i v e d : a r e a u n der the c u r v e (AUC), the q u o t i e n t o f m a x i m u m and m i n i m u m s e r u m l e v e l s ( C m a x / C m i n ) , and the f l u c t u a t i o n i n d e x (FI = ( C m a x - C m i n ) x t i m e / A U C ) . Results: - C m a x / C m i n is l o w e r in 14 p a t i e n t s d u r i n g DT w i t h 9 m e a n r e d u c t i o n of 4 . 1 % ( p = O . 1 3 1 ; W i l eoxon Matched-Pairs Signed-ranks Test). - In all p a t i e n t s (N=9) w i t h a C m a x / C m i n ) 1 . 3 0 on NF, t h i s q u o t i e n t is l o w e r on DT. - The FI is l o w e r in la p a t i e n t s d u r i n g DT w i t h a m e a n r e d u c t i o n of 1 6 . 3 % ( p = O . l 1 2 ) . The m e a n r a t i o A U C c b z / A U C e p o is a l m o s t i d e n cal for b o t h f o r m u l a t i o n s (NF: 21.6%; DT: 21.9%). - The m e a n A U C e b z is 1 2 . 7 % l o w e r for DT. - D u r i n g DT t h e r a p y no c h a n g e s in e f f i c a c y a n d t o l e r a b i l i t y are o b s e r v e d .

PIAg~ ~ T I O N ~ ~]N~(CBZ) AND I]~ -i0,Ii-EPOX]I~ M E ~ IN MANIC P A T I O . J.M. A ~ , G. l~*pesdli,~/h.Bottai and D. ~ . ~ e relationshipsof plasma levels of holh CBZ and its - 1 0 , 1 1 ~ d e metabolii~ to dose ~ ~ d clinical resDonseare still o~ntroversial in literatlme.C~cemir~ the last point, if there is sane general 8~reementthat plasma values of CSZ beb~een 5 and 12 microgr.lmL are widnin d~e dlerapeuticrange, Monaco et al (Neurology~5,9~5,1976) found no relation~dp between plasma concentrationof the -I0,ii- epoxide metaboliteand clinical8ntioonvulaivantresponse~%ile Post et al (Ardu.Gen.Psychia~ 40,673,1983)s u ~ dgat the metaboliteconcen~raticnmight be related to hhe degree of clinical efficacy in affectively ill patients. In ord~ to confirmthese data, we adTdr/steredCBZ to 18 manic patien~ fulfillingthe ~ criteria for MAD, manic episode. Pallets had to have no charge in ~neir medical h-eah~e~tdurin~ the two weeks preceeding the initiationof active drug d~er~py. CBZ was ad~istered for en average of 30 days at an average dosage of 978 rag/day.Clinical respcrse was evaluatedby mean of ~ Beigel-Murphyscale, the highest difference in r a t ~ between day 21 and day 0 reflectirgthe greatest clirdcal improvemsut. Plss~ samples were ~ at day 21 (8~4) in order to evaluate p l ~ ccncentraticllof both (]3Zand its -10,1/- epoxide metabolitewhich .e-~ured by ~ li~d ch~t~hy (~C). ~ e ~=u~cy of the ~say ~ s of the order of • 2% for both the dr~g ~nd the metabolite. Mean plasma concentrationof CBZ ~ s 7,6 +_1,92ndcrogr./mL (mean ~_ED), while the -10,]i- epoxide metabolitea v e r ~ 1,58 ~l,OZmicrot~,/mL. We found a positive correlationbetween the daily dosage of CHZ ~nd the plasm~ concentrationof beth C~Z (rs=O,518;p=O,05) and its metabolite (rs= O,6~38;p=O.01).A Dositive correlation~ also found between the plasma concentration of CBZ and d~at of its metabolite (rs=O,6~5;p=O.O]) } ~ e r , we did not find any correlationbei~eer~clinical response and plasma concentrationof both CBZ (rE -O,3;NS) and its metmbolite (r~= 0,043; NS). Our dal]arand to indicate that plasma concentration of boltnCBZ and its -i0,ii- epoxJde metabolite reflect the da~ly du~a~e of the s u b s ~ but not the degree of clinical L~rovement.

A

P s y c h i a t r i c H o s p i t a l V o o r b u r g , P.O. N L - 5 2 6 0 GB V u g h t , The N e t h e r l a n d s .

Box

10150,

Clinique de Psychiatrie, C4J Tin.he, Rue Saint Pier-r ~, F Ifi~ Mar~eille

C6clex5.

288

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P H A R M A C O K I N E T I C S A S P E C T S OF L I T H I U M T R E A T M E N T M. Alda, H. Papezova, P. Zvolsky and D. D u f k o v a This is a summary of t h r e e studies c a r r i e d out in o r d e r to e v a l u a t e p o s s i b l e factors w h i c h m a y i n f l u e n c e both i n t e r p r e t a t i o n of v a l u e s of l i t h i u m levels and also p o w e r of p r e d i c t i v e methods. I. L. has f r e q u e n t l y b e e n c o n n e c t e d w i t h the risk of renal damage. W h e t h e r r e v e r s i b l e or not it could lead to a c h a n g e of i. e l i m i n a t i o n and to the risk of i. i n t o x i c a t i o n . The s t u d y i n c l u d e d 29 p a t i e n t s s t a r t i n g I. t h e r a p y and 12 p a t i e n t s who had b e e n on i. from 2 to 18 years. The rate of e l i m i n a t i o n of i. was d e t e r m i n e d and m e a n v a l u e s in b o t h g r o u p s w e r e compared. L. h a l f life c o r r e l a t e d s l i g h t l y w i t h age of the subjects (r = .3), b u t there w e r e no d i f f e r e n c e s b e t w e e n the short- and l o n g - t e r m t r e a t e d g r o u p s (ms=16.9_+9.1 and m L = 2 0 . 2 + 8 . 0 , p> 0.I). 2. L. levels m a y f l u c t u a t e r a n d o m l y and the e x t e n t of these f l u c t u a t i o n s limits d i r e c t l y the i n f o r m a t i o n v a l u e of I. c o n c e n t r a t i o n s . Therefore, l o n g - t e r m c o u r s e of s t e a d y - s t a t e levels was s t u d i e d in 17 patients. An a t t e m p t was m a d e to draw all samples in p a r t i c u l a r p a t i e n t s u n d e r the same c o n d i t i o n s (with r e s p e c t to the p h a s e of illness, d o s a g e of I. and the d a y t i m e of c o l l e c t i o n ) . T h e value of i n t r a c l a s s c o r r e l a t i O n w a s r = 0.68, and it tells w h a t part of v a r i a n c e is a t t r i b u t a b l e to b e t w e e n - s u b j e c t d i f f e r e n c e s , and also limits power of v a r i o u s p r e d i c t i v e methods. 3. As the course of i. levels can be c h a r a c t e r i z e d by v a r i o u s p a r a m e t e r s , we w e r e i n t e r e s t e d which ones are s i g n i f i c a n t for the d e s c r i p t i o n of I. kinetics. C o m p u t e r s i m u l a t i o n e m p l o y i n g system of n e s t e d m o d e l s c o n f i r m e d (among o t h e r results) that o m i t t i n g the p a r a m e t e r of a b s o r p t i o n u s u a l l y d o e s n o t lead to s u b s t a n t i a l deviations.

EFFECTS OF CHRONIC LITHIUM TREATMENT ON S E R O T O N I N R E C E P T O R S A N D H Y P O T H E R M I C R E S P O N S E TO 8-OH-DPAT Y__~. O D A G A K I , T_~. K O Y A M A r R. M A T S U B A R A a n d I. YAMASHITA Serotonin (5-HT) receptors have been divided into two types (5-HT 1 and 5-HT 2 receptors). M o r e recently, 5-HT I receptors have been subdivided further into multiple subclasses (5-HTIA, 5HTIB, 5-HT I C , etc " ") We i n v e s t i g a t e d the e f f e c t s of l o n g - t e r m l i t h i u m a d m i n i s t r a t i o n on the 5-HT receptor subtypes and 5-HTIA mediated h y p o t h e r m i a in rats. Oral a d m i n i s t r a t i o n of l i t h i u m c a r b o n a t e for 3 w~eks did not alter [ H] spiperone or [JH]ketanserin binding in c e r e b r a l ~ o r t e x . On t~e other hand, the B m a x v a l u e s of [ H ] 5 - H T and [~]8-hydroxy-2-(di-n-propylamino)tetralin ([~H]8-OH-DPAT) binding in h i p p o c a m p u s were reduced significantly by lithium treatment w i t h o u t any c h a n g e in Kd. N e i t h e r b i n d i n g w a s affected in cerebral cortex. Binding characteristics of n o n - 5 - H T I A sites d e f i n e d as s p e c i f i c [~H]5-HT b i n d i n g in t h e p r e s e n c e of 100 nM 8 - O H - D P A T were not a l t e r e d in e i t h e r b r a i n region. These results indicate that lithium treatment selectively down-regulate the 5 - H T I A components of 5-HT I r e c e p t o r s in h i p p o c a m p u s , but not in c e r e b r a l cortex. Subcutaneous injection of 8-OH-DPAT induced dose-dependent hypothermic response assumably mediated by presynaptic 5-HTIA receptors. L i t h i u m a d m i n i s t r a t i o n for 3, 14, or 21 days did not altered the hypothermic response to 0 . 2 5 m g / k g 8-OH-DPAT. D e p a r t m e n t of P s y c h i a t r y and N e u r o l o g y , H o k k a i d o U n i v e r s i t y School of Medicine, N o r t h 15, West 7, S a p p o r o 060 J a p a n

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31.03.13

THE ACTIONS OF LITHIUM ON AGONIST-STIMULATED INOSITOL

NEUROCHEMICAL AND BEHAVIORAL STUDIES OF LITHIUM ON SEROTONERGIC SYSTEM R. Yoshida and S. Yamawaki Lithium(Li) is widely used for the t r e a t m e n t of a f f e c t i v e disorders, but the m e c h a n i s m of action of Li is unclear. In the present study we investigated the e f f e c t s of Li on s e r o t o nergic(5-HT) system; pre- or post-synaptic function and behavioral responses. Pre-synaptic function of 5 - H T neuron: L i t r e a t m e n t for 3 days signiflcantl~ increased the r a t e of 5-HT t u r n - o v e r and the release of H-5-HT s t i m u l a t e d by high K + in hippocampus, but not in frontal cortex. In hippocampus, the s a m e t r e a t m e n t suppressed the function of 5-HT a u t o receptors on the 5-HT terminal, which control t h e 5-HT release negatively. Post-synaptic function of 5-HT neuron: Chronic Li t r e a t m e n t decreased the density of 5-HT1 receptor in both frontal cortex and hippocampus. The s a m e t r e a t m e n t decreased the density of 5-HT2 r e c e p t o r s only in hippocampus. The activit'y of 5-HT-sensitive adenylate eyclase, which is coupling to 5-HTI, especially 5-HTIA receptors, was increased by chronic Li t r e a t m e n t . On the other hand, the rate of phosphoinositide turn-over, which is coupling to 5-HT 2 receptors, wa~ decreased by a c u t e and chronic Li t r e a t m e n t . 5-HT related behavioral responses: 5-HT syndrome(forepaw treading, flat body posture etc.) elicited by 8-OH-DPAT, a 5-HT1A agonist, was enhanced by chronic Li t r e a t m e n t . Wet-dog shakes elicited by 5-HTP, which relate to 5-HT2 receptors, were decreased by chronic Li t r e a t m e n t .

PHOSPHOLIPID TURNOVER IN RAT CEREBRAL CORTEX P.P. Godfrey, J. Swinswood and D.G. Grahams-Smith Since the initial observations that lithium ions inhibit the enzyme Inositol monophosphate phosphatase there has

been considerable speculation that the action of lithium on Inosi~ol phospholipid metabolism may explain its pharmacological and therapeutic effects (Berridge, M.J. etal, Biochem. J. 20_~6, 587,1982). Although the effects of lithium on inositol monophosphate metabolism are well establlshed its actions on other aspects of the 'PI' cycle in brain are still unclear. Here we investigate the action of lithium on both lipid and inositol phosphate intermediates in rat cortex. Cortical slices (SS0xS50 um) prepared from male SpragueDawley rats were preincubated for 60min at 37~ in HrebsREPES buffer; 50 ul aliquots of packed slices were then labelled in 250 ul of buffer for 60 min with either 3Hinositol (SuCi/ml), 32P-phosphate (20uCi/ml) or 14C-cytidine (1 uCi/ml). LiCI (0-30 mM) was then added, followed 10 min later by the a~onist. Incubations ~'ere continued for up to 60 min and stopped with 10% perchlorie acid (inositoi) or chloroform/methanol/HCl (32P and cytidine). Inositol phosphates were separated by anion exchange chromatography and lipids by TLC. LiCI dose-dependently (ED50-0.8 mM, max. effect ~t 3 mM) enhanced carbachol (1 mM)-~timulated IP I and IP 2 formation though it did not affect IP levels and actually inhibited 3

the formation of IP 4. LiCI greatly enhanced CMP-phosphatidate formation in the presence of carbachol (5-fold) and also had smaller effects on its own (1-2 fold increase); a similar, though smaller, potentiation was seen in the

presence of noradrenaline (300uM). Carhachol (imP) plus LiCI (iOmM) reduced the levels of S2P-PIP and 32P-PIP 2 following a 60 min incubation. We conclude that lithium greatly alters cerebral inositol phospholipid turnover. Department of Clinical Pharmacology, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, UK.

D e p a r t m e n t of Psychiatry and Neuroseience, Institute of Clinical Research, Kure National Hospital, 3-1 A o y a m a - c h o , Kure, Hiroshima 737, JAPAN

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LITHIUM INACTIVATES RENAL KALLIKREIN KININ SYSTEM C. Reinhard, A. Schlenker, H. Saner, G. B6nner, M. Marin-Grez, P.Gross eTh-e'-{e~alside effects of lithium(Li) therapy are incompletely understood.These side effects characteristically involve renal collecting duct functions.Kallikrein is a regulatory enzyme produced and secreted by this same part of the nephron.We therefore studied in patients(A) and experimental animals(B) whether there is an interaction between Li and renal kallikrein.We observed: (A) in 14 consecutive patients suffering manic-depressive psychoses studied prospectively urinary kallikreinexcretion(KE) was 267+70 U/day before and 118+40 U/day 14 days after the begin~f Li therapy(p<.OS;amid~lytic assay of kallikrein).In 14 other,unselected patients which had been on chronic Li therapy for several years KEwas 94+30 U/day significantly lower than KE of healthy controls:3T0+80 U/ day(p<.0S).Li treated patients had plasma Li concenTrations of .51+.08 mM/l.None had subjective or objective evidence of~nown renal side effects of Li treatment.ICE measurements obtained by amidolytic assay correlated significantly with those obtained by RIA.Li inthe urine did not interfere with the kallikrein assay. (B) in a polyuric rat model of Li treatment given over 11 daysCplasma Li concentration .44+.03 mM/l)KEwas 1.26+.08 ~/day during baseline and .45+.0TU/day on day 11 of L~ treatment(n=24;p<.05);KE on d~y 11 of sham treated control: 1.46+.12 U/day.This decline of KEafter Li applied eomparabl~to measurements of active and total kallikrein.Moreover renal cortical tissue kallikrein was .4+.04 mU/g protein(n=12)in Li treated and 1.24+.18 mU/g in-control rats on day 11(n=6;p<.05). Conclusion:Low therapeutic lithium concentrations in plasma inactivate the renal kallikrein kinin system by direct inhibition of connecting tubule cells.This functional alteration occurs prior to any overt side effects of lithium but may be related to them. Departments of Medicine and Psychiatry,University of Heidelberg,Bergheimerstrasse 56 a,D-6900 Heidelberg,FRG

LITHIUM:LONG-TERM EFFECT ON SEROTOI~IN METABOLISM IN BP~AIN REGIONS D.Ghoshdastidar end M.K.Poddar Long-term exposure(for 7 consecutive days) of lithium chloride (2.0-4.0 mmol/k~day, p.o. )to adult male albino rets(120-140 g) increased(a) steady state level of tryptophan(29-53%),serotonin(5-HT) (20-35%) and 5-hydroxy indoleacetic acid (5-HIAA) (30-65%) (b) pargyline-induced accumulation of 5-HT_(50-120%) and declination of 5-HIAA(50-85%) (c) probenecid induced accun%alat~n of 5-HI~A and(d) mitochondrial .v~a.Oactivity(2636%) in brain hypothalamus(H) end pons-medulla (PM) .Extention of the period of treatment to 14 consecutive days with lithium chloride(LiCl) at a dose of 2.0r~mol/k~/day ~ailed to produce any appreciable change in the above parameters of 5-HT metabolism in a n y of the brain regions. Administration of LiCI at a dose of 4.0 mmol/~/ day for 14 consecutive days, on the other hand, decreased the level of tryptophan(21-34 % ) , 5 - H T (25-35%), 5-HIAA (12-20%, pargyl ine induced accumulation of 5-HT(24-36%) and declination of 5-HI~A (20-34%) and orobenecid induced accumulation of 5-HIAA(20-35%) in H, striatum(S)and PM.But the MAO activity was increased in these regions u n ~ similar conditions. Further p r o l o n g a t i o n of treatment with LiCI (2.0 and 4.0 m~ol/k~/day, p.o) for 21 consecutive days produced greater effect on the above parameters in H,S and PM of rat brain regions. These results suggest that LiCI produces differential action depending on its dosage and the duration of treatment in serotonergic activity in brain. Purther it may also be stated that these long term effects of LiCI on serotonergic neuronal activity is specific to brain regions. Department of B i o c h e m i s t r y , U n i v e r s i t y of Calcutta 35 B.C.Road, Calcutta 700 019, India.

31.04.01

POSTER PRESENTATION 31.04

Treatment Approaches for Mania and Rapid Cyclers

290

REVERSE SEASONAL AFFECTIVE DISORDER (RSAD) WITH SUMMER DEPRESSION AND SPRING HYPOMANIA: A PROSPECTIVE STUDY M. von Bose, M. Zaudig, J. Zulley, W. Schreiber, K.M. Pirke, H. Emrich, W. Mombour In recent years, there has been an increasing number of case reports of patients who regularly become depressed in winter (Seasonal Affective Disorder: SAD), a condition that responds to treatment with l i g h t . In 1987, Wehr et al. published 12 case reports of patients with a reverse seasonal pattern: these patients become depressed in summer and euthymic, hypomanic or manic in winter. In addit i o n , most patients spontaneously reported a correlation between a rising environmental temperature and the onset of depression. To our knowledge, u p t i l now no study has systematically correlated environmental temperature (and related variables) with the course of the i l l n e s s . lhe M~x-Planck-lnstitutefor Psychiatryhas since Septenber1987 followed a 46-year-old female patient with 10 yearly episodes of surmer depression and regular spring hypo~ania. Ibis patient is a non-responder to Lithi~n and Tricyclic Antidepressives. Part of the prospective study was a systamatic and periodic asses~nt of envi,~L~tal, chronobiological and neuro-endocrinological variables believed to attribute to or dependon psyr3zpathological changesthroughout the course of the illness over one year. W~obtained daily recordings of the following ~mvir~mmrrtalfactors: meantemperature, meanduration of sin-shine, daylength, meanair hunidity, meanbarcmetric pressureand meanlight intensity.Chronobiologicalasses~rB~tsincludedperiodicpolysomegraphic sleeprecordings,EEG, EOG, heart rate and mstor activity. Periodicneuro-~ntcrinologicalprofiles (T3, B-FbA, MDPEG; basal Cortisol, TRH, Dexam~C~asone-Suppm_ssionTests, {~d~ostasis-Tests,Gonadotropin secretion,~xual hormones,etc.) were aimed at detectingfractional disturbancesof the HPA-, FPT- and ROG-axes - again with respect to changesin psychopathologicalvariables over the courseof 1 year.

31.04.02 USE OF V E R A P ~ I L IN SE\~RE ~ N I C EPISODES. A. Russova, D. Toschi, A. Lenzi, D. M a r a z z i t i . Several e x p e r i m e n t a l and c l i n i c a l data i n d i c a t e the e f f e c t i v e n e s s of c a l c i ' ~ b l o c k e r s in m a n i a . O u r study a i m was to i n v e s % i g a t e the t o l e r a b i l i t y and p o s s i b l e use of V e r a o ~ m i l in the t r e a t m e n t of p a t i e n t s a f f e c t e d by severe m a n i c episodes. F i f t e e n felame p a t i e n t s wi~h a m a n i c e p i s o d e so s e v e r e that they had to be h o s p i t a l i z e d , w e r e i n c l u d e d in the trial. The d i a g n o s e s were: m a n i c e p i s o d e (n. 13) and m i x e d e p i s o d e (n. 2). V e r a p a ~ i l was given at the initial d o s a g e of 240 m g thre times a day. Then, the t r e a t m e n t was m o d i fied a c c o r d i n g to c l i n i c a l r e s p o n s e and t o l e r a b i lity. A n a m n e s t i c data, s v r p t o m s and side effects of the drug were e v a l u a t e d by the con~non p s y c h o p a t h o l o g i c a l r a t i n g scales CAPDI, BPRS, CGI, DOTES, TWIS, PTR). All the p a t i e n t s showed an i m p r o v e m e n t of manic s y ~ p t o n s from the third day of treatment. H o w e v e r the initial d o s a g e was inable to c o n t r o l all the s ~ p t o m a t o l o g y and we bad to i n c r e a s e d it and to add n e u r o l e p t i c s in all the cases. This a s s o c i a z i o n s h o w e d to be well tolerated. This study c o n f i r m s the e f f e c t i v e n e s s of V e r a p a mil in mania, w i t h e a r l i e r e f f e c t s r e s p e c t to L i t h i u m and sinergic e f f e c t w i t h n e u r o l e p t i c s . In addition, it suggests the p o s s i b l e use of V e r a p a mil also in n a t i e n t s with severe manic episodes. D e p a r t m e n t o~ Psychiatry, U n i v e r s i t y of Pisa, Via Roma, 67, 56100 Pisa (Zzaly).

31.04.03 CLONIDINE FOR ACUTEMA,~IIA p.G. JANICAK, R.P. S H A R M A , 3,M. DAVIS, et aL Since some have reported that clonidlne may have antlmanic properties, it would be of great theoretical significance to confirm this in light of cIonidine's ability to reduce NE synthesis. Further, if clinically effective, employing clonidine could avoid the use of antipsychotics which may cause NMS and/or TD. We are conducting a double blind study in which acutely ill manic patients receive either clonidine or placebo. After giving informed consent, 20 patients have completed a washout phase (mean = 6 days) and then received either placebo or clonidine (up to .g rag/day). Patients were evaluated with the BPRS and the Young .'4ania Scale (YMS) at baseline and days 1,2,3,7,10,It+ or when dropped from the study because of significant worsening of symptoms. More patients" in the clonidine group failed to complete the study (primarily due to rash or hypotension) than did those on placebo. An end point analysis was used to include values in those patients who did not complete the I~ day trial." The BPRS and YMS change scores were analyzed by a repeated measures analysis of variance. There was virtually no differences in improvement based on the BPRS or YMS in the clonidine versus the placebo treated groups. The main e f f e c t of clonidine versus placebo yielded (F = .03, df = 2/17, p = .97). The BPRS clonidine versus placebo difference yielded (t = .23, p = .$2) and the YMS change score difference for clonidine versus placebo yielded (t = .03, p = .97). To our knowledge, this is the first report of a double blind, placebo control trial using clonidine as an antimanic agent. Based on our findings, we would conclude that clonidine produces exactly the same clinical effects on mania as placebo and that the

doses used (0.2 to 0.8 rag/daY) caused significant side effects.

31.04.04 THYROID FUNCTION ASSESSED BY TRH TEST IN RAPID CYCLING BIPOLAR PATIENTS AND THE CHOICE OF TREATMENT. Maria Knsalic Rapid cycling is the most malignant form of bipolar illness. It was a l r e a d y described in the premedication era predominantly among females. Thyroid function is involved in rhythmicity, e.g.: rats rendered e x p e r i m e n t a l l y hypothyroid show behaviour similar to that of rapid cyclers, and their b e h a v i o u r normalizes on treatment with thyroid hormone. Furthermore, 50 to 60 Z of bipolar rapid cyclers are hypothyroid. TS~ is elevated in 92% of rapid cyclers compared to 32% of non-rapid cycling bipolar patients. Hypermetabolic doses of thyroid hormone stabilized rapid cyclers into a euthymic state. It also appears that any psychotropic medication other than mood stabilizers can induce rapid cycling in bipolar patients. Ten patients fulfilling Dunner's criteria for rapid cycling were investigated. Five of these (3 women, 2 men) were hypothyroid. The other five were euthyroid according to the TRH test. In some patients, we measured free T-3 to assess true thyroid state as it has been reported that some depressed patients have low free T-3 akin to that found in the euthyroid sick syndrome. Thyroid therapy normalized 80% of the hypothyroid patients (2 women, 2 men); the third woman continued rapid cycling. One euthyroid patient responded to treatment with carbamazepine. Another, after failing on carbamazepine, responded to elonazepam. A third euthyroid patient withdrew from the study. The fourth has just started treatment with carbamazepine. The tenth patient is in the process of being investigated. St. Mary's Hospital, McGill University, 3830 Lacombe Ave., Montreal, PQ, Canada, H3T IMb.

291

31.05.01 ~'~ITRYPTILINE AIYD SLEEP PATTERN IN HEALTHY N~LES

POSTER PRESENTATION 31.05

The following chan~es of sleep parameters have been described in healthy subjects after amitryot~line: inerease of deep sleep,reduction of P~EM sleep,decrease of R ~

activity.

5 physically and mentally healthy males / 27-42

Sleep and Sleep Disorders

years / were studied. The poly
31.05.02 THE I ~ L U F N C E OF A~IT>YPTILIh[E ON L~I~ AND OTHER PJ~ SLEEP E ARA~ETFRS IN ~IPOLA~ DEPRFSSION. W . Jernajczyk Parameters of RE~ slee p were measured in lO endogenous bipolar depressive drug tree patiens and on 7th day of amitryptiline treatment. Each subject was examined during two consecutive nights before treatment and two nights during amitryptiline treatment.The following components of R ~ sleep were studied: 1.REM time, 2.REM latency,3.Rl~ activity, ~.REM density, 5.Time of interruptions during P~EM, 6.Latency of eye mdvement/LE~/. The results obtained were largely assessed by Student "s t-test.Moreover the neerest neighbor decisionrule / N N r u l e / w a s s;plied. The increase of: REM latency /0.O18 / , REM density / O.OO1 / ,

L~m lO.Ol~ I were found during amitryptiline treatment

WrocZaw,Poland.

31.05.03 THE EFFECT OF BARBITURATES ON EEG FREQUENCY SPECTRA IN RATS J. Plevov~, J, Form~nek Multiple time series of the voltages in the delta, theta, alphal, alphay, beta I and beta 2 frequency bands were measured in rats using the implanted epidural electrodes and a hybrid electronic system. The generally known changes of the EEG signal after the narcotic doses of barbiturates were replicated and described quantitatively. It was possible to show using factor analysis /principal component model/ that two factors determine the majority of the total variance of the voltages in the six frequency bands ms measured before, during and after the barbiturate narcosis. Chair of Clinical Pharmacology,Postgraduate Medical Institute and Institute of Hygiene and Epidemiology, Vfdensk~ 800, pay. B-3, Prague 4, 140 O0 Czechoslovakia

Institute of Psychiatry and Neurology,II Psychiatric Clin. al. S o b i e ~ i e g o 1/9 02-957 qarsaw, Poland.

292

31.05.04

31.05.05

TNE EFFECTS OF TRIM1PRAMINE ON DERRESSIVE SLEEP DISORDERS : A MULTICENTER OPEN STUDY. PiEMOINE. J.MOURET. F. RAFFAITIN

MELATONIN MODULATES THE ~ITANSERIN-INDUCED SLEEP CHANGES

Six hundred and seventy four depressed outpatients (431 females, 243 males, age : 43 +/- 11.9 years) gave their informed consent to participate in a multicentric open study on the effects of Trimipramine, a tdcyciic antidepressant, on clinical assessments of depression and measures of depressive sleep disorders obtained from visual analogue scales. Admission criteria included MADRS score > 21, clinical ratings and a check list of depressive symptoms allowing e multiclassification of depressive disorders (LEPINE). Moreover, patients had to complain of sleep disorders. Clinical assessments were performed at days O, 7, 14 and 28, using COV/anxiety scale, MONTGOMERY and ASBERG Depressions Rating Scale (MADRS), SPIEGEL sleep scales. In addition, patients had to fill 6ut dayly MOURET analogue visual scale concerning sleep quality and morning alertness. Each patient was prescribed oral Trimipramine with dayly doses ranging from 50 to 150rag (mean : 105 +/- 45 rag) The results showed a significant improvement of MADRS (days 14, 28 ) and COVl (days 14, 28 ). Whereas upon inclusion insomnia was a prominent symptom : difficulties to initiate (98.9 %} and maintain ((96.2 %) sleep and morning insomnia (87.2 %), a clear-cut improvement took place during the study since the percentage of patients who slept "perfectly" or "well" (0.8 % at day 0) reached 67.7 % at day 28. The subjective quantification on intra-sleep wake events dropped by 78.4 % during the study and so was it for the estimated sleep latency. The conciusiorl of this study suggests a beneficial effect of Trimipramine on the sleep disorders of depressed patients. Unite Clinique de Psychiatrie Biologique, CHRS LE VINATIER, 69677 LYON BRON, FRANCE

IN THE RAT

C. DuKovlc and A. Wauquier In humans, the selective serotonln-S 2 antagonist rltanserin increases slow w~ve sleep (SWS) (stages 3 and 4). I% has a more pronounced effect when it is given in the morning than in the evening (Idzlkowskl et al., Brain Bes. 378, 164, 1986). In rats, the deep SWS (SWS2) promoting action of rltanserln has been shown after administration during the light period (Dugovic and Wauquler, Eur. J. Pharmacol. 137, 145, 1987). In a first experiment, we investigated whether the effects of ritanserln in rats were modified by the light-dark cycle. Ritanserln (0.63 mg/~g l.p.) injected at the onset of the dark period produced no change in the amounts of SWS2 throughout the 24 h recording period. Paradoxical sleep (PS) amounts were not modified during t h e dark period but were significantly increased in the subsequent light period. When injected daring the light period ritanserln.induced a signls increase of SWS2 and concomitant decrease of PS daring 8 h. In a second experiment, we examined whether melatonln would interact with the ritanserin-induced sleep changes. Indeed, melatonin secretion exhibits a circadian rhythm, night concentrations are s e v e r a l times higher than the daytime ones. Melatonin alone injected 15 min before the light onset (1 mg/kg i.p.) had no effect on the different sleep stages during the 8 h recording period. When combined with ritanserin injected 15 min later (0.63 mg/kg i.p.), melatonln antagonized both ritanserin-lnduced SWS2 increase and PS decrease. In conclusion, the SWS2-increasing property of rltanserin is only evident during the light period of the rat, when the levels of melatonin are low. The fact that ritanserln fails to induce any sleep changes in melatonln-pretreated rats lends support to the hypothesis that circadian variations in melatonin co-determine the differential effects of ritanserin on sleep. Department of Neuropsychopharmaeology, Janssen Research Foundation, B-23~0 Beerse, Belgium

31.05.06

31.05.07

EFFECTS OF ETHYL LOFLAZEPATE (CM5912) ON SLEEP IN NORMAL HUMANS Y. Mizuki, N. Kajimura, M. Yamada, M. Tanaka and K. Inanaaa The e f f e c t s o f 2 mg and 4 mg of e t h y l l o f l a z e p a t e (CM6912), a new a n x i o l y t i c benzodiazeoine, on sleep were studied ~n 12 h e a l t h y male subjects. Polygraphic recordings were made f o r 6 consecutive nights from each subject. An i n e r t placebo was given on the f i r s t 3 nights and on the s i x t h n i q h t , and 2 mq or 4 mg of CM6912 was administered on the f o u r t h and f i f t h nights to 6 subjects, resp e c t i v e l y . The drug and placebo were administered o r a l l y 30 min a f t e r supper, and the record of polysomnoqrams s t a r t e d at 2230 hr and continued u n t i l the natural awakening o f the subjects in the next morning. The p o l y somnograms were evaluated by comnuterized automatic anal y s i s usina the method of i n t e r v a l histogram. Both doses of CM6912 ~ncreased t o t a l sleep time, and reduced sleep latency and t o t a l awakening time in a dose-dependent manner. Both doses s l i g h t l y decreased stage 1 sleep, s i g n i f i c a n t l y increased stage 2 sleeo, but s l i g h t l y decreased stages 3, 4 and REM sleep. These changes continued i n t o the s i x t h recovery n i g h t . No obvious changes were observed in s u b j e c t i v e assessments a f t e r administr a t i o n of CM6912. These r e s u l t s suggest that CM6912 is an e f f i c a c i o u s compound and has minimal adverse e f f e c t s on sleep. Dept. of Neuropsychiatry, Yamaguchi U n i v e r s i t y School of Medicine, 1144 Kogushi, Ube 755, JaDan

SLEEP AND SLEEP APNEA IN THE ELDERLY *Shingae T. * * ~ h r i Y. **Chiba S. **Matsumoto M. **Tanaka Y. **Nunomura A. and *Ohta K. Nocturnal sleep of 22 healthy aged subjects (aged 68-88 yrs.) was examined polygraphically to reveal the sleep characteristics in the elderly. The sleep architecture and apnea during sleep of the elderly were compared with those of 5 healthy young adults (aged 20-21 yrs.). The results were as follows: 1)Sleep architecture in the elderly was characterized by a prolonged TIB, a low SEI, a high ZSW, a high %SI and a low %SWS. 2)Number of apnea during sleep in the elderly was significantly large(av. 20.6 per night) compared with that of the young adults(av. 0.4). 3)There were a positive correlation between the number of apnea and the amount of %SI, and negative correlation between the number of apnea and the amount of %S2. 4)There wa~ a difinite sex difference in the sleep architecture and sleep apnea. The sleep characteristics of the elderly was more pronounced, and the number of apnea was larger in male subjects than in female subjects. These'findings indicates that the sleep in the elderly is light and disrupted and that the frequent apnea might contribute to these sleep changes, particularly in males. In addStion, findings of MSLT and daytime psychological functionings will be presented. * Sapporo Ohta Hospital,5-1,5-jo,Yamanote,Nishi-ku, Sapporo 063,Japan ** Department of Psychiatry and Neurology, Asahikawa Medical College, 4-5, Nishikagura, Asahikawa 078 Japan

293

31.05.08

31.05.09

ARE TWO GENETIC FACTORS INVOLVED IN NARCOLEPSY? T. Pollm~cher, P. Geisler and H. Schulz The Human Leukocyte Antigen (HLA) DR2 or a closely adjacent gene is necessary f o r the development of narcolepsy. We hypothesized, t h a t there might be a subclinical form of the disease among DR2 positive relatives of narcoleptic patients. As part of a study conducted at the Max-Planck-lnstitute of Psychiatry, we compared DR2 positive and DR2 negative f i r s t degree relatives, which did not show any clinical symptom of narcolepsy, with respect to their sleep pattern during the M u l t i p l e Sleep Latency Test (MSLT). The only s t a t i s t i c a l l y significant difference between the two groups was a higher number of naps with sleep latencies lower than 5 min in the DR2 negative group. On the other hand 6 out of 16 relatives (38 %) showed mean sleep onset latencies (mSOL), which in comparison to normative values are suspectable or indicate daytime drowsinessl Four showed a mSOL between 5 and lO min and two subjects a mSOL shorter than 5 min. Five of these subjects were DR2 negative. I t is not surprising to find subjects with a high tendency to sleep during the day among relatives of narcoleptics, since t h i s has been reported by other groups and family studies clearly have shown, that excessive daytime sleepiness (EDS) is found in more r e l a t i v e s than clearcut narcolepsy-cataplexy. But, our results suggest, that EDS may not be linked to the HLA-DR2 and raise the question, whether for the development of narcolepsy-cataplexy two genetic factors are necessary, The fact, that we found more DR2 negative "sleepy" subjects among healthy relatives, may indicate, that the combination of both genetic factors may lead to a high risk to develop narcolepsy/cataplexy. Department of Psychiatry, University of Freiburg, Hauptstrasse 5, D-7800 Freiburg, West-Germany

EFFECTS OF MODAFINIL ~ AN ALPHA ! ADRENERGIC TYPE PSYCHOSTIMULANT ON THE SLEEP OF MONKEYS. C. MILHAUD ET D. LAGARDE Modafinil is a new psychostimulant molecule already succes sfully tested in the treatment of narcolepsy. Its active mechanisms studies in mice evidenced a specific modulating (activating) action on central post-synaptic alpha ! adrenergic receptors. METHOD - Behavioral sleep of rhesus monkeys was observed in a first series of experiments using near infra-red camera recordings. 16 subjects were injected with 45 mg/kg, 12 with 22.5 mg/kg and 8 with 12 mg/kg Modafinil. The StudentFisher test for matched series was used. In a second series of experiments the electrographic recordings (ECoG) of 4 subjects were studied during chronic administration (4d) of 22.5 mg/kg MODAFINIL and ECoG of 4 more subjects were studied during acute per os administration of 3, 6 and 12 mg/Kg Modafinil. RESULTS - The percentage of total behavioral wake periods significantly increased compared to that observed under placebo conditions for the three tested doses (p
CERMA-DIVISION NEUROPHYSIOLOGIE 5 his AVENUE DE LA PORTE DE SEVRES 75731 PARIS-FRANCE ~ Laboratoire LAFON-94701 }~ISONS-ALFORT FRANCE

31.05.10

31.05.11

EFFECT OF DELTA SLEEP-INDUCING PEPTIDE (DSIP) O N G R O W T H H O R M O N E R E L E A S E (GH) IN V I V O IN R A T S E. K a w a t a , N. K a t o , K. T s u n a s h i m a , A. M a s u i , S. T a k a h a s h i a n d Y. A o k i DSIP originally isolated from rabbit serum, has been proposed to be a natural sleep-promoting substance. We have developed an assay for measuring DSIP and have found the presence of the circadian rhythm of plasma/urine DSIP. Recently D S I P is r e p o r t e d t o i n c r e a s e G H s e c r e t i o n in rats. It is t h u s p o s s i b l e t h a t t h e p e p t i d e is i n v o l v e d in m e d i a t i n g s l e e p - i n d u c e d G H r e l e a s e since the episodic secretion of GH occurs during slow wave sleep after sleep onset at least in humans. In t h e p r e s e n t s t u d y t h e e f f e c t o f D S I P administered intraventricularly on GH release w a s i n v e s t i g a t e d in r a t s a n d c o m p a r e d w i t h t h a t of i n t r a v e n o u s r a t G H - r e l e a s i n g f a c t o r (rGRF). Male Wistar rats weighing 300-400g were used. Cannulae'were implanted into the third ventricle and into the right jugular vein prior to the experiment. Blood was dra~ serially before and a f t e r the p e p t i d e a d m i n i s t r a t i o n and plasma was subjected to the assay for rGH (NIDDK). Under hhe anesthesia with pentobarbital, DSIP f a i l e d : t o i n d u c e an e l e v a t i o n of G H w h i l e r G R F exhibited a potent effect. However, DSIP was f o u n d t o h a v e a G H - r e l e a s i n g a c t i o n in u n r e s t rained, freely-moving rats. In c o m p a r i s o n w i t h r G R F , the a c t i o n o f D S I P a p p e a r s t o b e s l o w , and less marked, but long acting with a peak at 60-min after the injection. The results suggest that DSIP exerts GH releasi n g a c t i o n i n d i r e c t l y to t h e h y p o p h y s i s , w h i c h can be abolished under some non-physiological conditions. G R F s e e m s to h a v e a p r i m a r y e f f e c t on the somatotrophs. The effects of P-DSIP and anti-DSIP antibody will be discussed. D e p a r t m e n t o f P s y c h i a t r y , S h i g a U n i v . M e d . Sci. Seta Tsukinowacho, Otsu 520-21, Japan

A SLEEP LABORATORY COMPARISON OF LOKAZEPAM & FLURAZEPAM AS HYPNOTIC AGENTS IN CHRONIC INSOMNIACS D.J. McClure, J. Walsh, H. Chan@, A. Olah, R. wilson, J.C. Pecknold Lorazepam 2 mgm and Fl~razepam 30 mgm were found to be effective and safe for treating chronic insomnia with lorazepam having more favourable effects on sleep than flur azepam. Eight chronic insomniacs aged 29-60 years were monitored in a sleep laboratory twice weekly for a total of 25 nights in a 16 week double-blind cross over clinical trial. The two drugs lorazepam and flurazepam were given for 3. weeks each with 3 weeks of placebo between the drug periods and also after the second drug period. Baseline values were recorded during a 2 week placebo period before the first drug was given. In addition subjective estimates of sleep, vigilance tests and adverse effects were recorded. Findings showed l o r a z e p a m p e r f o r m e d better than flurazepam in most sleep parameters. With lorazepam there was improvement from baseline in percentage of sleep time (P<. 05) ; in total wake times after sleep onset (F(.01) and in last third of night (P<.05); in percentage of stage 2 (P<.05) (weeks I, 2, 3) and in percentage of night in stage 4 (weeks 2 and 3). Only total wake time from baseline improved (P<.05) with f!urazepam (week 2). Objective and subjective sleep parameters did not correlate well for either drug and neither drug impaired REM sleep or vigilance test performance. Side effects were few and none was unexpected. Neither rebound insomnia nor early morning insomnia occurred with either drug. Some of the findings are in agreement with previous investigations others are not. The reasons for this are discussed. University of British Columbia, Department of Psychiatry, Vancouver General Hospital, Room 3150, 910 West IOth Avenue, Vancouver, B.C. , CANADA V5Z 4E3

294

31.05.12

31.05.13

EFFECIs OF ~ITANSE~IXON CLINIC~ AX) s

SLEEP VARIABLES IN )YSIHYH!C PATIENTS

!:hi~: F.~rr_i~g!~6._.Ltug~i~=.E:_L_~rh 8: _L_arg_o _.._dJ._Lu~._.t t_..,:_~g ~itansm-in ie ~ eelecHve 5-NT2 antag0ni~t ~hich ioocr~e.~ s t ~ wa~e sleep (.~NB) in .noraal volunteer~. Several clinical studies show that this coagound is therapeutically ef..'ecti~e in dysthyek patio.ups, iepr0vir, g the depressive sy=pt0ms as ~ell as the subjective sleep disturbances. Therea0re, the hypothesis urines that the therapsuticil ~fects of ritanserin ~re related to i t s $leep ieprcving qaatitiesl na~el,v to a speci;ic increase of ~gS. ~, order

te ts=A this hypoth.~sis,

.e studied .~he eL%c~n ~ tiler:eerie

i.~ a

sample of d isthyeic ~.~tiemts "-.n:;l)selected accordi.ngto ~ i11 criteria. Fatie.nts ~ere given ,no eedicaii0n, except contraceptices, 2 -~-s prior t.n the baseline reccrdinI. Afterwards s the.* received a double-blindtreat~en.t el[her , i t h ritaneerin (!0 ~B/day, p.o.) or =e,tching placebo during 4 ,ks. A sscond rec.nrdin~~s z:aded~ring the !est 7 days nf trset~e.nt. E~ch recording include,~ three nonse..utivenights. P0ligraphic variables sttldiedincluded EEG in four OF nine ch~nnel~c 2 E~G channsle~ EEG respiration and digital p~ise. ~e clinical evolution ,as *onitored ~ith p.~.*chiatri~Fating scales ".'or anxiety and deprssion. Statistical co,~parisons~ers perfor=ed {or both c.q.ni:a!and sleep ~,arieb'es, be(nre a.nd a~ter treatment, in the two groups of patients (rilanserin% .n=!i~ placebo~ n:iO),. FLitanserintre.:t~entproduced en increase of -~;~8~-4 NRs ~ut ~he p~.-a~eters related to s)e.~,ncntlnuib,,and RE~ s!eep ,~,erenot changed. Furthermore~ more cycles of SWS ne:e ~hner.~d, F~sitiveand significantcorrelations~ere found be~.~.ee.nthe i~row~ent of soce cli.n~celvariables and the increaae of S@S:both }n !he ritanseri.ngroup and in the total sample. ~itarssrin also changed the amoun~ end di~tributio.n of sees pha:~s events, ~.ith a clear e,;Fect on the occurence u( [-coeplezes. These rl:'.-l!]ie~g~eS ~dth U!e i~y~ol{~esi.:that the there~euiicei properties ~{ =it=,:::;:i: ere :eiaied l:oi;,se:;scte o.n aleep. r e~.pla~a'.'_i~ can poesi~i!. ~.e Found consideringthe role of ~e~::tonero_ic9~ti~a.s in the ~en~.ro"cF L~th sleep a~d mood. ]t is also ~_u~g~sted that a detailed a.na~ysie o~ phasic as,eats ~ay

constitute a ,-,se.%lapproachto study the effects of ce,~tralh aot'~e d~u@s. LehoratOrio de EEB. Centr~~e Estudos E)as Ii, onis~ Hc.epitaide SaF:ta ~aria, Li sbc.a. F'o~tubal.

31.05.14 SLOW ~AVE AND REM HOVING RATS AND CATS.

THE EFFECTS 0s CHRONIC RITANSERIN TREATMENT AND kffTHDRAWAL

ON SLEEP. G. Hammond, C. Idzikowski t S. Burton and R. James Previous studies have shown that 10mgs ritanserln, a 5-~T2 antagonist, increases greatly the duration of Slow Wave Sleep (SWS) (Idzikowski at al, Brain Research, 378, 164, 1986) and that this increase is maintained for at l e a s t two weeks (Idzikowski et el, Psychopharmacology, 93, 416, 1987). A dose-response study has also shown that Img ritanserin can increase the duration of SWS (Idzikowski et el, Sleep Research, 16, 83, 1987). This pilot study extends those findings by examining the effects of 4 weeks treatment with img ritanserin and also looks at the effect of withdrawal. Six healthy volunteers participated in this single-blind study. Subjects began with a one ~eek placebo run-in, followed by 4 weeks treatment and then a 1 week wash-0ut, The sleep recordings made on triplets of nights were scored using Rechtschaffen and Kales. (Times in minutes) Stage 1 Stage 2 SWS KEM Total Sleep Baseline Early drug 1 week " 2 weeks " 3 weeks " 4 weeks " Initial withdrawal One week withdrawal

I0 5 5 5 6 5 6 8

273 250 256 235 251 259 259 281

62 89 81 92 92 85 73 53

95 98 105 III 99 102 Iii 99

446 450 451 449 453 455 454 462

The duration of SWS increased significantly with rftanserin (F=4.7, df=23, 114, P
31.05.15 SLEEP ARE ENHANCED

BY RILUZOLE IN FREELY

J.M. Stutzmann , J.C. Blanchard and P.M. taduron R j l u z o l e (2-amino 6-trJfluoromethoxyhenzothJazole, PK 26124 or 54274RP) is a drug that possibly i n t e r f e r e s at the glutamate neurotransmission. This drug protects animals against different models o f convulsions i n c l u d i n g those induced by glutamate Icy in r a t s or g l u t a m i c a c i d d e c a r b o x y l a s e i n h J b i t o r s ip In mice and r a t s and t h o s e induced by maximal e l e c t r o s h o c k in mice ; i t a l s o affects epileptogenic d i s c h a r g e s in t h e k i n d l i n g phenomenon in r a t s . B u t i n c o n t r a s t w i t h b a r b i t u r a t e s and b e n z o d i a ~ e p i n e s , it is ineffective against seizures induced by p e n t y l e n e t e t r a z o l e , bicuculline or pJcrotoxin. Moreover, i n biochemical models, i t decreases the spontaneous r e l e a s e of g l u t a m a t e , t h e r e l e a s e of dopamine induced by g l u t a m a t e in t h e p u s h - p u l l model in t h e c a t s t r i a t u m and the g l u t a m a t e induced r e l e a s e of aspartate in r o d e n t c e r e b e l l a r c e l l s . The p r e s e n t e l e c t r o c o r t i c o g r a p h t c (ECoGI s t u d y i s d e a l i n g w i t h t h e c h a r a c t e r i s a t i o n of the c e n t r a l e f f e c t s of t h i s compound : 1) on t h e s l e e p - w a k e f u l n e s s c y c l e in t h e r a t and in t h e c a t ; 2) on t h e ECoG s p e c t r a l a n a l y s i s i n the r a t , using a fast fourier transform analyzer. R i l u z o / e was g i v e n by o r a l r o u t e a t 0.5, 1, 2 and 8 mg. k g - I in f r e e l y moving r a t s Ca=6 per d o s e ) . D u r a t i o n o f slow wave s l e e p (SWS) and r a p i d e y e movement s l e e p (REM) was found to I n c r e a s e in a d o s e - d e p e n d e n t manner from 1 mg. kg-1 (+10~, +46~, +52~ r e s p e c t i v e l y f o r SWS ; +37~, +84~, +89% r e s p e c t i v e l y for REM) at the expense o f awakeness (-12%, -27~, -36~ r e s p e c t i v e l y ) . S~rS l a t e n c y was significantly reduced from 2 mg/kg whereas t h e f r e q u e n c y o f a p p e a r a n c e o f REM p h a s e s was statistically Increased. An i n c r e a s e o f t h e power s p e c t r u m s p e c i a l l y in t h e t e t h a (4-7 Ha) and t h e d e l t a (~4 Ha) a c t i v i t i e s In t h e f r o n t o - p a r i e t a l c o r t e x was shown a f t e r 2mg. k g - I o f R i l u z o l e . In the c a t a t t h e s i n g l e dose o f 2 mg. kg-1 p.o. R i l u z o l e was a l s o a b l e to i n c r e a s e SWS and REM. Awaking effect of caffeine (an a n t a g o n i s t of central adenosine receptors) but not t h a t of DL-amphetamJne (which increases the release of b i o g e n i c amines) was blocked by t h e hypnogenic e f f e c t of riluzole in t h e r a t , thus t h e a d e n o s i n e hypothesis i s p l a u s i b l e to e x p l a i n i t s e f f e c t on s l e e p . Since R i l u z o l e i n c r e a s e s SWS but a l s o REM, t h e p r e s e n t s t u d y s u p p o r t s the h y p o t h e s i s t h a t RJluzole m i g h t he of i n t e r e s t i n the t r e a t m e n t of p r i m a r y s l e e p d i s t u r b a n c e s related to e f f e c t i v e d i s o r d e r s and p r e l i m i n a r c l i n i c a l s t u d i e s i n d i c a t e that Rilu~ole can improve negative symptoms in schizophrenic p a t i e n t s . RHONE POULENC SANTE, Centre de Recherches de V / t r y , 13 quai J. Guesde, 94400 V]TRY SUR SEINE, FRANCE.

EFFECTS OF M O C L O B E M I D E (Re 1 1 - 1 1 6 3 ) ON SLEEP IN HEALTHY SUBJECTS Th. R e i n e r t s h o f e r R. L u n d , E. R ~ t h e r , G. L a a k m a n n The antidepressive effect of most antidepressant drugs is s u p p o s e d to be connected with their REM sleep suppression. Mainly classical ~AO-inhibitors cause a marked REM suppression. Moclobemide (M),a selective,reversible,and short-acting (half-life about 2 h) i n h i b i t o r of the type A MAC showed antidepressant efficacy, yet no suppression of REM sleep in d e p r e s s e d patients,though REM sleep suppression was observed in c a t s in c o m p a r a b l e doses.As an explanation for this finding,the time of administration and the half-life of M were discussed. In t h i s s t u d y t h e i n f l u e n c e of M o n s l e e p p a r a meters is c o m p a r e d to placebo was investigated in h e a l t h y subjects,especially the influence on REM sleep after drug intake just before sleeping time. Methods: 20 h e a l t h y male subjects (aged 22-44) were included in t h e double-blind study (two drug groups: Group A: PPPV~'PP,group B: PPPPP V%').Placebo resp. 150 mg M were administered at 10:30 p.m. Polygraphic sleep recordings were performed for 7 consecutive nights (lights off: 10:30 p.m.,lights on 6.30 a.m.). Results: Preliminary data do not show statistically significant differences between placebo and verum nights regarding sleep latency,REMlatency and duration of the first REM episode. Summary: M in an e f f e c t i v e antidepressant dosage does not suppress REM sleep in healthy subjects.This result indicates that the antidepressant efficacy of a compound and REM sleep suppression are not necessarily connected. Psychiatrische Klinik der Universit~t Mdnchen, NuRbaumstraRe 7, D - 8 0 0 0 M ~ n c h e n 2

295

32.01:01

POSTER PRESENTATION 32.01

Receptor Studies

EFFECT OF THE ANTI-DEPRESSANTS ON ~-ADRENOCEPTORS AND ISOPROTERENOL INDUCED CYCLIC AMP ACCUMULATION IN C6 GLIONA CELLS T.Ebisawa.A.Noriya.Y.Watanabe,T,Higuehi and T,Yamauch~ The direct effects of chronic treatment with the antidepressants on the number of ~-adrenoceptors and the accumulation of cyclic AMP stimulated with isoproterenol were studied on C6 intact cultured cells. The cells were treated chronically for 5 days with I0 - s M decipramine(DNI), imipramine(INI) o r mianserine(NIA). Binding studies were performed with the radioligand [ 3 H]CGP-12177. These treatment did not induce t h e d e c r e a s e in the number of fl-adrenoc e p t o r s nor t h e change of a f f i n i t Y . On the o t h e r hand, c h r o n i c exposure(4 days) to DMI or NIA led to a decrease in isoproterenol-induced accumulation of c y c l i c AMP in a dose dependent manner ( 1 0 - 7 ~ 1 0 - s N). When t h e c e l l s were cultured with ha!eperido!, the decrease in isopr~tereno!-induced accumulation of cyclic AMP was found only in the concentration of 10-bM and 5 Xl0 -a M. These result suggest that antJdepressants(DMI and MIA) directly act on the second messenger system without any change of fl-adrenoceptors when these drugs were administered chronically. In addition, the concentration of 10 -s~10-TM of antidepressants should be used for these kind of experiments because the change of the response of cyclic AMP with I0- s ~ 10-aM was found to be not specific for antidepressants Department of psychiatry, SaJtama Medical School, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama 350-04 Japan

32.01.02

32.01.03

PLATELET 3H-CLONIDINE AND aH-IMIPRAMINE BINDING IN DEPRESSION T.Takeda t T.Harada~ Y.Fujiwara, T.Yamalnoto and S.Otsuki We measured both platelet all-clonidine ( a2adrenergie agonist) and aH-imipralnine binding in 17 normal controls and 14 d e p r e s s e d patients (iS unipolars, 1 bipolar) without medication. An increase in the Bmax for aR-clonidine binding and a decrease in the Bmax fo~ the 3Himipramine binding from depressed patients were observed as compared to controls. There was positive correlation between the Bmax of the 3H-clonidine and aH-imipramine in normal controls, but no significant correlation between these p&rameters in depressed patients.There was significant positive correlation in all-clonidino binding between the Bmax and the total score of the Hamilton Depression Rating Scale in depressed patients,'and between the Bmax and the age in normal controls. On the other hand,in SH-imipramine binding,no significant correlation was observed among Bmax, the total score for the Hamilton scale and age. These data suggest that platelet SH-clonidine and sH-imipramine binding may represent different biological and clinical markers and that SH-clonidine binding may be more dipendent on the clinical state of depression than 3H-imipramine binding. Department of Neuropsychiatry, Okayama Univer & sity Medical School, 2-5-1 Shikata-cho, Okayama 700, Japan

AUTORADIOGRAPHIC LOCALIZATION OF 3 H-IMIPRAMINE BINDING SITES IN RAT BRAIN T. Tsuiimura , T. Aso, A. Himeno, K. Hayashida, M. Hayashida, T. Tateishi~ Y. Nakane, M. Niwa*~ M. Ozaki* The quantitative autoradiographic localization of ~HImipramine (IMP) binding sites in the rat brain was studiedusing a modified version of the technique used by Grabowsky et al.. Likewise localization of ~-5HT binding sites in the rat brain were studied using a modified version of the technique used by Rainbow et al.. The areas of highest concentration of 3H-IMP binding sites were observed within the dorsal raphe nucleus, and the reuniens thalamic nucleus. These areas were also found to have high concentrations of 5-HT cell body an~ 5-HT neuron respectively. Further, the distribution of ~H-IMP binding sites showed good correlation withthat of 3H-5HT binding sites. i ~ administered twice daily for 14 days caused a signlflcant decrease in H-IMP binding sites in both the dorsal raphe neucleus and the reuniens thalamic nucleus, but not in other regions. The decrease was observed 48 hours after the last injection, hut at 72 hours the effect had disappeared.

296

9

.

.

3

Department of Neuropsynhiatry, Nagasaki University School of Medicine 7-1 Sakamoto-machi , Nagasaki 852 Japan ~Department of Second PharmaCology, Nagasaki Universiy School of Medicine 12-4 Sakamoto-mchi 852 Nagasaki

32.01.04

32.01.05

PGE, F O R M A T I O N IN B L O O D P L A T E L E T S F R O M H E A L T H Y CONTROLS AND SCHIZOPHRENICS H. Kaiya*, M. U y e m a t s u x, E. Idaka ~, M. Nozaki* Abdulla & Hamadah(1975) first showed marked r e d u c t i o n in PGE, f o r m a t i o n b y s t i m u l a t i o n of A D P in b l o o d p l a t e l e t s from schizophrenics, which was assayed by a silica thin layer c h r o m a t o g r a p h y . T h i s r e s u l t is one of the b a s e s of PGE, d e f i c i e n c y h y p o t h e s i s of s c h i z o p h r e n i a . To c o n f i r m the hypothesis, we r e - t e s t e d the study, using high performance liquid radi o c h r o m u t o g r a p h y ( radio -HPLC ) . All subjects including normal control and schizophrenics who were out-patients or i n p a t i e n t s in t h e o p e n - d o o r s t a t i o n c o n s e n t e d to this study. P l a t e l e t rich p l a s m a was m a d e from 9 ml of b l o o d c o n t a i n i n g 1 ml of 2 . 5 % s o d i u m citrate. In t h e first experiment, washed plate]ets were prepared by a gel filtration method using Sepharose 2B. U p t a k e of [l-z~C] 8,11, ]4-eicosatrienoie acid by the washed p l a t e l e t s in the p r e s e n c e of A D P ( 0 - 5 0 G - ~ M ) - w a s investigated. Metabolic products were determined by a r a d i o - E P L C . In this e x p e r i m e n t no PGE, was d e t e c t a b l e , b u t PGF, ~ was i d e n t i f i e d . The b a s i c c o r p o r a t e d ratio was 0 - 1 . 3 % for n o r m a l control, a n d 0 - 0 . 0 3 % for s c h i z o p h r e n i c s . In t h e s e c o n d e x p e r i m e n t s , w a s h e d p l a t e l e t s w e r e p r e p a r e d by a m e t h o d as d e s c r i b e d b y A b d u l l a a n d Hamadah. In t h i s c a s e PGE~ c o u l d be i d e n t i f i e d . The basic e o r p o r a t e d ratio was 0 - 0 . 1 % for n o r m a l c o n t r o l s and 0 - 0 . 0 1 % for s c h i z o p h r e n i c s .

P L A T E L E T M O N O A M I N E O X I D A S E IN D E M E N T I A OF ALZHEI MER TYPE U.Bonuccell~,P.Piccini,P.BongioannJ,A.Nuti,G.M. Pacifici,A.Muratorio P l a t e l e t m o n o a m i n e o x i d a s e ( M A O ) a b n o r m a l ~ t ~ e s have b e e n p r o p o s e d as a m a r k e r ~n several n e u r o p s Z c h ~ a t r i c d ~ s o r d e r s . Some a u t h o r s o b s e r v e d an ~nc r e a s e d p l a t e l e t MA0 a c t i v i t y Jn p a t i e n t s w i t h senile d e m e n t i a of A l z h e J m e r type(SDAT), w h i l e others did not report s ~ m ~ l a r f~ndJngs. The a~m of p r e s e n t study is to v e r i f y these d a t a , u s i n g a d ~ f f e r e n t s u b s t r a t e and c o n s i d e r i n g l a r g e r control and p a t i e n t groups. We a s s a y e d p l a t e l e t MAO a c t i v i t y by m o d i f i e d B e l m a k e r et al.'s method, w i t h b e n z y l a m ~ n e as s u b s t r a t e , ~ n 30(12 males and 18 f e m a l e s ) d r u g - f r e e SDAT patients. The d i a g n o sis was made on the b a s ~ s of an e x t e n s i v e ser~es of n e u r o p s y c h o l o g ~ c a l t e s t s , n e u r o l o g i c a l exams, and c o n f ~ r m e d by CT. T w e n t y h e a l t h y subjects( 9 males and II f e m a l e s ) w h o had no e v i d e n c e of neur o p s y c h i a t r i c ~ l l n e s s s e r v e d as a g e - m a t c h e d controls. We r e p o r t e d that the p a t i e n t s had a s ~ g n l f ~ c a n t l y ( p < O . O O l ) h d g h e r enzyme a c t i v i t y than nor mal s u b j e c t s : 4 3 . 2 7 ~ l . 9 1 vs 2 6 . 8 4 ~ 0 . 9 5 ( m e a n ~ SEM~ nmols/mg protein/h. Our f i n d i n g s agree w ~ t h A d o l f s s o n et a l ( L i f e S c s 2 7 , 1 0 2 9 , 1 9 8 0 ) w h o r e p o r t e d a s i g n i f i c a n t ~ncrease in b r a i n MA0 a c t i v i t y of p a t i e n t s w ~ t h S D A T , a n d s u g g e s t that b i o c h e m i c a l d e f i c i t s in SDAT may i~ volve m o n o a m i n e r g ~ c o t h e r thsncholiner~icsystems.

*Dep~rtment of N e u r o l o g y and Psychiatry, and ~Pharmaeology, Gifu University School of Medicine, Tsukasamaehi 40, 5 0 0 G i f u , Japan. ~Department of C h e m i s t r y , F a c u l t y of E n g i n e e r ing, Gifu U n i v e r s i t y , 501-11 Gifu, Japan.

I s t i t u t o di C l i n i c a N e u r o l o g ~ c a , U n i v e r s i t & sa. V i a R o m a 67, 5 6 1 0 0 P~sa, Italy.

dJ P~

32.01.06

32.01.07

PLATELET SURFACE M ~ B R A N E 5-HT BINDING SITES: MODULATION AND INVOLVEMENT OF G-PROTEINS; PRODUCTION OF MONOCLONAL ANTIBODIES. K. S[ha, A. A. Sankar~ J. M. Wilkinson and N. Crawford

OCMPARISON OF 5-HT INDUCED SHAPE CHANGE ~,--CI~125I-LSD BINDING IN HUMAN ~ . C. Brazell r S. J. M ~ l u e and S. M. Stahl. Evidence suggests that the 5-HT receptor situated on human platelet membranes is analogous to the 5-HT 2 receptor in the CNS (D. de Chaffoy de Cou~ccelies et al., J. Biol. C ~ . , 260, 7603, 1985). ~nerefore, the platelet shape change and subsequent a g . ~ t i c n induced by 5-HT may provide a functional assay for 5-HT2 receptors (M. Graf & A. Pletscber, Br. J. Phazmac. 65, 601, 1979). Unfortunately, the effect of 5-HT on h%~an platelets is weak and reversible, which makes t/he detezmination of sub-maximal s ~ p e change difficult. The present study describes the advantage of using an analogue to digital converter (ADC) to represent the degree of platelet shape c ~ n g e in n~nerical fozm. ~3ne correlation of 5-H~ induced shape 12~ige with platelet binding of the 5-HT 2 ligand, -LSD, was then determined. H ~ a n platelet samples (1-2 x 108 platelets/500 ul) were measured for shape change by a PA.D-4 platelet aggregometer (BiG-Data Corp. ). 5-HT induced shape change in a dose dependent manner, EC50 1.8 ~M. IC50 values w~re obtained by adding test drug 5 rain prior to addition of 5-HT (3 MM). Binding was perfozmed using 125I-LSD (2 rLM), specifically defined %&th ketanserin (i0 ~M). A single receptor population was found with a K D of i.i0 + 0.12 nM and Bmax of 14.5 + 6.0 pm/g protein. ~mparison of IC50 values for inhibition of binding and shape change (potency series s p i ~ > ketanserin > RU 24969 > 80H-DPAT > sulpiride) showed a significant correlation (r = 0.75, p = 0.007, n = 2-5) and validates the determination of shape d~nnge via ADC as a functional assay for platelet 5-HT 2 receptors. ~ e regulation of platelet 5-HT 2 receptors and those in the CNS ~ill be discussed. Merck Sharp and Dchme, Terlings Park, ESst%ick Road, Harlow, Essex, England.

(3H)5-HT binding and displacement studies with highly purified platelet surface membranes have been carried out to further characterize the human blood platelet 5-HT receptor and transport systems. Additionally, 5-HT dependent OTPase activity (i) has been measured, the involvement of O-proteins studied using bacterial toxins (1,2) and the role of some effeetors of membrane signalling investigated. As shown for spinal 5-HT binding sites (3), the platelet surface membrane (3H)-SHT binding states are subject to peptinergic modulation. This feature is also reflected in changes in GTPase activity and in the sensitivity of some of the G-proteins to ADPribosylation. 5-HT bindin~ proteins have been solubilised from human platelet surface membranes using digitonin (4) and purified further by affinity chromatography on 5-HTlinked to Sepharose 4B (5). Mice were immunized with these proteins and the resulting ELISA and Wester~ blot positive sera used in displacement studies with ( H)5-HT and platelet surface membranes. Six hybridoma cell lines have been cloned and the monoclonal antibodies produced partially characterised and used for further studies of the interaction of 5HT platelet surface membrane receptor and transport complexes. i. Housley, D. et al. Biochem. J. (1986), 234, 737-740. 2. Aktories, K. et al. Nature (1986), 322, 390-392. 3. Fuxe, K. et al. Neuropharmacology (1983), 22, 3B, 389400. 4. Wesemann, W. & Hoffmann, D. Thromb. Res. (1985), 39, 639-700. 5. Sturgeon, R. J. & Sturgeon, C. M. (1982) Carbohydrate Research, 103, 213-219. Department of Biochemistry, Hunterian Institute, Royal College of Surgeons of England, Lincoln's Inn Fields, London, WC2A 3PN, U.K.

297

32.01.08

32.01.09

HIGH N O N - S P E C I F I C B I N D I N G OF C H L O R I M I P R A M I N E TO PLATELET AND N E U R O N A L M E M B R A N E S E. T. M e l l e r u p and P. Plenge In patients or v o l u n t e e r s treated w i t h chlori m i p r a m i n e p l a t e l e t 3 H - i m i D r a m i n e b i n d i n g is strongly reduced. The r e d u c t i o n l a s t e d for 7 days after intake of one single dose of 50 m g of c h l o r i m i p r a m i n e . Also in vitro t r e a t m e n t of p l a t e l e t m e m b r a n e s w i t h low c o n c e n t r a t i o n s (25 nM) of c h l o r i m i p r a m i n e r e d u c e d 3 H - i m i p r a mine binding. The e x p l a n a t i o n for the r e d u c t i o n was simply that a large amount of c h l o r i m i p r a mine r e m a i n e d in the m e m b r a n e s d u r i n g washing. In fact more p r o t e i n than c h l o r i m i p r a m i n e was removed from the m e m b r a n e s d u r i n g the initial washes, so that the c h l o r i m i p r a m i n e c o n t e n t per mg m e m b r a n e p r o t e i n increased. S i m i l a r results although to a lesser degree was o b t a i n e d u s i n g paroxetine, whereas i m i P r a m i n e c o u l d be w a s h e d away. In rat as well as in h u m a n neuronal m e m b r a n e s c h l o r i m i p r a m i n e and D a r o x e t i n e was even more resistant to w a s h i n q p r o c e d u r e s and p r a c t i c a l l y remain4d c o n s t a n t in r e l a t i o n to m e m b r a n e protein. The a m o u n t of c h l o r i m i p r a m i n e r e m a i n i n g in the m e m b r a n e s e x p r e s s e d as f m o l / m g p r o t e i n was 10-30 times g r e a t e r than Bmax for 3H-imip r a m i n e b i n d i n g . These findings raises the q u e s t i o n w h e t h e r c h l o r i m i p r a m i n e could be g i v e n in smaller doses than the usual p r e s e n t practice. P s y c h o c h e m i s t r y Institute, R i g s h o s p i t a l e t , DK-2100 Copenhagen, Denmark.

DECREASE OF PLATELET SEROTONIN LEVEL IN RATS ,~ A MONITOR OF SEROTONIN UPTAKE II~iBITION IN THE COURSE OF TREATMENT WITH VARIOUS A N T I D E P R ~ N T S B. Jernej, L. ~i~in-~ain ~nd S. Iskrid

32.01.10

32.01.11

D-I AND D-2 RECEPTOR ACTIVATION CONTRIBUTE TO 7HE LOCOMOTOR ACT[%qTY EFFECTS OF DOPAMINEAGONISTS J. Offermeier and J.M. van Rooyen Dopamine receptors have been classified into t~'o biochemically distinct classes (D-I and D-2). The functional roles of these receptors in the generation of dopamine mediated behaviours remain unclear. In this study selective D-I and D-2 agonists and antagonists were used in an attempt to clarify- the roles of D-I and D-2 receptors in the mediation of locomotor activity (K&). K& was measured with the aid of a Digiscan Animal Activity .Monitor System. Seatchard analysis of 3H spiperone binding provided Bmax- and KD-values for striatal D-2 receptors. Dopamine concentrations in the striatum were determined by HPLC. The selective D-I agonist SKF 38393 did not increase LA in rats. The LA-increases produced by the selective D-2 agonists apomorphine and bromocryptine were attenuated after pretreatment with sulpride (a selective D-2 antagonist) and SCH 23390 ( a selective D-I antagonist). Pretreatment with metyrosine attenuated apomorphine and bromoc~-ptine induced LA and significantly decreased the dopamine concentration in the striatum, but did not alter the densities or affinities of ~H spiperone binding sites in the striation or nucleus aceumbens. The metyrosine attenuation of the D-2 agonist induced L~ could be reversed by SKI= 38393. It is concluded that D-I receptor activation by endogenous dopamine may modulate the I_~ induced by D-2 selective agonists.

DEGLYCOSYLATIO~ OF MUSCARINICACETYLCHOLINE RECEPTORS K. Ohara, T. Haga, A. lchiyama and ..Ken_:_Ohara

Platelets are nowadays widely accepted as a peripheral pharmacologic and toxicologic model for presynaptic serotonergic nerve terminals, primarily with respect to serotonin (5-hydroxytryptamLne) uptake. Since platelets lack the potential for serotonin biosynthesis their content of this amine depends on its uptake from the surrounding plasma. The pharmacodynamic effect of various antidepressants is believed to be associated with the inhibition of serotonin reuptake into presynaptic serotonergic nerve terminals in the brain. These drugs lead to an analogous inhibition of serotonin uptake into platelets. We have recently developed a reliable model for prolonged individual monitoring of platelet serotonin levels in rats (I). Here we apply the mentioned model in psychopharmacologic research. In the course of chronic treatment of rats with different antidepressants we monitored their platelet serotonin levels. ~rhis simple method enabled us to get insight into pbarmacodynamic effects (serotonin uptake inhibition) of investigated antidepressants "in vivo" regarding dose-response relationship, time-course of the effect and to compare their relative potencies (i.e. effects of equimolar doses). (I) B. Jernej, L. ~i~in-~ain and S. Iskri6. Neuroscience, Supplement to vol 22 (1987) $371 Institute"Ruder Bo~kovi6", YU - 41001ZAGREB

~uscarinic acetylcholine receptors ~ere purified from p o r c i n e cerebrum by means of s i n g l e a f f i n i t y chromatography as described previously (specific [3H~ QNB binding a c t i v i t y , 2-4 nmol/mg of protein) (Haga K. and Haga T. J.Biol.Chem. 260, 792% !985). After treatment with appropriate concentration of endoglycosidase F, the molecular weight of muscarinic acetylcholine receptor were deduced from about 70 KDa to about 50 KDh and the r e s i d u a l glucose was not detected by ~heat germ agututinlne pero• Displacement curve of a g o n i s t for the

[3HZ Q~B

binding with deglycosylated receptor preparations ~ere almost same as that ~ith original receptor. Scatchard analysis of

[3H~ Q~B binding also showed

that deglycosylation had no effect for the affinity. These results suggest that glucose of receptors do not play an i m o p r t a n t r o l e f o r t i g a n d s b i n d i n g to receptors. Dept. of Neurology and Psychiatry Hamamatsu Eniv.

Dept. of Pharmacology and ~RC Unit for the Design of Catecholaminergic Drugs, Potchefstroom University, POTCHEFSTROOM, 2520, South Africa.

298

School of ~edicine, 3600 Handa-cho, Hamamatsu City, Shizuoka Prefecture, JAPAN431-31

32.01.12

32.01.13

LOCALIZATION OF HUMAN DIAZEPAM BINDING INHIBITOR (DBI) GENE BY "IN SITU" A.~fBRIDIZATION. M.A. DE BERNARDI and I. MOCCHETTI Diazepam Binding inhibitor (DBI) is a putative allosteric modu!a
ETHANOL PREVENTS ADAPTIVE CHANGES OF BRAIN RECEPTORS AND BEHAVIOR TO CHRONIC TREATMENT WITH PSYCHOACTIVE DRUGS H. Rommelspacher and J. Wolffgramm, Dept. Neuropsychopharmacology, Free University, D-IO00 Berlin !9, F.R.Germany. Ethanol prevents the decrease of the number of 8adrenoceptors in the cerebral cortex of rats induced by chronic treatment with desipramine. The activation of the adenylate cyclase, the second messenger, by B-adrenergic agonists is reduced less than a f t e r treatment with DMI alone. ETOH i n h i b i t s the neuronal adaptation at the functional level as well. Examples were exploratory behavior (crossings, rearing), cognitive performance in an active avoidance paradigm, and 5hydroxy-tryptophan-induced wet dog shake behavior, in two paradigms spontaneous m o t i l i t y and apomorphineinduced hypothermia, ETOH did not affect the action of DMI. Analogous experiments were performed to investigate adaptive changes of dopaminergic receptqrs to chronic haloperidol treatment. The increase of [~ binding sites in s t r i a t a l membranes was prevented by concomitant treatment with ETOH. H induced an i n i t i a l drop of locomotor a c t i v i t y followed by a recovery during the second week of treatment. This recovery was missed when H and ETOH was applied simultaniously. Comparable effects were found with other paradigms like catalepsy, sedation in the open f i e l d , and rota rod performance. Injection of apomorphine in rats treated chronically with H showed an increase of the number of l i c k i n g s , sniffings, and stereotypies of the paths. Some of these behaviors were reduced by concomitant treatment with ETOH.

32.01.14 P R E S E N C E OF A 3H-FLUNITP~.ZEPAM B I N D I N G I N H I B I T O R tN THE S E R A OF P S Y C H I A T R I C P A T I E N T S A. L u c a c c h i n i , G. G i a n n a c c i n i , C. M a r t i n i , C. Sanna, S. M i c h e l i n i , G.B. Cassano, D. M a r a z z i t i The p r e s e n c e of s p e c i f i c r e c e p t o r s for the b e n z o d i a z e p i n e s in b r a i n of m a n y species, i n c l u d i n g man, s u g g e s t s the p o s s i b l e e x i s t e n c e of e n d o g e n o us l i g a n d s a c t i n g on these r e c e p t o r s . Our s t u d y a i m w a s to e x p l o r e w h e t h e r c o m p o u n d ( s ) interacting with benzodiazepine receptors might exist in p s y c h i a t r i c p a t i e n t s ' sera. We i n c l u d e d in the study 52 p a t i e n t s a f f e c t e d by d i f f e r e n t p s y c h i a t r i c d i s o r d e r s , a c c o r d i n g to DSM II[ c r i t e r i a . The c o n t r o l s w e r e 20 h e a l t h y v o lunteers. D e p r o t e i n i z e d ~ r u m was a s s a y e d on the b i n d i n g of 3 H - F l u n i t r a z e p a m to b o v i n e b r a i n m e m branes. O u r r e s u l t s showed that, in the r a n g e of c o n c e n t r a t i o n used, the sera from p s y c h i a t r i c p a t i e n t s i n h i b i t e d the b i n d i n g of 3 H - F l u n i t r a z e p a m , a l t h o ugh an i n t e r i n d i v i d u a l v a r i a t i o n was p r e s e n t . A rough b i o c h e m i c a l a n a l y s i s of this i n h i b i t o r has s h o w n that it is d i a l y z a b l e ( m o l e c u l a r w e i g h t b e l o w 1000), is h e a t - and f r e e z i n g r e s i s t a n t , and! is r e s i s t a n t to p r o t e o l y t i c and a c i d d e g r a d a t i o n . The p r e s e n c e of this i n h i b i t o r in p s y c h i a t r i c patients' sera o p e n new and i n t e r e s t i n g p e r s p e c tives in the k n o w l e d g e of b i o c h e m i c a l b a s i s of anxiety. D e p a r t m e n t of P s y c h i a t r y and " I s t i t u t o p o l i c a t t e dra di D i s c i p l i n e B i o l o g i c h e , U n i v e r s i t y of Pisa, 1-56100 Pisa, Italy

32.01.15 PUIIIFICTION OF ENDOGENOUS INltlBITORS OF [ a H]-FLL~ITRAZEP~ BINDING FROM BOVINE BRAIN

H.Kawasaki, N.Itoh, A.Nohtomi, M.Fukahori, H.Takeshita Endogenous brain substances having benzodiazepinebinding inhibitory activity have been extracted with hot acetic acid from bovine brain. After ultrafi]tration, material with molecular weight less than 10,000 dalton was e ~ t o g r a p h e d on Sephadex 6-10. At least three peaks (peak 1,2,3) were shown to inhibit the binding

of

[a H]-Flunitrazepam

to

synaptosomal membranes. Two of the peaks (Peak 2,poak 3) had smaller molecular ~eights (below 500 dalton) aria were shown to contain inosine (peak 2) and hypoxanthine (peak 3) by using TLE method. Another peak (peak i) lind relatively higher ,molecular weights than other two peaks and inhibited f]unitrazepam binding dose-dependently and non-competitively. The present results suggest that

this

substance

(peakl) may be a possible modulator for central benzodiazepine receptor.

Department of Neuropsychiatry,FacuIgyof Medicine, KyushuUniversity,Fukuoka812,JAPAN.

299

32.02.01 MILD DEFICIT SYNDROME IN LATE MIDDLE AGE : A NEW RATING SCALE

POSTER PRESENTATION 32.02

Stdru,L*, Vetel,JM**, Sevestre,M***, Lancrenon,S*, K.iepferld-Saya,L*, StdrthD* * : LT.E.M., 93 4v. de Fontainebleau, 94270 Kremlb,-Bic~tre, France. ** : Ser~4ce de G6riatrie, Le Mann, France *** : Laboratoires Clin Midy, 20 me des Foss~s-St Jacques, F-75240 Palls Cedex 05

The presentation will describe a new rating scale for the assessment of mild cognitive and socio-professional symptoms associated with ageing deficits. A collection of 41 items was validated on a sample of 185 pre-geriatric (age 50-65) patients before any drug treatment and after exclusion of patients either anxious or depressed. The patients were rated by 40 general practioners trained together.

Basic and Clinical Aspects of Alzheimer's Disease - New Drugs in Memory

A principal component analysis dearly identified a factor representing 19 % of the total variance demonstrating the existence of the syndrome studied. Refered to in French as "Ddllcit Neuro-Biolog~que de la post-Cinquantaine (DNBC)'. From *the 13 items best correlated with the principal factor (R > 0.50) was established a list of 10' items selected according to both statistical and clinical criteria : (1) Difficulty. in gathering his/her ideas ; (2) Difficulty in concentrating, inattentive, loses the thread of ideas ; (3) Slow and impoverished association of ideas (difficulty., poverty and slowness of narration) ; (4) Difficulty in expressing his/her ideas dearly, making him/her understood ; (5) Decreased intellectual capacity (reasoning, calculation) ; (6) Loss or lack of confidence in his intellectual capacities ; (7) Difficulty and hesitance before taking a decision ; (8) Loss of interest for his profession or daily tasks if not at work ; (9) Feeling of inadequate performance, of not being at his/her best ; (10) Decrease in social contacts or friendship. Principal component analysis of these 10 items identified a first factor representing 44 % of the total variance. These 10 items therefore clearty participate in the factor and appear to provide the best representation of the severity, of the syndrome studied.

32.02.02

32.02.03

E F F E C T S OF ACETYL-L--CARNITINE

ON C E R E B R A L

B L O O D F L O W IN

C[TIDIIE DI~a0$~]0S0LIH (13?-CaOLIIE) I I IBX THEL~PYOF CEXE~EILIISU?HCIHCI

PATIENTS WITH ORGANIC BRAIN SYNDROME S. Passero~

R. Eherherdt, K.D.

N. B a ~ t i s t i n i

In several e x p e r i m e n t a l r e p o r t s an e x c i t a t o r y a c t i v i t y on e h o l i nergic n e u r o n s was a t t r i b u t e d to a c e t y l - l - c a r n i t i n e (LAC),

and in c o n t r o l l e d

clinical

duced i m p r o v e m e n t in several cerebral f u n c t i o n a l a c t i v i t y blood flow

trials

the d r u g has pro-

c o g n i t i v e a c t i v i t i e s . Since is c o u p m e d w i t h cerebral

(CBF) the above m e n t i o n e d

results

suggest

a

p o s s i ble effect of LAC on this p a r a m e t e r . The p r e s e n t study i n v e s t i g a t e d the effects of acute LAC a d m i n i s t r a t i o n on CBF. Ten p a t i e n t s w i t h organic brain s y n d r o m e due to c e r e b r o v a s c u l a r d i s e a s e and w i t h a degree of i n t e l l e c t u a l impairment from mild to m o d e r a t e w e r e studied. CBF was

?his double-blind cross-oyez s~udl of 14 ,eeks ~es perfur:ed ~o assess the influence sod effectivezess uf C~Y-choline in ~eristric pezien:s with cerebral insufficiencI of diffe:eu: ezlologl in comparison with phoebe, liter an initial ~esh-out period of t i t weeks :he patients re:aired according to randomized order either CD~-choline or phoebe for 5 weeks; after a seooud ~ssb-out period of further t~o ~eehs the ;s:!e=s received the sheroati~e drug {C~-choline or ;h:eho) for sddidu:al ~ reeks in :he second cross-over ;~ese. 6 pss ~nd clinical tests (~::e~e:; Geriatric Inventorl, 5:~G} ~ere performed at the end of each medication ;eris~ according to the cross-oyez phases with CDP-choline or pls:ebo trestmenL .. -

m e a s ured

by the X e n o n 133 i n h a l a t i o n

method

over eacg h e m i s p h e r e prior and 30 m i n u t e s infusion of the drug (i g in I0 minutes). matter flow

(FI) e x p r e s s e d

in 16 r e g i o n s

a f t e r the i.v. V a l u e s of g r a y

in ml/lO0 g / m i n w e r e analyzed.

initial values of CBF were on average 69.2 + 11.9 in left and 7 0 . 0 . • I0.2 in right hemisphere. A f t e r drug a d m i n i s t r a tion mean h e m i s p h e r i c CBF values i n c r e a s e d to 8 0 . 8 + 13.6 (left) and 80.5 + 12.2 (right) w i t h a p e r c e n t u a l i n c r e m e n t of 16.7 (P ~ 0.0001) and 13.8 (P < O.O001) r e s p e c t i v e l y . Ana lysis of regional CBF data showed that the increase in flow was diffuse to all e x p l o r a t e d r e g i o n s but was more evident in p r e c e n t r a l and central regions. Our r e s u l t s show that the a d m i n i s z r a t i o n of a single i.v. dose of LAC can induce a s i g n i f i c a n t increase in CBF in p a t i e n t s w i t h vascular o r g a n i c brain syndrome and point to c o n c l u s i o n that these chan~es in cerebral c i r c u l a t i o n are r e l a t e d to :he neural e x c i t a t o r y activity of the drug. 31inica della h]alattie Nervose e hlen
300

Piazza Ouomo 2, 1-53100

Italy.

e,a,~;~;.~ : f a!l ~es:s revealed: :Dg-choline, as firsz :rasrment improved the clinical szazus when compared

in~raindividuatll ~u baseline with a statistical signifka=ce of p ( 0,001 in 5 of the 6 tests a:~ uf ; ( 0.01 in one test. - Plsceho, us first ~rsszlm=~, cum~ured to hese!ine sho~e~ s statistically significant improvement :f ; t LO01 in 4 of the 6 parameters end of p ( 0.01 in one ;est and no signific~: ~ifferenoe h the remaining test. - The further improve~em: during CD?-choline udministraticn ms second treat=ant in

:unpurfsan with the ffrnt :reetment (placebo) sas nora distinct and siqnificantlX better fer e!! ~ ;srnleters, whereas placebo es second treatment did not show further statist!rail? significant improvement in an? test. - The in~erindividuai::n;arismm between the tw0 treat=en:s proved e stadstioallx significant better effecm for CDP-choline as first tree:meet in 2, and for CDPcholine as second :reezae:: in 3 of the 6 peru=enema tested.

In general, there ~ss e si;mifican: inprovenent in nhe f!cst cross-over period fur b0th treatment groups; a further significant i|provewent during the second cress-0ver period o:i? ::z:r:ed after treatment =ith C~P-choline, whereas the pheebo treetmeo~ did :=: show further improvement in sol :est. ~A~ALOG Institute f:: =ini:el Research, ?reueoiobs~resse 2L Z-S~G ~nchee 2 / F~G

32.02.04

32.02.05

SCREENING OF T H E A N T I D E P R E S S A N T MINAPRINE ON E N C E P H A L O T R O FIC E F F E C T S VS PIB.&CETAM AND PLACEBO A F T E R A C U T E AND S U B C H R O N I C ~ L A D M I N I S T R A T I O N IN HUMANS - USING H Y P O X I A - M O D E L

PHASE i STUDY OF DM-9384 M. Murasaki, S. Miura, J. Ishi$ooka, H. Wakatabe, M. Uchiumi, Y. Fukuyama, Y. Mochizuki, and A. Sumiyoshi DM-9384 is a new pyrrolidone derivative which has been developed in Japan. In pharmacological studies, it has shown excellent antiamnesic and antihypoxic effects and also greatly potentiated the action of learningacquisition. In neurochemical studies, DM-9384 has sNown to activate cholinacetyltransferase. These evidences suggest the possible involvement of central cholinergic mechanism of DM-9384 and the effectiveness for the disturbance of psychomotor function in the aged people. Phase 1 study was performed using male healthy volunteers. i. Clinical pharmacology: Few subjective and objective findings were observed with single administration up to 1200 mg daily. No findings were recognized during one week-consecutive administration of 600 mg daily. 2. Influence on the following tests (i) blood pressure, pulse rate, body temperature (2) urinalysis, hematological parameters, bloodbiochemical parameters (3) endocrinological parameters (4) ECG and EEG (5) equilibrium test (6) psychomotor performance tests It should be specially mentioned that DM-9384 showed no undesirable influence on the psychomotor performance test~ because almost all psychotropic drugs show some harmful influence on these tests. 3. Pharmacokinetic study: The plasma levels of DM-9384 were dose-dependently elevated and the significant correlation was recognized between dose and AUC. Tmax was 1.2-1.8 hours and TI/2 was 3.3-5.9 hours. No accumulation was observed with consecutive administration. Judging from the above-mentioned results, DM-9384 is safe and worthy enough to conduct phase 2 study. Department of Psychiatry, Kitasato University School of Medicine, 863-1 Asamizodai, Sagamihara, Kanagawa, Japan, 228

K. Schaffler',G. Kauert-Minaprlne - an an~no-phenylpyridazinederivativeo used as an antidepressant,e~peciMly in inhibitorystates,is devoidof m~ticholinergiceffects,but facilitatesdopaminergic, serotonerglc(pre? and postsynaptic)and r transmission.ClinicM studieson depressionin demented patientswere done and showed positiveresultsvs pl~cebo.In seniledementia- especiMlyofAlzheimertype(AT) - thereexistsa lackin dop~ninergic~ d cholinerglcmechanismswithor withoutconcomlt~ntdepressivestates.Due to itspharrn~cologicalprofile{procbolinergieand prodopaminerglc)the drug seemsto be ttsefulinAT and NAT seniledementias. A.UlmM ~nd human modelsof hypo~dahave demonstratedto be an adequate'approach for partialsimulationof dementiastates(withthe respectiveinfluenceson cerebrM metabolismand bloodsupply)and a resultingdown-regulationof CNS-relatedinformation pr~:essing (decrease in performance). To approach the respective potency of minaprine as an encephalotropic - a first-step experinaentM set-up was designed in healthy subjects, z~s a partial simulation model, to avoid drawing of statistically inhomogeneous samples of dementia patients (with

differentpathophysiologlcMstates). It w~s a r~ndornised,placebo-controlled,double-bllnd3-way crossoverstudyin9 healthymalesubjectswithacute~nd subchronicaladministration(1 week) of minaprine and pix~cet~rnms reference(dosagesac/sc:200 and 400 mS, 2400 and 2400nagrespectively). P~ycho- and electrophysiologicMmethods used were: Oculodynamic Test (ODT, 20 rain;Electrooculographyvmd choicereaction;Resting- and VigilancecontrolledEEG, each under the normobaricadministrationof 10.5~ oxygen).After norm0xic ~ d hypoxicprevaiuesfurtherp.a.-assessmentswere done at hrs I, 2 and 4 (~t day 1 and g of e~ch medicationperiodwith a one week washout-periodin between). Main vm-iable~of O D T (latency,reactiontime~correctresponses),which have a tight relationto everydaylifeconditlons(and itsresultingsocio-econornicconsequences), were positivelyinfluencedunder hypoxiain the directionof a returnto normoxia[improvement)by the mlnaprinetreatmentin the acuteand evenmore accentuatedin the s~bchroulcMphase.Piracet~mdemonstratedpositiveinfluencestoo,but was lessconsistentinitspatternand evendecreasinginitsefficacyfrom the acuteto the subchroulcaldrug ~dn~nistrationregimen.Time-efficacypatternseemsto be ~ttributedmore to the p-OH-metabolite of minaprlne than to the mother drug or the lactmnderivative- as seenin correlationof pharmacodynamics(I) and quMitativekinetics (2) in thisstudy. Drug effectson EEG were mainlyseen in V-EEG. Hypoxia itselfraisedtotalpower and absolutepower of the singlefrequencybands.Again minaprlnedemonstrateda more stimulatingpattern(a decreasein the lower and an incre~ein the higherfrequency bands in relativeEEG-power),more consistentand longer-lastingeffectsthan pir~cetam- thusfittingthesame EEG-patternm~ seeningeronto-psychiatricpatients - trea;edwithencephaiotroplcs. I. Institutefor Pharmacodyn~xnicResearch,Charf~rnfmsterstr.4a, D-8000 Munich, FRG 2. Instisu~efor ForensicMedicine,Universityof Munich, Fr~uenlobstr.7a, D~ Munich 2,FRG

32.02.06

32.02.07

CLINICAL TRIAL FOR S O L C O S E R Y L ~ I N DL~MENTIA PATIENTS H. Suzuki, S. Harisuchi, T. Nishimura

PRELIMINARY RESULTS OF A SIX-MONTH, DOUBLEBLIND CROSS-OVER STUDY OF P}EOSPHATIDYLSERINE VS PLACEBO IN PATIENTS WITH EARLY SENILE DEMENTIA OF AI.ZHEIMER'S TYPE W. S a t z g e r , D. B o v e , S. G e r k e , W. G Q n t h e r , U. M U n c h , R . R . ~ [ l T h e g o a l o f t h e s t u d y w a s to a s s e s s the efficacy and safety of Phosphatidylserine (BC-PS, Phosphatidylserine preparation from bovine brain) ir~ patients with early dementia of Alzheimer's type. In a d d i t i o n the predictability cf therapeutic outcome and pzactice effects were examined. The study design consisted of a 4-week wash-out phase, an 8-week first treatment phase (I), another wash-out phase of 8 weeks, and an 8-week second treatment phase (2). B C - P S a n d p l a c e b o were randomly assigned to t r e a t m e n t phases 1 a~d 2. T h e ' e f f i c a c y was assessed through CGI, Gottfries-Brane-Steen Scale, psychological tests, P-S00, and brain mapping. Mini-Mental State, a compliance questionnaire, suggestibility, depression and short-term increase in cognitive functioning by means of multiple exerc i s e s w e r e u s e d as p o s s i b l e predictors of efficacy. T h U s f a r 35 p a t i e n t s w i t h e~,rly d e m e n t i a of Alzheimer's type (Mini-Mental State between 15 a n d 27) h a v e e n t e r e d the study, 13 o f w h o m h a v e completed it. PS w a s w e l l t o l e r a t e d . During the FS-phase patients showed a significant increase in p a i r e d associate learning and tended to i m prove in DSST, Color-Word-Interference-Test and CGI. Patients with higher Mini-Mental State at the begin of the study improved significantly m o r e ir~ c o g n i t i v e test scores (Benton, DSST) during the course of the study than those with lower scores. Psychiatrische Klinik der Universit~t M~nehen NuBbaumstr. 7, D - 8 O O 0 M U n c h e n 2

Open clinical trial of S o l c o s e r y l ~ i n j e c t i o n was performed to dementia patients in presenility and senility and the general improvement index and the usefulness index were evaluated. I) S o l c o s e r y l @ (4 ml) was intravenously injected once a day for 8 weeks to 35 patients, 29 patients with cerebrovascular dementia, 5 patients with dementia of Alzheimer's type and i patient with dementia associated with alcoholism. The general improvement rate and the usefulness index after 8 weeks were 82.9 %. 2) The improvement rate varied according to symptoms, with an improvement rate of 7 7 . 1 % in psychiatric symptoms, 66.3 % in subjective s ~ p t o m s and 50.0 % in neurologic symptoms. 3) The high improvement rate was ob:ained in psychiatric symptoms such as hallucination (75.0 %), delusion (66.7 %), aggressive ~ehaviour (66.7 %) and excitement (66.7 %). It was effective in controlling emotional disturbance, reducing frequency of abnormal behaviours and also improving depressive mood (70.8 %). 4) The general improvement index revealed a higher in eerebrovascular dementia (86.2 %) than in dementia of Alzheimer's type (60.0 %). 5) Neither subjective nor objective symptoms and signs of adverse side-effects were not observed. There were almost no change in labolatory findings. It was confirmed that S o l c o s e r y l ~ i s a drug of high safety with excellent applicability to elderly patients with dementia.

301

32.02.08

32.02.09

EFFECTS OF PHOSPHATIDYLSERINE THERAPY IN GERIATRIC P A T I ~ S WqTH DISTHk~IC DISORDERs

LONG-TERM ACETYL-L-CARNNITINE MODIFIES EXPERIMENTALLYINDUCED CONFLICT BEHAVIOUR IN THE AGED RAT O. Ghirardi, S. Milano, M.T. Ramacci and *L. Angelucci. Acetyl-L-carnitine (ALC) is known to be present in the CNS with a role in energy metabolism and in the turnover of the phospholipid component of the neuronal membrane structure. Previous studies have shown that chronic treatment with ALC in aging rats preserved the morphology of some brain structures and learning capacity at the same time. The purpose of the present study was to investigate the effect of a chronic treatment with ALC (74 mg kg -I daily per os for 9 months) on the experimentally-induced conflict behaviour (aversive stimulation contingent to drinking in thirsty animals) in the old rat (age, 25 months when tested). Latency before the first lick, the time required for 300 licks, total number of licks and water consumption were recorded for i0 min during three days of habituation (no aversive stimulation) and t~Ddays of test sessions. Basal values showed no significant differences between the control iC) and ALC-tretated (T) groups i n all parameters consideredL The differences between the values obtained during test and basal sessions expressed in percent were evalu/ted and showed the following: latency before first lick: C = +126%; T = +177%; time required for 300 licks: C = +137~; T = +27%; number of licks: C = -51%; T = +8% (p~0.02); water consumption: C = -70%; T = -21% (p~
Mag~ioni M.*,Picotti G.B.**,Bondiolotti G.p. ~, Panerai A. ~ Brambilla F. w A double blind study was done in iO hospitalized geriatric women with disthymic disorders( DSM III).to evaluate the therapeutical effects of phosphatidu on mood,behaviour,cognitive functions and memory.Patients were treated with placebo for 15 days followed by Bs-Ps (300 mg/day)for 45 days.Before placebo,at uhe end of it and after Bs-Ps therapy patients were administered the Hamilton,Buschke,Gottfries-Brane-Steen and NOSIE rating scales,to monitor the effects of the drug on psychopathological symptomatology.At the same time ,they received a GHbeta-endorphinl~-Ep) clonidine test,and basal plasma levels of MHPG.h~A',DOPAC and 5HIAA were measured. Our data revealed a consistent improvement of depressive symptomatology of cognitive functions and memory,with no changes in previously normal behaviour.GH and ~-EP responses to clonidine were blunted before and after therapy.Baseline MHPG, HVA,DOPAC and 5HIAA levels did not change after Bs-Ps therapy.Bs-Ps-induced positive effects are not mediated by changes of brain monoamines activity. *Villa Zucehi-Carate;**Istituto Farmaeologia Universit&Genova;~ Farmaoologia Universita-Milano; Ospedaie Psiehiatrico Pini-Milano - italy

32.02.10

32.02.11

EFFECT OF LONG-TERM ACETYL-L-CARNITINE ON THE OLD RAT PERFORMANCES IN THE EIGHT-ARM MAZE A. Caprioli, O. Ghirardi, M.T. Rmmacci and *L. Angelucci Acetyl-L-Cmrnitine (ALC) is a natural substance known to play an essential role in the turnover of the phospholipid component of the neuronal membrane structure. A retardir~ effect on the age-related loss of neurons in the hippocampus, the integrity of which is indispensable for a correct performance in the radial-arm maze, was observed after chronic treatment in the rat. This study was aimed at investigating the possible effect of a -i long-term treatment with ALC (74 mg kg daily per os for 8 months) on the performances of the old rat (SpragueDawley, aged 24 months when tested) in the radial maze in the absence of visual cues. Previous studies (Ghirardi et 8/, 15th CINP, 283, 1986) had sho~xl that maze performance was strongl~ impoverished in old rats compared with young ones. In ALe-treated animals, the number of correct choices was found to.increase significantly in the course of the 14 sessions (one a day), whereas the control group showed no s i~n ifica'nt modification. ALC-treat ed animals showed better/pe~rformances with respect to control animals under both ~he quantitative and the qualitative aspects: they performed a higher number of correct choices using more effective strategies in the choice sequence, so that their performances approached those of younger animals. Thus, ALC can be said to have a retarding effect on age-related memory and learning deficits, presumably ibecsuse of its capacity to preserve hippocampal morphology and function in old rats. Biological Research Labs., Sigr~ Tau S.p.A., 00040 Pomezia, Rome, Italy and *Pharmacology II, School of Medicine, "La Saoienza" University, Rome, Italy

The synergistic effect of cerebroactive drugs on vascular smooth muscle T. Shibuyal,2, H. Matsuda I , H. H0nda 1,2, Y . Watanabel,2~ H. Shimural , H. Tsu~il and M. Izumisawal Recently, it was reported that the combined administration of ifenprodil tartrate and calcium hopantenate produced a benefical synergistic effect in the treatment of cerebrovascular diseases. In order to study the mechanism of this synergistic clinical phenomena, changes in blood flow of vertebral and internal carotid arteries were measured in rats using the transit-time ultrasonic volume flowmeter. Furthermore, the isometric tension of isolated canine basilar and internal carotid arteries was tested. The increase in vertebral and internal carotid arterial blood flow induced by ifenprodil tartrate was significantly enhanced by calcium hopantenate. In canine basilar and internal carotid arteries contracted by K +, the doserelaxation curves of ifenprodil tartrate were shifted to the left by preincubation in calcium hopantenate. The ifenprodil tartrate inhibition of on K + -induced Ca 2+ uptake in canine cerebral and internal carotid arteries was significantly enhanced by calcium hopantenate. Results suggest that the calcium hopantenate enhancement of the ifenprodil tartrate-induced relaxation in basilar and internal carotid arteries may be due to an influence on Ca 2+ movement in the vascular cell, unimately reflected in their synergistic effect of on cerebrovascular disease through increased arterial blood flow.

302

I. Department of Pharmacology, Tokyo Medical College, Tokyo 160, Japan 2. Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, Ill. 61107-1897, U.S.A.

32.02.12

32.02.13

A new nootropic drug, minaprine, improved the s c o p o l a m i n e - i n d u c e d spatial c o g n i t i v e disruption M.Fujiwara and K.Iwasaki

"TOTAL" CHOLINERGIC FOREBRAINNUCLEUS LESIONS: LACK OF BEHAVIORAL

M i n a p r i n e exerts c h o l i n e r g i c a c t i v i t y and dopamine uptake blockade such as nomifensine. Minaprine also protects the ischemia-induced neural d y s f u n c t i o n in rats and m o n g o l i a n gerbil. Therefore, minaprine was expected to be b e n e f i c i a l in the t r e a t m e n t of v a s c u l a r related dementia. The present study examines the effect of minaprine on disruption of spatial c o g n i t i o n following the scopolamine(Scop.) in an e i g h t a r m r a d i a l m a z e performance. Male Wistar rats(200-250g) were pretrained until correct choice 80% above in first 8" choices. Scop.(0.5mg/kg i.p., 3 0 m i n before a session) significantly decreased the correct choices and increased error choices. Minaprine(10~50mg/kg p.o.) was significantly impro{red the S c o p . - i n d u c e d disruption of spatial cognition in an i n v e r t e d - U dose d e p e n d e n t manner. On the other hand, this disruption was reversed by cholinergic, catec h o ] a m i n e r g i c or s e r o t o n e r g i c drugs. Scop. d e c r e a s e d brain n o r a d r e n a l i n e ( N A ) levels in frontal cortex and hippocampus. And minaprine(50mg/kg,p.o.) i n c r e a s e d NA levels in t h e s e r e g i o n to the level of n o r m a l control rats, in a c c o r d a n c e w i t h r e c o v e r i n g spatial cognition. I m p r o v e m e n t of m i n a p r i n e for S c o p . - s p a t i a ] disruption involved the interactions of those m u l t i p l e neuronal systems. M i n a p r i n e can be considered a candidate drug for the treatment of Alzheimer's disease.

raze, in whic~ a ~-hour delay ~r~sinterpolatedbe~eeo {he firs{ six

RECOVERY O.G. ~ r , J. TPa~Bp

Jr.,

E. Horv~'{h, T. SoF~JUPm~n, H. D o , p e r t , U. Ber~, and

Rats ~ e r e ~rained %o m a r l y errorless perfor~manc~ in an B-arm

32.02.14 B!0C~ffCAL

arw~ l a s { ~

arm choices.

A{ an age o f ~ ~ { h s ,

r~dial

r a { s were given

el{her sham surgery or a bilateral mullisi{e ibo{enic acid lesion aloog the en{ire lengthof {he for~r~in chollnergic nuclei: medial

sep{um, nuclei of lhe vertical and harizcntal lirdos of {he dlagonal b~nd, and s t ~ s t a n t i a i n ~ 0 ~ i n a { a / n t J c l ~ basalis magnocellularis, A ~o{al of 16 ibo{ere{e injection s i { e s ~ere rt~uired, in which rela{ively low concehn{ra{ions and v o l ~ ~ e os~<~: ibo{~na{eII mg/ml) br~ prepar-edin a saline/NaHCO solu{ion IpH ?,@), and volumes of 0.~-0.6 ~I, depending on s i t e , ~ e r e slowly injected. Rats so treated sho,~ed a large

p o s l - d e l a y d e f i c i t in ~ B-am r a d i a l maze r e l a t i v e d i d no{ re~over over Q ~ { ~ of r~-

{o c ' ~ { r o l s , ~nd { h i s d e f i c i ~

{ r a i n i n g . Control percent accuracy p o s t - ~ l a y during this period aver-~ged a p p r o x i m a t e l y 70Z while {ha~ of t~e lesioned r a t s about

~.. 71~reaf{er, a number of f u r { h a t behavior-a1 {es{s were performed wi~h ~he lesioned and c o n t r o l r a t s , along ~ i ~ an a d d i t i o n a l grc.~p of i n e>qo~ri~d agile%chad subjee{s. The b~havioral defiei% of the lesio~ r a t s g e n e r a l i z e d to {he ether b ~ v i o r ~ l procedures, y i e l d i n g a p a t { e r a o f e f f e c t s s i m i l a r ~o ~=a{ seen in normal r=a{s ~ f { e r treatment wi~h s c o p o l a m i n e . . S ~ t hls{ological examir~{io~

~fi~ the large Pe~Jc%ion in AChE-positive forebrain cells. This finding was a l s o c o r r o b o r a t e d by lowered c ~ o l i r ~ a c e t y l t r a n s f e r ~ s e ~c{ivi~y a~ 1 week ~r~ 1~8 ~ays posi-l~ion in another group of rats. The present r e s u l t s support the u~e o f animals so l e s l o r ~ d as 9 r~recoverlng model of h u ~ n d~mentla.

Neurobiology O~pari~t, T r ~ r k e

(B~y~r), Ne~Jra{harRing 1,

D-SOOO KBln 80, FRO

32.02.15 C~ANG~S

IN THE BRAIN OF AGING RATS.

0.Benew H.Te~kalov~, Z.Kri~toffkovd~ B.BInkeyS, N . D l o h o ~ o v ~ k~ M.Burq~ovd ~ A.Pavlik~ Brains divided in 7 parts ( cortex, hippocampus hypothalsmus, c.stristum, brain stem, cerebellum, b.olfactorii) were analyzed in rats, male Wistar, at the age of 8, 14, 20 and 24 months. The concentrations of DNA, RNA, protein and its soluble and insoluble fractions, neurotransmitters (noradrenaline, dopamine, serotonin and their me{abel{tea), density of dopsmine receptcrs, rate of lipid peroxidation and high affinity choline uptake were estimated and compared with the values in the brains of 3-month-old rats. Alterations in the components of the doosminergic synapsis Cdopamineland homovanilic acid concan{rations, dopsmine receptor density)indicating functions1 disturbances in c. striatum were detectable already in 8-month-old rats and were increasing during the period of investigation. At the age of 14 months, decreases of noradrenaline concentrations in the hypothalamus~ s~riatum and brain stem were found together wzth a higher rate of lipid peroxidation in the cortex~ In 20-month-old rats, all these changes persisted at the same or higher degree with addition of decreased hypothalamic serotonin level and the rise of water insoluble protein fraction in the cortex. No significant alterations were found in other variables under study. Psychiatric Research Institute, 18103 Prague 8, ~stavnf 91, Czechoslovakia. Research Institute of Pharmacy and Biochemistry, 13000 Prague 3. ~ Institute of Physiology, Czechoslovak Academy of Sciences, 14220 Prague 4.

FACILITATION OF MENTAL RETENTION CAPACITY BY BACOSIDESTIE ACTIVE CONSTITUENTS OF BACOPAMONNIERA B.N. Dhawanand H.K. S i n g h - In our previous studies i t has been shown that ethanolic extract of Bac_~ monniera whole plant produced better acquisition, improved ret@ntion and delayed extinction in several schedules of shock conditioning in rats (H.K. Singh and B.N. Dhawan, J. Ethnopharmacol. 5, 205, 1982). Subsequent studies have shown the activTty to be due to two saponins named Bacosides A and B. The mixture of two saponins was active as individual saponins. The e f f e c t o f the m i x t u r e was s t u d i e d in two schedules o f shock c o n d i t i o n i n g . In the shock motivated b r i g h t ness d i s c r i m i n a t i o n r e a c t i o n employing a semiautomatic Y maze a s i n g l e o r a l dose o f I0 mg/kg s i g n i f i c a n t l y reduced the time per t r i a l and increased the number of positive trials as well as the r e l e a r n i n g index. For the a c t i v e c o n d i t i o n e d avoidance response the p r o cedure o f . Cook and Weidley (W.J. Cook and E. Weidley, Ann. N.Y. Acad. Sci. 66, 470, 1957) was used. Bacosides were given in a dose ~ I0 mg/kg o r a l l y e v e r y a l t e r n a t e day. A s i g n i f i c a n t r e d u c t i o n was obtained in the r e a c t ion tiF~e from the f o u r t h day and a l s o in the number o f days f o r completing the t r a i n i n g f o r 8 days to 6. The conditioned t a s t e aversion t e s t was performed by the method o f Brozek et a l . (G. Brozek, O. Buresova and J. Bures, Physi ol . Bohemslov. 28, 537, 1979). Bacosides produced a dose r e l a t e d inc-r-ease in the sucrose intake and a s i m i l a r decrease in the l i t h i u m c h l o r i d e in t r a i n e d r a t s . They are devoid o f any o t h e r s i g n i f i c a n t CNS e f f e c t and have a high LD5_. D i v i s i o n o f Pharmacology, Central Dru~ Research I n s t i t u t e Lucknow 226 001, I n d i a

303

32.02.16 EFFECT

OF

32.02.17 NAF'flDROFUI;IYL

OXALATE(LS-121)

ON

EXPERIHENTAL AHNESIA HODEL IN RATS. T. Kameyama, T. Nabeshima, A. Katoh and S. OBawa Effects of LS-1218(Nippon Roussel K.K.) on amnesia m o d e l s i n d u c e d by c y c l o h e x i m i d e ( C X M ) , scopolamine(SCOP) and basal-forebrain(BF) lesion were investigated in comparison with Ca-hopantenate(HOPA) and physostigmine(PHY) using step-through passive a v o i d a n c e r e s p o n s e in r a t s . In the r e t e n t i o n t e s t , cut-off t i m e of 600 s e c was e m p l o y e d f o r t h e measurement of s t e p - t h r o u g h l a t e n c y ( S T L ) . The animal showed over 300 sec of STL was r e g a r d e d as having the criterion of memory r e t e n t i o n . % of r e t e n t i o n = lOOx(the number of animal c l e a r e d the c r i t e r i o n ) / ( t h e number of animal t e s t e d ) . I n c r e a s e in both p a r a m e t e r s of STL and % of r e t e n t i o n was r e g a r d e d as the drug i s a b l e to i m p r o v e t h e a m n e s i a . I f o n l y one o f two p a r a m e t e r s is i n c r e a s e d , we c o n s i d e r e d t h a t the drug has a t e n d e n c y to i m p r o v e t h e a m n e s i a . LS-121(25 sg/kg) and PHY(O.1 mg/kg) improved the CXM- and SCOPi n d u c e d a m n e s i a , when a d m i n i s t e r e d in t h e p r e t r a i n i n g , p o s t - t r a i n i n g and p r e - r e t e n t i o n t e s t s , while they showed a t e n d e n c y to i m p r o v e t h e BF l e s i o n induce~l a m n e s i a , when a d m i n i s t e r e d in t h e p o s t t r a i n i n g t e s t . HOP~ only showed a tendency to improve the CXH- and SCOP-induced a m n e s i a . These r e s u l t s s u g g e s t t h a t the a n t i a m n e s i c a c t i o n of LS-121 may be p r o d u c e d v i a the d i r e c t or i n d i r e c t a c t i v a t i o n of a c e t y l c h o l i n e r g i c n e u r o n a l s y s t e m . S i n c e i t improved the amnesia ~hen a d m i n i s t e r e d in the p r e - r e t e n t i o n t e s t , t h e r e is a p o s s i b i l i t y t h a t LS121 has not only protective effect, but a l s o t h e r a p e u t i c effect. Furthermore, i t i s s u g g e s t e d t h a t t r e a t m e n t with LS121 may be u s e f u l f o r the Alzheimer d i s e a s e , s i n c e i t showed a tendency to improve the BF l e s i o n - i n d u c e d amnesia. D e p a r t m e n t of C h e m i c a l P h a r m a c o l o g y , F a c u l t y o f Pharmaceutical Sciences, ~ e i j o U n i v e r s i t y , Tenpaku-ku,

PROTECTIVE EFFECT OF E-2001, A NOVEL Ah~fI-ISCHEMIC AGENT ON CEREBRAL ISCHEMIA IN MONGOLIAN GERBILS M. Ueno, M. Mihara, T. Nakazawa, M. Ikeda, Y. Furuya T. Kaneko and K. Yamatsu Glutamate is suggested to contribute to the development of ischemic cell damage in brain (S. M. Rothman, Ann. Neurol. 19, 105, 1986). E-2001, a newly synthesized piperidine derivative, has an inhibitory effect on high K+-induced glutamate release from brain slices (N. Karibe ,JUC. PHARM. SCI'87, H04-W-II). Thus, in the present experiment, the protective effects of E-2001 on cerebral ischemia in gerbils were studied. l)Effects on the survival rate and the severity of neurological deficits: E-2001 (i0 and 30 mg/kg, p.o.) administered to stroke-positive gerbils I and 4 hrs after unilateral carotid arterial ligation reduced the mortality and the stroke index. 2)Effects on passive avoidance response (PAR) and conditioned avoidance response (CAR): E-2001 administered orally 1 h~ before ischemia induced by bilateral carotid arterial ligation (BCAL) of 5min-duration improved the impaired P~2. and CAR in a dose range of 3 to I0 mg/kg. 3)Effects on ischemic cell damage and extraeellular accumulation of glutamate in the hippocampus: BCAL of 5min-duration caused a delayed neuronal cell death in the hippocampal CA1 subfield and a marked increase in extracellular glutamate. Pretreatment of E-2001 (3, i 0 and 30 mg/kg, i.p.) protected the loss of pyramidal cells in CA1 in a dose-dependent manner and reduced the extracellular accumulation of glutamate determined by microdialysis technique. These data suggest that E-2001 has anti-ischemic effects, and the effects may, at least, partly be due to the suppression of extracellular accumulation of glutamate. Tsukuba Research Laboratories, Eisai Co., Ltd. 5-1-3 Tokodai, Tsukuba, Ibaraki 300-26, Japan

Nagoya 468, Japan

32.02.18

32.02.19

MINAPRINE IMPROVES I M P A I R M E N T OF W O R K I N G M E M O R Y INDUCED BY SCOPOLAMINE AND CEREBRAL ISCHEMIA IN RATS T. Yamamoto, S. Yatsugi, M. Ohno and S. Ueki The present study was carried out to elucidate the effects of minaprine on amnesia induced by three different methods. For studying w o r k i n g memory, we used a repeated acquisition procedure (2 min interval) in the three-panel runway apparatus (Japan. J. Pharmacol. 46, 183, 1988). Male Wistar rats m a i n t a i n e d at a p p r o x i m a t e l y 80% of the free feeding level in body weight were trained with 6 consecutive trials (one session) per day. The training was r(zpeated until they showed total errors (the number of pushing incorrect gates) and latency (the time required to take foodpellets) less than I0 and 50 sec, respectively. Minaprine at doses of I0 and 32 m g / k g i.p. significantly reduced the increase of errors (24.9 Z 2.1) induced by 0.56 mg/kg of scopolamine. However, the prolonged latency (100.8 • sec) was not affected by minaprine at any doses up to 32 mg/kg. Intrahippocampal ethylcholine aziridinium ion (AF64A; bilateral 2.5 nmol/~l) also produced increase~ in both the number ~ of errors and the latency. However, minaprine up to doses of 32 mg/kg failed to reduce the increase in both items. Depending upon the duration of cerebral ischemia induced by the method of Pulsinelli and Brierley, both the number of errors and the latency w e r e increased. Minaprine (3.2 or i0 mg/kg i.p.) a d m i n i s t e r e d i m m e diately after blood recirculation and 30 min before the runway test d e c r e a s e d the i n c r e a s e d e r r o r s (21.6 • and latency (112.7 • 6.2 sec) induced by 5 min ischemia. Thus minaprine has a beneficial effect on i m p a i r e d working memory induced by scopolamine and by cerebral ischemia in rats. Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University 62, Fukuoka 812, Japan

BIOCHEMICAL AND BEHAVIORAL CHOLlqqERGIC PHARMACOLOGY OF TETRAHYDROAMINOACRIDINE L. A. A. van Pooijen, J. Trat~r, B . Schmidt and T. S c_huuzman The acetylcholine esterase (ACHE) inhibitor tetrahydroaminoacridine (THA) has been used clinically for the treatment of Alzheimer patients. We here report pharmacological studies on cholinergic effects of THA. The drug potently inhibited rat brain AChE with a K~ of 80 nM. THA competed with -H-pirenzepine (MiACh-recepto~subtype) binding (Ki 1.4 ~M), while the affif~ty for the -H-ACh ~inding site was 10 fold lower. THA alone did not affect H-inositol (poly)phosphate (IP) production in rat+cerebral cortex slices, even in ~henpresence of high [K ]. Carbamcs,icholine stimulated - H - I P production was antago~ ized by THA (ICN~ 10 ~uM, K R 1 ~M)~.* In behavioral studies THA dose-depend~Stly prevented the anlnestic action of 0.31 mg/kg b.w. scopolamine in a mouse passive avoidance test. In.a narrow dose-range THA slightly improved acquisition of 24 months old rats in a water labyrinth test. Taken together, these data indicate that THA does not act solely by inhibiting the ACHE. NetLrobiology Department, Tropor~erke, Neurather Ring 1, D-5000 ESln 80, F. R. Germany

304

32.02.20 EFFECT OF DI BENZOXAZEPI NE ANALOGUE ( BY- 1949} ON ACQUI SITION PROCESS OF OPERANT BEHAVIOR IN AGED RATS. Y. 1 keda, S. Tanabe and M. Takat oh. The present experiments were undertaken to investigate the effects of BY-1949 and aniracetam, cognitive e n h a n c e r , on a c q u i s i t i o n p r o c e s s o f two t y p e s of o p e r a n t t a s k i n aged F i s c h e r 3 4 4 male r a t s . (I) Light-dark discriminative l e a r n i n g t a s k of food reinforced lever-pressing;Learning abilities, such as a c q u i s i t i o n c u r v e s and f i n a l p e r c e n t a g e of c o r r e c t response i n t h i s task, ware decl i ned gradual I y with aging ( 2-25 months). B Y - 1 9 4 9 { I - I 0 m g / k g / d a y o r a l l y t r e a t e d f r o m 10 days b e f o r e d i s c r i m i n a t i v e learning to the end) improved these reduced learning abilities in the bell-shaped dose-response manner i n aged r a t s { 1 9 - 2 t l m o n t h s ) . Optimum dose seems t o be 10 mg/kg. A d d i t i o n a l l y , some o f r a t s t r e a t e d w i t h BY-1949 showed i n c r e a s e o f t o t a l lever-pressings. Ani r a c e t a m al so i m p r o v e d t h e s e abilities. (2} Siclrnan t y p e c o n d i t i o n e d a v o i d a n c e t a s k ; In e n s u i n g s e s s i o n s , r e d u c i n g o f shocks r e c e i v e d i n adult(8 months) was more r a p i d t h a n t h a t in aged!25 m o n t h s ) . Whereas i n t h e aged r a t s t h e number of total lever-pressings increased progressively by r e p e a t i n g t h e s e s s i o n , i t was maintained constant in adult ones. Both B Y - 1 9 4 9 ( I - I 0 mg/kg) and a n i r a c e t a m ( I 0 mg/kg) ware r e d u c e d t h e number o f shocks r e c e i v e d and i n c r e a s e d t h e number of t o t a l lever-pressings. These results suggest that repeated a d m i n i s t r a t i o n of BY-1949 e x e r t s an a m e l i o r a t i n g effect on l e a r n i n g memory i m p a i r m e n t i n aged rats. Department of P h a r m a c o l o g y , Fuj i gotemba Research Labs., Chugai Pharmaceutical Co., Ltd., Komakado, Gotembashi , S h i z u o k a , 412, J a p a n .

32.02.21 THE ROLE OF DOPAMINERGIC RECEPTOR SUBTYPES iN SPATIAL WORKING MEMORY: EFFECTS OF DOPAMINERGIC ANTAGONISTS UPON RADIAL-ARM MAZE BEHAVIOR iN RATS.

Y. Hira.~a1 and T. Iwasaki 2 In our previous study (Hiraga and Iwasaki, 1984), we found that a dopaminer~c antagonist, chlorpromazine (CPZ) did not affect spatial working memory in rats, which was evaluated in radial-arm maze task (Olton and Samuelson, 1976). On the other hand, Beatty and Rush (1983) reported the disruptive effect of haloperidol (HPD) on spatial working memory. There is a difference in D2 receptor subtype specificity between these antidopaminergic drugs. In the present study, therefore, we compared the effect of the following dopaminergic antagonism differing D2 receptors selectivity on 8-arm radial maz.e behavior; CPZ (2 mg/kg, i.p.), HPD (0.25 and 0.5 mg/kg, i.p.), and sulpiride (SPR; 50, 75, and 100 mg/kg, i.p.). These drugs were treated 30 rain prior to testing. The animals were tested once under a particular treatment condition at intervals of a few days. The order of treatments was counterbalanced among subjects. HPD and SPR'significantly decreased the number of correct choices in the first 8 choices whereas CPZ had no effect. However, SPR was less effective than HPD in spite of the highest selectivity to D2 receptors among the drugs investigated. It might be due to the less penetration of SPR into the brain (Mizuchi et al., 1983). Since there was no relationship between running time and the number of correct choices, these performance deficits were not caused by drugs-induced motor disturbance and/or sedation. These results suggest that dopaminergic D2 receptors are important in the processing of spatial working memory. I. Central Research Laboratories, Zeria Pharmaceutical Co., Ltd., 2512-1 Oshikiri, Konan-machi, Osato-gun, Saltama 360-01, Japan. 2. Institute of Psychology, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305, Japan.

32.02.22

32.02.23

ANTIAMNESIC EFFECTS OF DM-9384, A PYRROLIDONE DERIVATIVE, ON DRUG-INDUCED AMNESIA A!(I~AL MODELS T. Nabeshima~ Y. Noda, l(. Tohyama, S. }farter and T. ](ameyama In r e l a t i o n to the p r o l o n g a t i o n of l i f e - s p a n , an i n c r e a s e d number of p a t i e n t s of dementia is making a new s o c i a l problem. The development of the e f f e c t i v e n o o t r o p i c drugs is a s o c i a l r e q u i r e m e n t . We a t t e m p t e d to e v a l u a t e an a n t i a m e s i e e f f e c t of N - ( 2 , 6 - d i m e t y l p h e n y l ) - 2 - (2-oxo- 1 - p y r r o l i d i n y l ) a c e t a m i d e (1).~-9384, Daiichi Seiyaku Co. L t d . , Japan), a c y c l i c d e r i v a t i v e of 6ABA. An e f f e c t of DM 9384 on the cyclohe• M)-, scopolamine(SCOP)- and h e m i c h o l i n i u m - 3 ( H C - 3 ) i n d u c e d a m n e s i a was i n v e s t i g a t e d in mice of ddY s t r a i n u s i n g p a s s i v e a v o i d a n c e ( P A R ) and r a p i d l y l e a r n e d c o n d i t i o n e d s u p p r e s s i o n ( C S ) of m o t i l i t y . The s t e p - d o w n l a t e n c y ( S D L ) of PAI~ was s i g n i f i c a n t l y prolonged after training. The m o t i l i t y was s i g n i f i c a n t l y d e c r e a s e d a f t e r t r a i n i n g . The t r e a t m e n t with CXff(s.c.) shortened t h e SDL o f PAR and a t t e n u a t e d the CS of m o t i l i t y ( a m n e s i c e f f e c t ) . The t r e a t m e n t with SCOP(s.e.) and H C - 3 ( i . e . v . ) showed the same a m n e s i c e f f e c t in PM~. DM-9384(3-60 mg/kg) improve~l the CX~(30 and 60 m g / k g ) - i n d u c e d amnesia in PAR and CS of m o t i l i t y m e t h o d s when a d m i n i s t e r e d b e f o r e ( p . o . ) and i m m e d i a t e l y ( i . p . ) a f t e r t r a i n i n g . The e f f e c t of DM-9384(5 mg/kg) was a t t e n u a t e d by t h e trea'tmeat with hicuculline(0.5 and 1 mg/kg) and pierotoxin(1 = g / k g ) . The SCOP- and f l C - 3 - i n d u c e d amnesia was improved by DM 9384(30 and 60 mg/kg) when a d m i n i s t e r e d b e f o r e t r a i n i n g . He have r e p o r t e d t h a t DM-9384 was a b l e to i m p r o v e t h e p i c r o t o x l n and b i c u c u l l i n e - i n d u c e d amnesia models. Taken t o g e t h e r , t h e s e r e s u l t s i n d i c a t e that D.~-9384 may i n t e r a c t with GABfiergic and a c e t y l c h o l i n e r g i c n e u r o n a l systems and produce i t s a n t i a m n e s i c e f f e c t s . Faculty of Pharmaceutical S c i e n c e s , ~ e i j o U n i v e r s i t y , Tenpaku-ku, ~agoya 468, Japan

EFFECT OF DM-9384, A PYRROLIDONE DERIVATIVE, ON BENZODIAZEPINE INDUCED A~NESIA K. Tohyama, T. habeshima and T. Kameyama Benzodiazepines are widely used as anxiolytics, h y p n o t i c s and p r e m e d i c a t i o n f o r s u r g i c a l p u r p o s e s . However, they are known to o f t e n produce a n t e r o g r a d e a m n e s i a in p a t i e n t s . T h i s a m n e s i c a c t i o n may be desirable in c e r t a i n s i t u a t i o n , e.g., preceding surgery, but is a s e r i o u s problem for o u t p a t i e n t s . I t has been a l s o r e p o r t e d t h a t b e n z o d i a z e p l n e produced an amnesia in l a b o r a t o r y a n i m a l s . B e n z o d i a z e p i n e s r e p o r t e d l y p r o d u c e t h e i r e f f e c t s by f a c i l i t a t i n g central GABAergic transmission via specific benzodiazepine r e c e p t o r s . In our p r e v i o u s study, N-(2, 6-dimethyl-phenyl)-2-(2-oxo-l-pyrrolidinyl)aeetamide (DM-9384, Daiichi Seiyaku Co. L t d . , J a p a n ) , a c y c l i c d e r i v a t i v e of G~BA, a t t e n u a t e d GABA a n t a g o n i s t - i n d u c e d a m n e s i a . T h e r e f o r e , we a t t e m p t e d to e v a l u a t e t h e e f f e c t of.DM-9384 on b e n z o d i a z e p i n e - i n d u c e d amnesia by using a o n e - t r i a l p a s s i v e avoidance response(PAR) in ddY mice. Chlordiazepoxide(CDP) impaired the PAR when administered s . c . 20 min b e f o r e the t r a i n i n g t e s t . DM9384 a d m i n i s t e r e d p.o. 15 min b e f o r e the t r a i n i n g t e s t improved the CDP-induced amnesia, but a n i r a c e t a m , the o t h e r c y c l i c d e r i v a t i v e of GABA, [ a i l e d to improve i t . Muscimq], a GABA a g o n i s t , improved the CDP-induced amnesia when a d m i n i s t e r e d i . p . immediately a f t e r the t r a i n i n g t e s t , but not b e f o r e the t r a i n i n g t e s t . The a n t i a m n e s i c e f f e c t of DM-9384 on t h e C D P - i n d u c e d a m n e s i a was a n t a g o n i z e d by b i c u c u l l i n e , a GAB~ antagonist. These r e s u l t s s u g g e s t t h a t DM-9384 improves the b e n z o d i a z e p i n e - i n d u c e d amnesia via GABA neurons. However, since aniracetam and t h e p r e t r a i n i n g a d m i n i s t r a t i o n of muscimol f a i l e d to improve the CDP-induced amnesia, D~-9384 may i n t e r a c t w i t h n o t o n l y G~BAergic, b u t a l s o o t h e r n e u r o n a l systems. Faculty of Pharmaceutical S c i e n c e s , Meijo U n i v e r s i t y , Tenpaku-ku, Nagoya 468, Japan

305

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EFFECT OF DM-9384, A NEW PYRROLIDONE DERIVATIVE, ON LEARNING BEHAVIOR AND CEREBRAL CHOLINE ACETYLTRANSFERASE ACTIVITY IN RATS S. K a w a j i r i , T. Sakurai, H. Ojima, S. Hatanaka,

DISPOSITION AND METABOLISM OF DM-9384, A CYCLIC GABA DERIVATIVE, IN THE RAT, DOG AND MONKEY K.Sudo, K.Hashimoto, Y.Fujimaki and H.Tachizawa DM-g384,N-(2,6-dimethylphenyl)-2-(2-oxo-l-pyrrolidinyl) acetamide , a new cyclic GABA d e r i v a t i v e , has potent effects on improvement of learning and memory in animal models(S.Kawajiri et ai.,1988). In the present study, the metabolic disposition of DM9384 was studied in the r a t , dog and monkey given I~CDM-g384 o r a l l y at a dose of 30 mg/kg. 14C-DM-9384 was well absorbed by the three species, and distribute~ rapidly and widely to the rat tissues. The peak blood levels of z4C in these species were attained at I-2 hrs a f t e r the dosing, and declined with biological h a l f - l i v e s of 2-3 hrs. Tissue/blood ratios of 14C were approximately 1.0 in most of the r a t tissues, indicating DM-9384 and i t s metabolites were capable of crossing the blood-brain barrier rapidly. However, from our autoradiographic studies, na specific l o c a l i z a t i o n of 14C was found in the rat and monkey brain regions at the dose of 30 mg/kg. Approximately 82-84% of the administered dose were excreted into the urine of these species.ln the serum and urine of these species, M-3(hydroxylated DM-9384) was found as the major metabolite with several kinds of minor metabolites. In addition, metabolite patterns in the rat brain indicated that unchanged DM-9384 accounted for the majorypart of t o t a l z4C, suggesting that the active substance in vivo a f t e r the dosing might be DM-9384 i t self. This study also c l a r i f i e d no species difference in the metabolic dispositions of the drug among the r a t , dog and monkey. Thus, i t is conceivable that metabolic disposition of DM-9384 in humans may be s i m i l a r to that in the animal species. Research I n s t i t u t e , Daiichi Seiyaku Co., L t d . , 1-16-13, Kitakasai, Edogawa-ku, Tokyo, 134 Japan

T. Yamasaki, H. Kojima and A. Akashi. N-(2,6-dimethylphenyl)-2-(2-oxo-l-pyrrolidinyl) acetamide (DM-9384) has been shown to antagonize the amnestic effect induced by picrotoxin or bicuculline in mice (Nabeshima et ai.,1987). In the present work, the e f f e c t of DM-9384 on learning behavior, ATP content and choline acetyltransferase a c t i v i t y was examined in rats. Electroconvulsive shock (ECS, 30mA, O.2sec), given immediately following acquisition t r a i n i n g in o n e - t r i a l step-through avoidance task, reduced passive avoidance at 24h l a t e r . The passive avoidance was also disrupted by scopolamine i n j e c t i o n (Img/kg, i . p . ) 15 min p r i o r to the acquisition t r a i n i n g . These d e t e r i o r a t i o n s in passive avoidance were prevented by p r i o r treatment with DM-9384 (l-3mg/kg, p . o . , 60 min before t r a i n i n g ) . In rats that were sacrificed by microwave i r r a d i a t i o n immediately a f t e r ECS, c o r t i c a l and hippocampal ATP was decreased to 85% of control level. DM-9384 (3mg/kg, p.o.) prevented this decrease. In the l i g h t - d a r k discrimination task, rats were trained with positive reinforcement for 20 days. Rats that received DM-9384 (3mg/kg/day, p.o.) acquired more than 85% correct response on the 14th day, whereas rats receiving vehicle alone achieved this level on the 18th day. Choline acetyltransferase a c t i v i t y in the cerebral cortex and hippocampus of rats receiving DM-9384 (l-lOmg/kg/day, p.o.) for 14 days was s i g n i f i c a n t l y increased by 7-9%. These results indicate that DM-9384 improves the impaired l e a r n i n g and f a c i l i t a t e s the a c q u i s i t i o n , e f f e c t s which may be in p a r t due t o p r o t e c t i o n against the decrease in ATP and the augmentation o f c h o l i n e acetyltransferase activity. Research I n s t i t u t e , D a i i c h i Seiyaku C o . , L t d . , 1-16-13 K i t a k a s a i , Edogawa-ku, Tokyo 134, Japan.

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32.02.27

DENBUFYLLINE - A NOVELDRU6FORTHE TREATMENTOFCEREBRALVASCULARDISEASE W.H.Greb, M.O'Connollv. M.-E.R.Mayer; D.Wolf DENBUFYLLIRE (BRL 30892), ~as tested against placebo in a two-part study using a total of II0 patients with cerebrovascular disease (CVD) 97 patients with mlti-infarct and mixed type dementia, 13 patients with senile dementia Alzheimer's type). The clinical diagnosis was confirmed by the clinical picture and the Syndrome Short Test.The diagnoses multi-infarct dementia and senile dementia Alzheimer's type wore characterized by Haschinski Ischemic Score. THe effect of treatment was examined monthly by the Flicker Fusion Test, a psychometric test battery (including Benton Test, Digit SyE~bol Substitution Test and Pauli Test), and two external assessment scales (SCA6and NDSIE). In the f i r s t part of the study patients were treated with 50 ~ Denbofylline t.i.d, or placebo respectively. In the second part an additional group with an administration of 25 mg DENBUFYLLINE t.i.d, was included in the study. Both parts were carried out as double blind parallel studies over a period of three m~nths. In this presentation the results of the cofmmonevaluation of the %~ parts of the study are reported concerning the comparison of the 50 mg t.i.d DENBUFYLLINE with the placebo group. The evaluation was carried out by ANOVA considering the patients fully corresponding with the conditions of the protocol including the r-cmpliance. From the statistical comgarlson beti~en the two treat~ment groups an extensive improvement after Oenbufylline compared to placebo could be found. After one month Ig of 22 criteria showed a statistically significant difference between the trea=nt groups increasing to 21 significant criteria after two and three months. In most of the criteria a very high significance level was detected. Considering the calculations after the second and the third month the probability of means being the same was less than I k, mostly less than 0.i k, in all points of the psychometric test battery except the sign "corrections" in the Pauli-Test. Similar results wore seen using the external assessment scale NDSIE and the flicker fusion test. Moreover the investigations by means of the external assessment scale SC~G showed statistically significant differences b e t ~ n active and placebo on the 0.I k level in all points already after I month of treatment. Thus efficacy of DENBUFYLLINE was clearly ;hown compared to placebo. In respect to their mental, emotional and social capacities the patients receiving DENBUFYLLINE benefitted already after I month of treatment. Under DENBUFYLLINE treatment ii patients complained about mild to moderate gastrointestinal disco.nCort, and 2 patients dropped out because of nausea and vomiting. Gastrointestinal side effects are typically known to be associated with treatment by Xanthine-derivatives.

PRECLINICAL EVIDENCE FOR BENEFICIAL EFFECTS OF THE CALCIUM ENTRY BLOCKER NIMODIPINE IN T H E T R E A T M E N T OF GERIATRIC DISORDERS T. S c h u u r m a n and J. T r a b e r There is e v i d e n c e that a d y s r e g u l a t i o n of the C a 2 + - h o m e o stasis in n e u r o n s p l a y s a role in the a g i n g p r o c e s s of the rat brain. B r a i n a g i n g in the rat and a g i n g i n general are c h a r a c t e r i z e d b y a v a r i e t y of b e h a v i o u r a l a n d other deficits. A m o n g these are r e d u c e d l e a r n i n g and m e m o r y capacity, disturbed social b e h a v i o u r , impaired m o t o r c o o r d i n a t i o n etc. In a series of e x p e r i m e n t s w e Z+ i n v e s t i g a t e d the e f f e c t s o f the C a -entry b l o c k e r nimod i p i n e o n b e h a v i o u r a l f u n c t i o n s o f o l d rats. Re s u l t s : - 16 m o n t h s old rats t r e a t e d for 6 days w i t h i0 m g / k g n i m o d i p i n e e s c a p e d f a s t e r f r o m a w a t e r - m a z e and m a d e fewer errors than v e h i c l e c o n t r o l s - 25 m o n t h s old rats fed for 4 w e e k s w i t h n i m o d i p i n e c o n t a i n i n g food (860 ppm) s h o w e d more e x p l o r a t o r y b e h a v i o u r in an o p e n f i e l d test t h a n n o r m a l l y fed rats - the a b i l i t y to k e e p b a l a n c e on a small rod was m u c h b e t t e r p r e s e r v e d in 2 4 - 3 0 m o n t h s o l d rats fed w i t h n i m o d i p i n e - f o o d t h a n in a g e - m a t c h e d c o n t r o l s - c h r o n i c n i m o d i p i n e f e e d i n g d e l a y e d the o n s e t of abn o r m a l w a l k i n g p a t t e r n s (foot p r i n t test) and i m p r o v e d l o c o m o t i o n in old rats. T h e s e d a t a s u g g e s t that n i m o d i p i n e improves (central) n e r v o u s s y s t e m f u n c t i o n in old age. N e u r o b i o l o g y Department, T r o p o n w e r k e , N e u r a t h e r R i n g I, 5000 K 6 1 n 80, FRG

Beecham-WOlfing Clinical Pharmacology Research Institute, Stresemnnallee 6, D-r Neuss I.

306

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MICXOH~lu~,N~4CD{.s ~ THE N ~ O H ~ : ~IIEO~ODblM~)RyEFFECTS ON CEF~L S~APTIC ~I'IVITY ~ E D ON~ICROIOI~tOP~O~TICsTUDIES. A. Nnillis,. E. Kout~oukos, E. ~gelopoulo~,W. Sm~rnis and C.

Stofanis. Hraoetam, Anirncetam, Prnmirncetam and Oxiracetas, the representatives of a non class of droga, the Nootropics, have been ahown to improve memoryand learning iua variety of animal models.Hoxever, lhe exact mechanism of action of the nootropi~n is s t i l l obscure but it ham been shoe= that all the abovm substances are able to prevent scopolamine-induced amneaia in both rats and mce by iof]ue~cingbrnln cholinergio mechanisms (I,2). !o an effort to elucidote further their mode of action we have ~tudied the effect~ of Pirecstam- the prototype of the ~ootrop,cn - ca s~ngle central neuronal activity of the ~matosensory cortex and the hippocamposof ~ho rat following sTstemic and microiontophoretic administrations of the substance ~d ~e here reported that Piracetam~es able to modify single ::euron actsvity on a great number of epontaneoualy firing neurons. Cortical ~euro=s respondedmostly w~th depression, whale almost equal percentages of ~he hippocempal z~eoronaresponded e~ther wtib depressionor iae~:Jtat~on. ~oreover ~t was shown ~o :nteract xl~n :~e ~napcic effects of ~lutamic acid, ~oetyi~hoi{:;e .=~ $~F.J$., either ~ynergtaticniiy ur =nc~onl~t!ca,:y, -hen liven i~gether w*th each of the above ~ucetances (3,~ ). s .ddition ~o ~ne above observat{ons~e have ~Lud,ed the ~:~:~r~c~iooof Pzracetam~,th the synap%iceffects of l.opam~ne ann Yorsor~na*ice on the e=mebra;n =,nee end ~e have f:~l~d that Pi=~c:~amr sy~ergls%lcc;ly ~!h ~he ~epre~=nt ~ffects ot oatechoiamlneeon th~se :euroaa~hi~n ~ere ~enaltive to both =cbstcnces.Hcwever, ::0 .cnszsten: ~:.on ,,th azetylcholine,c~t~chol~mzn:s or cm;:c~c,dswas ound. -:.e above ohservationa, ~upportthe assumptionthat ~raretam ia cbla to modify ~eurc~a! activity ca ~ell ~n ::euroiro:ism~tiarreceptor interactions at the central ~ynapt,c e:tea. E.N.P.L Dept. of Psychiatry, Zginzmion ~oepztal, Mhene, G~eece. Pepeu G. and SpignoliG.(lg~6):CI.Neuropharm.9:huppi.4:2~-300 Giurgea C. and Salama~.(1577): Prog Neufcp~ychopharmae.l:235-247 Maillls ~. et al.(~9~S):hbstracts p.2a.,:.p.A. Reg. ~ymposium, ~then~ 13-17 0~t. Haillia ~.(1~5?):~bs.,p.llg,Iii Congr.l.P.A.,Cbicago,2:-31 Aug.

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32.02.31

LONG TERM OUTCOME OF BENZODIAZEPINE U.Dickmann,

BENZODIAZEPINE USE AND DEPENDENCY RISK IN GERIATRIC PATIENTS. E.Tempesta,A.Di Giovanni,L.Janiri,P.Mannelli,A.Persico, L.Antico. Benzodiazepine prescriptions to elderly patients should be cautiously given because drug metabolism is progressively impaired by age and a prolonged use of benzodiazepines,even at low doses,is liable to induce dependency. In the present epidemiological study,carried out in a southern Italian region(Molise),446 primarycare institutionalized geriatric patients were screened about psychotropic drug consumption. Out of this sample, 35 subjects who had received benzodiazepine prescriptions underwent a protocol consisting of data collected on personal,health and drug history and data from an interview.about their subjective perception of the drug's effects and their attitudes regarding its use.A number of these patients discontinued therapy and were assessed in the following 4-7 days by means of a withdrawal symptom questionnaire . The results were concerned with : 1) epidemiological traits of the population investigated; 2) clinical diagnosis; 3) tteatment's aspects (source of prescription,indication onset,duration,breaks,main and side effects,associated therapy,etc.); 4) patients feeling and compliance to the treatment; 5) eventual withdrawal symptoms . Results are discussed with regard to the risk of benzodiazepine dependency in elderly subjects . Drug Dependence Unit , Dept. of Psychiatry , Catholic University S. Heart , Largo A. Gemelli 8 , 00168 Rome , Italy

W.Poser

DEPENDENCE

and S . P o s e r

The l o n g t e r m o u t c o m e o f p a t i e n t s with benzodiaz e p i n e d e p e n d e n c e o r abuse was a n a l y z e d . A c o h o r t consisting o f 991 b e n z o d i a z e p i n e patients was o b s e r v e d f o r an a v e r a g e o f 5 y e a r s . A l l f u l l filled the DSM-III criteria f o r a s u b s t a n c e use disorder(nicotine excluded). They t o o k b e n z o d i a z e p i n e s f o r a t l e a s t one m o n t h . 491 a l c o h o l i c s ( a b u s e and d e p e n d e n c e ) s e r v e d as c o n t r o l s . Only a small proportion of the benzodiazepine patients used t h e s e d r u g s e x c l u s i v e l y ( 1 2 % ) , the majority w e r e p o l y d r u g a b u s e r s , Some p r e l i m i n a r y results of the follow-up were: I . B e n z o d i a z e p i n e abuse was a r a r e p e n d e n c e was much more f r e q u e n t . T h e a rather chronic condition.

disorder. Delatter was

2. I s o l a t e d benzodiazepine d e p e n d e n c e had a b e t t e r p r o g n o s i s t h a n a'ny o t h e r a d d i c t i v e disorder. 3. I s o l a t e d benzodiazepine d e p e n d e n c e was o f t e n complicated by s e v e r e w i t h d r a w a l symptoms ( f i t s and p s y c h o s e s ) . 4. The s o c i ~ l i m p a c t o f b e n z o d i a z e p i n e dependence was s m a l l i n c o m p a r i s o n w i t h o t h e r s u b s t a n c e use disorders. 5. The m o r t a l i t y of benzodiazepine dependent patients was i n c r e a s e d ( 2 - 3 f o l d ) but less than that of alcoholics o r p o l y d r o g a b u s e r s . In c o n trast t o o t h e r s u b s t a n c e use d i s o r d e r s most deaths occured for natural r e a s o n s . The o n l y exception was s u i c i d e , Psychiatrische und N e u r o l o g i s c h e Universit~tskliniken, v. S i e b o l d s t r . 5, D-3400 G 6 t t i n g e n

~.aTONIN, N-ACETYLSEROTONIN AND SENOTONIN IN PINEAL ORGANS OF SUICIDE ~ NON-SUICIDE VICTTWS. G.Kauert, W.Eisenmenger and E.Liebhardt In 200 pineal organs, which have been prepared from cases with documented time and cause of death after legal autopsies (collection period: March to August 1987) the content of Melatonin {MT), N-acetylserotonin (NAHT) and Serotonin (hHT) was estimated by High Performance Liquid Chromatography with Electrochemical Detection, After testing the dependencies on demographic parameters (age, sex, weight, height and post mortem delay) the contents of pineal HT, NAHT and 5HT were plotted versus time of death and checked for differences between suicide and non-suicide victims with regard to the circadian rhythm. Results: I) There could be found significant differences in the day-night content of pineal ~T with large amplitudes (Xday=l,84• ; ~night=23,3+43,6; median: 0,0 and 10,8 resp.-ng / pineal organ) with--similar behavior of NAHT and inversed behavior of 5HT in the non-suicide cases. 2} In the suicide victims in average there could be observed a marked lower amplitude of the MT rhythm with significa_nt higher MT values during day time (Xday =12,8 +16,2; Xnight = 43,8+59,4; median: 6,6 and 8,0 resp. n g / pineal organ) and also similar behavior of NAHT and 5HT. Conclusions: The pineal content of ~T in most non-suicide cases reflects the time of death at day or night. Suicide victims exhibit a changed pattern in pineal MT biorhythm compared to cases with death of another cause. From the literature there is evidence that stress and enhanced sympathetic activity do not influence the pineal MT rhythm in humans. The question, whether or not the altered MT rhythm in suicide is a pathogenetic factor prior to suicide, cannot be clarified from our results and must be subject of elucidation by investigations of patients with suicidal behavior. Institute o f F o r e n s i c Nedicine, U n i v e r s i t y o f Munich, Frauenlobstra~e

7a , D-8000 MCmchen 2 , F . R . G .

307

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THERAPEUTICALPROBLEMSWITH LON6-TE~BENZ~IAZEPINE_ DEP~iOENCYA~) OD~PARISONOF lie ABUSEPOI~IAL OF TWO BEIfZODIAZEPINERECEPTORAGONISTS

THE DIFFERENT EFFECTS OF HYPNOTICS ON SHORT-YERM MEMORY

S. Apelt, C. Schmauss and H.M. Emrich

The effects of hypnotic drugs on short-term memory were investigated using Sternberg memory scanning task. The drugs tested were flurazepam 15mg, triazolam 0.25mg, zopiclone 10mg and placebo. Eight male volunteers aged 23 to 26 were given flurazepam or triazolam at 8 in the evening in a double-blind cross-over method, and zopiclone in a single-blind manner. Sternberg memory scanning task was carried out before and 1 hour after the administration of a test drug and in the next morning. Overall reaction times were increased 1 h following treatment with all three drugs, especially with significant differences in treatment of flurazepam and zopiclon~ Interactions between drug effect and response pattern at i h were observed in treatment of flurazepam or zopiclone, with statfstical difference in the latter. On the other hand, triazolam treatment showed a significant interaction between drug effect and set size at i h. These effects were not observed in the next morning. Th~ results obtained in the present study showed that these three hypnotics could affect short-term memory by the possible effect of flurazepam and zopiclone on the response-selective organization, while by that of triaiolam on the serial comparizon stage.

~itndrawal phenomena in long-term Benzodiazepine (BDZ) users were evaluated in a clinical study in 14 inpatients Specifity and intensity of BDZ withdrawal symptoms' were

similar in high- and low-dose dependent patients. Another 12 patients with long-term BDZ dependency participated in a double-blind study comparing the "liking"-potential of alprazolam and diazepam. The hypothetical equivalent dose as to the hypnosedativeanxiolytic potency was assumed f o r alprazolam : diazepam as 1 : 10. In a drug-choice t e s t 11 of 12 patients preferred alprazolam t o diazepam. The data suggest

that in patients with long-term BDZ dependency alprazolam has a higher abuse-liability than an equivalent dose of diazepam. Max-Planck-lnstitute f o r Psychiatry Kraepelinstr. 10, D-8000 Munich 40

Fed.Rep. of Germany

32.O2.34 T E N I L S E T A M (CAS 997) P R E V E N T S L E A R N I N G DEFICITS, A N D P R O T E I N B I O S Y N T H E S I S I M P A I R M E N T I N D U C E D BY F O R E B R A I N I S C H E M I A IN G E R B I L S U. Schindler, E. S c h r a v e n and R. Beyerle T r a n s i e n t f o r e b r a i n i s c h e m i a has b e e n s h o w n to induce p r o f o u n d l e a r n i n g d e f i c i t s in g e r b i l s t r a i n e d one day a f t e r the i s c h e m i c insult. In a d d i t i o n a p r o l o n g e d r e d u c t i o n in b r a i n p r o t e i n biosynthesis follows transient cerebral ischemia. The e f f e c t of the n o v e l n o o t r o p i c t e n i l s e t a m (CAS 997, ( ~ ) - 3 - ( 2 - t h i e n y l ) - 2 p i p e r a z i n o n ) was e v a l u a t e d in the g e r b i l f o r e b r a i n i s c h e m i a model. Bilateral carotid o c c l u s i o n (3 min) of m a l e m o n g o l i a n g e r b i l s was conducted under halothane anesthesia. The d r u g was a d m i n i s t e r e d (i.p.) a f t e r the end of ischemia. T r a i n i n g and r e t e n t i o n t e s t i n g in a one-trial passive avoidance paradigm was performed one and two days a f t e r ischemia, respectively. In a s e p e r a t e set of e x p e r i m e n t s b r a i n s w e r e r e m o v e d f o l l o w i n g v a r i o u s p e r i o d s of r e c i r c u l a t i o n and the i n c o r p o r a t i o n of t r i t i u m - l a b e l e d l e u c i n e was u s e d to m e a s u r e hippocampal protein biosynthesis. T e n i l s e t a m at doses of 0.3 to i00 m g / k g dosed e p e n d e n t l y r e v e r s e d the i s c h e m i a i n d u c e d l e a r n i n g deficit. G e r b i l s t r e a t e d w i t h I00 m g / k g p e r f o r m e d as w e l l as s h a m - o p e r a t e d controls. At t h i s d o s e t e n i l s e t a m s i g n i f i c a n t l y a t t e n u a t e d the r e d u c t i o n in h i p p o c a m p a l p r o t e i n b i o s y n t h e s i s at v a r i o u s p e r i o d s of r e c i r culation. T h e s e data s u g g e s t t h a t the b e n e f i c i a l e f f e c t of t e n i l s e t a m a g a i n s t the i s c h e m i a i n d u c e d l e a r n i n g d e f i c i t c o u l d be due to the a m e l i o r a t i o n of p r o t e i n b i o s y n t h e s i s . P h a r m a f o r s c h u n g C a s s e l l a AG, H a n a u e r Landstr. 526, D - 6 0 0 0 F r a n k f u r t am M a i n 61

308

J. Ishi$ooka, M. Murasaki, Y. Ishii, T. Kasahara, M. Aida, N. Watanabe, M. Suzuki, H. Tskeuehi and S. Miura

Department of Psychiatry, Kitasato University School of Medicine, 863-1 Asamizodai, Sagamihara, Kanagawa 228, Japan.

32.03.01

POSTER PRESENTATION 32.03

Benzodiazepine and Alcohol Dependency

~LONIDINE IN THE OPIATE WITHDRAWAL SYNDROME M. 3a~ovi~Ga~ic t V. ~. Paunovic, S. D._Totic, M. R. Boqdanovic ana G. P. Niko!ic-Balkoski Disturbed noradrenergic transmission is partially zes~onsidle for the withdrawal symptoms that arise due ~o tqe abrupt discontinuation of the opiates (M. S. Gold et al., Lancet: I, 92g-930, i~78; M. S. Gold et al., 3A~A: 2~3, 343-346, 1980). Application of clonidine (presynaptzc aL~na agonist) may reduce the excessive noraorenergic a ~ i v i ty and prevent the withdrawal syndrome. This study reports the results of the in-patient %zeot~er;t of the opiate addicts by abrupt Piscontinuation of ire o~lares and application of a) clonicine and D) neuroleptic drugs ~phenothiazines).Six%een ~ib) male opiate ae~icts submitted to abrupt discontinuation of the opiates ~m;e treated with clonidine (8 patients) and promethazine ~ Da tients). Clinical assesment was sone on the 2nd, 4%n amc 7th day after the discontinuation of the opiates ant cmmsisted of measuring the blood preassure ~BP)~ freque
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32.03.03

COMPARISON OF FLUVOXAMINE VERSUS ARGININE IN 50 PATIENTS HOSPITALIZED FOR ALCOHOLIC WITHDRAWAL

PLASMA CYCLIC AMP IN NON-ABSTINENT CHRONIC ALCOHOLICS. RELATION TO CLINICAL PARAMETERS. G.Moussas, L.Lykouras, M.Markianos. P l a s m a c y c l i c A M P (cAMP) l e v e l s w e r e d e t e r m i n e d in a g r o u p o f 36 m a l e c h r o n i c a l c o h o l i c s d u r i n g a period of their usual alcohol intake and c o m p a r e d t o 29 n o r m a l c o n t r o l s s i g n i f i c a n t l y l o w e r v a l u e s ( p < 0 . 0 0 5 ) w e r e f o u n d in t h e p a t i e n t group. The possible influence of age, chronicity of drinking, family history of alcoholism, dementia and liver injury on plasma cAMP levels was examined by multiple regression analysis. No influence of those factors could be established except that demented alcoholics showed a trend toward higher levels than non-demented subgroup. The results suggest a reduced ~-adrenergic receptor activity during chronic alcohol ingestion. Department of Psychiatry, Athens University M e d i c a l S c h o o l , 115 28 A t h e n s , G r e e c e .

ARCHAMBAULT 3.C.* 50 a!coholic-demendant patients {D.S.M. I I I c r i t e r i a ) Dave been h e s p i t a l i z e d for 28 days withdrawal. They ~ e ~ . _ d . in an ,open study, a f t e r randomization, e i t h e r fiuvoxamine (200 mg/day of F l o x y f r a I R ) , or a r g i n i n e t a b l e t s / d a y of Eucol 150). 2~ p a t i e n t s , with a mean age of 41,7 ~ 10,4 years, ~eight 68.3 + 11,1 kg, received fluvoxamine. 25 p a t i e n t s w;th a mean ~ge of 40,1 + 11,5 years, weight 71,2 <2,4 kg, received a r g i n i ~ e . The scores of scales of depression (M.A.D.R.S.) anxiety (Tyrer), of alcohol craving, of c l i n i c a l global impression and the anto-evaluation of sleep q u a l i t y , s;eep lenght and time before sleeping, decreased in the 2 groups. E!uvoxamine was more e f f i c i e n t than a r g i n i n e on a l l these ~tems and a s i g n i f i c a n t d i f f e r e n c e was observed on days 3, 7, 14 and 28. All p r e d e l i r i u m symptoms disappeared more q u i c k l y in the fluvoxamine group. Both drugs were well t o l e r a t e d . Normalization of hepatic b i o l o g i c a l disturbances was observed in the 2 groups. No side e f f e c t s were observed in the 2 groups. Eluvoxamine improved the q u a l i t y of withdrawal and was more a c t i v e than a r g i n i n e .

- Dr ARCHAMBAULTJ.P. - Centre R~gional d ' A l c o o l o g i e ~e Picardie - C.H.S. - 02560 PREMONTRE

309

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32.03.05

ABNORMAL P3 IN ALCOHOLICS WITH DISORDERED MOOD AND AGGRESSION. M. Branchey, L. Buydens-Branchey and C.S. Lieber.

EFFICACY OF PIRACETAM IN THE TREATMENT OF ALCOHOL ORGANIC MENTAL DISORDER C.Miller, C h . B a r n a s , V.GOnther, H.Ehrmann,

Abnormalities in the P3 component of event related potentials (ERP) have been found in alcoholics taken as a group, but these abnormalities have not been specifically studied in subgroups of alcoholics. Our goal was to investigate the P3 component of auditory ERP in alcoholic patients with and without mood and aggression disorders and in a control population (non-alcoholic hospita& patients) in order to determine whether alcoholics with depressive, suicidal or aggressive tendencies differ in their P3 characteristics from patients without these tendencies. A significantly lower P3 amplitude was observed in alcoholics who had a history of incarceration for crimes involving violence. The mean • SD P3 amplitude for these patients was 3.3• ~V vs. 6.8• pV for alcoholics without such a history (p <.0Ol) and vs. 6.9• ~V for the controls (p <.001). Low P3 amplitudes were also found in patients with depressive and suicidal tendencies when compared to alcoholics without these tendencies but differences failed to reach significance. A P3 deficit could thus characterize a subgroup of alcoholics with disordered regulation of aggression, such as described in type 2 alcoholics. Alternatively, P3 deficits could be linked to some psychopathological condition other than alcoholism in individuals who also abuse alcohol. In conclusion, the decrease in P3 found in alcoholics could be associated with disorders in mood and aggression regulation in this patient population. VA Medical Center, Bronx, NY and Mt. Sinai School of Medicine, New York, NY

Piracetam (2-oxo-pyrrolidine-l-acetamide) is a derivate of g a m m a - a m i n o b u t y r i c a c i d . D e s p i t e the lack of c o n t r o l l e d trials p r o v i d i n g p o s i t i v e e v i d e n c e of any c o r r e l a t i o n between dose and efficacy, there has been a marked t e n d e n c y in recent years to i n c r e a s e the dose of p i r a c e t a m in t r e a t m e n t of o r g a n i c mental d i s o r d e r s of varying etiology. The f o l l o w i n g paper p r e s e n t s an i n v e s t i g a t i o n of the efficacy of p i r a c e t a m in a l c o h o l i c organic mental disorder. A doubleblind p l a c e b o - c o n t r o l l e d study design was used to compare two dosages of the s u b s t a n c e in 60 patients. E x c l u s i o n criteria were forms of a l c o h o l i s m s e c o n d a r y to e n d o g e n o u s psychoses, marked c ~ i n i c a l m a n i f e s t a t i o n of cerebral a r t e r i o s c l e r o s i s , severe c r a n i o c e r e b r a l trauma, and major physical illness, e s p e c i a Z l y a l c o h o l i c cirrhosis. The study was started after the acute w i t h d r a w a l s y m p t o m s had subsided. This was b e t w e e n 7 and 10 days after the last alcohol consumption. The patients were assigned to the follqwfng 3 groups in a random d o u b l e - b l i n d manner: group 1 placebo, group 2 2x3g piracetam, group 3 2x12g piracetam. The c o g n i t i v e f u n c t i o n s of the patients, e s p e c i a l l y short term memory were assessed by the d-2 Test, d e t e r m i n a t i o n of C r i t i c a l Flicker Fusion, the P a u l i - T e s t and the " S y n d r o m k u r z t e s t " (subtypes A to E) on the days 0,7,14,28 and 42. For e v a l u a t i o n of the data the W i l c o x o n - W i l c o x signed rank test and the Mann W h i t n e y - U - T e s t were used. D e p a r t m e n t of Psychiatry, Innsbruck U n i v e r s i t y Clinics. Anichstr. 35, A-6020 Innsbruck.

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32.03.07

E F F E C T S OF M A T E R N A L A L C O H O L E X P O S U R E D U R I N G G E S T A T I O N A N D / O R L A C T A T I O N P E R I O D S ON R A D I A L A R M M A Z E L E A R N I N G IN O F F S P R I N G RATS. T. IWASAKI Fetal a l c o h o l s y n d r o m e (FAS) is one of the i m p o r t a n t c u r r e n t t o p i c s in b e h a v i o r a l t e r a t o l ogy. Several s t u d i e s u s i n g l a b o r a t o r y rats have shown that p r e n a t a l a l c o h o l e x p o s u r e results in h y p e r a c t i v i t y and d e f i c i t s in a v o i d ance learning in the o f f s p r i n g . Appetitive learning, in a d d i t i o n to a v e r s i v e one, s h o u l d be e m p l o y e d to get a c o n c l u s i v e e v i d e n c e of the learning deficiency. M o r e o v e r , e f f e c t s of p o s t n a t a l as w e l l as p r e n a t a l a l c o h o l e x p o s u r e should be e x a m i n e d in the rat, w h i c h was a l a t e - m a t u r i n g animal. Thus, the p r e s e n t s t u d y was d e s i g n e d to i n v e s t i g a t e the e f f e c t s of m a t e r n a l a l c o h o l (15%) c o n s u m p t i o n d u r i n g the g e s t a t i o n a n d / o r l a c t a t i o n p e r i o d s upon l e a r n ing of an 8-arm r a d i a l maze task by the rat offspring. A c q u i s i t i o n of the m a z e l e a r n i n g was found to be p r o f o u n d l y r e t a r d e d only in the o f f s p r i n g of m o t h e r s t r e a t e d w i t h a l c o h o l during gestation. This r e s u l t could not be exp l a i n e d by a s e c o n d a r y e f f e c t of m a l n u t r i t i o n p r o d u c e d by the a l c o h o l treatment, b e c a u s e b o d y w e i g h t increase in the o f f s p r i n g was s u p p r e s s e d by the alcohol t r e a t m e n t d u r i n g l a c t a t i o n but not during g e s t a t i o n . The p o s s i b i l i t y of i n v o l v e m e n t of d e f i c i t s in brain d e v e l o p m e n t (especially of the h i p p o c a m p u s ) in the l e a r n i n g i m p a i r m e n t was suggested. Institute of P s y c h o l o g y , U n i v e r s i t y of Tsukuba, Tennodai, Tsukuba, Ibaraki 305, J a p a n

EFFECT OF ETHANOL ON 3H-DOPAMINE RELEASE IN RAT NUCLEUS ACCUMBENS AND STRIATAL SLICES V.A. Russell, M.C.L. Lamm, and J.J.F. Taljaard

310

Ethanol (lO-2OOmM) transiently increased tritium overflow from superfused rat nucleus aco~t~s slices previously incubated with 3H-dopamine (DA) and C-choline. The effect was greater in striatal tissue and did not appear to be a non-specific membrane effect since 14C-acetylcholine(ACH) release was not affected. Lack of antagonism by picrotoxin suggested that y-aminobutyric acid (GABA) receptors were not involved. Calcium was not a requirement and the DA uptake blocker, nomifensine, was without effect. Ethanol appeared to be causing 3H-DA release into the cytoplasm. K+-stimulated release of 3H-DA and 14C-ACh from nucleus accumbens and striatal slices was not affected. Clonidine-mediated inhibition of the K+-evoked release of 3H-DA remained unaltered. Ethanol attenuated the isoproterenol-inducad enhancement of 3H-DA release. Ethanol therefore appeared to interact with components of the DA terminals causing a transient increase in the release of neurotransmitter without impairing K+-evoked release but apparently interfering with the isoproterenol-induced effect. MRC Research Unit for the Neurochemistry of Mental Diseases. Department of Chemical Pathology, University of Stellenbosch. Tygerberg Hospital, P.O. Box 113, Tyge~berg 7505, Republic of South Africa.

32.03.08

32.03.09

THE SEROTONIN UI~AKE INHIBITOR, FLUOXETIN~ REDUCES ALCOHOL CONSI.Jq~SYTIONIN PROBLEM DRINKERS. C.A. Naranjo, E.M.Sellers, P.Sanhueza, H. Valencia. D.V.Woodley-Remus, G.Kenne~, ICE.Kadlec In our previous studies the serotonln uptake inhibltors zimelidlne, citalopram and viqualine decreased alcohol consumption in rats and humans. We assessed the effects of fluoxetine, a relatively selective long-acting serotouln uptake inhibitor, in 29 male early stage problem drinkers randomly assigned to receive fluoxetine 40 rag/day (n=8), fluoxetlne 60 rag/day (u= 11), or placebo (n=10) for 4 weeks. Alcohol intake a~d compliance with drug therapy were assessed by seff-rcports and objectively and no other treatment or advice was given. Fluoxctine 60 rag/day decreased alcohol consumption by 16% compared to pre-treatment. Total drinks per 14 days decreased from CE-+ SEM) 115.8-+ 9.3 to 96.5-+ 9.5; mean daily drinks decreased from 8.3 + 0.7 to 6.9 -+ 0.7; and mean drinks per drinking day from 8.6 -+ 0.7 to 7.1 -+ 0.6 (all p < 0.01). Decreases in alcohol intake with fluoxetine 60 rag/day were associated with reductions in serum gamma-glntamyl transpepfidase (p = 0.10). Neither fluoxetine 40 rag/day nor placebo had effects on alcohol intake. Fluoxetlne 60 rag/day decreased drinking compared with fluoxetine 40 rag/day (ANCOVAs, all p < 0.02), and decreased the variance of the response (change in alcohol intake) compared to placebo (p < 0.01). Effects on drinking appeared and disappeared rapidly. There were large interindividual variations in pattern of response. Decreases in alcohol consumption were not related to aide effect% an alcohol sensiti25ng reaction, changes in depression or anxiety, or any other subject trait or drug factor. These results indicate that all serotonin iaptake inh~itors tested thus far decrease alcohol intake in humans. Such drugs may be effective pharmacological treatments for reducing alcohol consumption in problem drinkers. Clinical Pharmacology Program, Addiction Research Foundation, Clinical Institute and Departments of Pharmacology, Medicine and Psychiatry, University of Toronto, 33 Russell Street, Toronto, Canada M5S 2S1.

ON THE RELATIONSHIP BETWEEN ALCOHOL AND DRUG ABUS,

D~SSZON A~D s~zcz,:~z~. o. ~s.~ovk. The rising occurrence rate of depressive states and suicides among alcoholics and subjects addicted to other substances has induced an increased interest in the problem c o n c s r ~ g the relation between depressivity and the effect of alcohol and other addictive materials. The pathoEenesis of these states was obscure, recent biochemical ~nd receptor hypotheses have provided new approaches to possible explanations of the depreasogenic effect of alcohol and other addictive materials. Alcoholism and addiction are often taken to be essential factors furthering suicidal action.The shs_,-e in suicidal action of persons addicted to alcohol and other agents is growing higher.~ese persons reach the firs~ rank in the number of finished suicidal cases. These facts can be supported by our ~ n experiences gained from a systematical observatiimn of finished suicides.in o u r study we submit an analysis of the finished suicides of drug-addicts,the observed group comprosed 244 cases/230 men and 14 Women /. O. TESAi~OV~,M.D.,Ass.prof. Postgraduate Medical Institute,Dept.of Legal Medicine,Sasinkova 4,81108 Bratisiava,CzechosloTakia.

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32.03.11

WEIGHT LOSS INDUCED BY SEROTONIN UPTAKE INH]BITORS (SUI) IN MALE HEAVY DRINKERS EM.sellers. r ICE.Kadlcr_ DN.Woodlev-Remus SUI attenuate ethanol intake and may affecI other consummatory behaviours in humans. Effects of four SUI (zimelidine(Z), dtaloprum(C), viqnaline(V), flanxetineCF')) on body weight and appetite were assessed in male non-depressed, normal weight, early stage problem drinkers who were not trying to control food or alcohol intake in double-blind, randomized studies. Compliance with SUI treatment was objectively determined and no other treatment or advice was given. In a double-blind crossover trial, 2 weeks of treatment with Z200 rag/day (n = 13) decreased body weight by 0.5+ 0.3 leg (~+ SEM) compared to a weight gain of 0.5 + 0 2 kg during 2 weeks placebo (P) (p < 0.10). In two other double-blind crossover trials weight losses were observed with 4 weeks C40 rag/day (0.8+ 0.2 kg) (n = 19) and 2 weeks V100 rag/day (0.6 + 0.9 kg) (n = 15) and V200 rag/day (0.8 _z 0.4 kg) (n= 14) compared to weight gains (i = 0.3 + 0.3 kg) during pla~ (all p < 0.05). A similar weight loss (0.6--+ 0.4 kg) during 4 weeks C20 rag/day (n= 20) was not significantly different from the placebo (gain of 0.1-+ 0.3 kg). In a double-blind parallel design study, 4 weeks of F40 rag/day (n=8) and F60 rag/day (a=11) decreased body weight by 1.9+ 0.3 kg and 2.1+ 0.8 kg, respectively, while weight gain (0.1-+ 0.4 kg) was observed with P (n = 10), (F40 vs P: p<0.0R F60 vs P: p<0.05). F, therefore, was the most effective weight loss treatment. Weight losses were not due to dec.reuses in calories from alcohol since V100 and F,40 rag/day had no significant effects oll alcohol intake. Furthermore, the changes in weight and drinks were not correlated within any treatment group (e.g., C40 ~ag/day, r = ~ F40 rag/day, r = 0..56; F60 rag/day, r = -0.15, all n.s.). Subjects reported decreased appetite during C40 rag/day compared to P (p<0.0S) and during F, especially the first 2 weeks, compared to baseline (F40: p=0.10, F60:. p<0.05). Decreased caloric intake from food was likewise reported during C.40 rag/day (I)<0.05 compared to P) and during 4 weeks of F40 rag/day (I)<0.05) and F60 rag/day (i)<0.10). Side effects, such as mild, transitory nausea and diarrhea, winch occurred with some SUL were not related to weight loss. These results confrere the role of the serotonergie system in the regulation of consummatorybehaviours and may have implicatiuns for the development d pharmacological interventions for weigl~ loss and appetite control Clinical Pharmacology Program, Addic~km Re,~uch Foundation, Clinical Institute and Departments of Pharmacology aad Medicine, University of Toronto, 33 Russell Street, Toronto, Canada MSS 2SI

TRANS~E~.IAt'CLONIDINE VERSUS CELORDIAZEPOXZDE TN ALCCEOL WITHDRAWAL G.R. Baumgartner, R.C. Rowen recent report in the l i t e r a t u r e suggested that oral clonidine may represent a new a l t e r n a t i v e agent for thq management of acute alcohol withdrawal syndrome (G Baumgartner, R Rowen: Arch Intern Yed 1987;147: 1223-1226). However, no study has yet investigated the transdermal form of clonidine for this i n d i c a t i o n . In a double-blind prospective controlled evaluation, 42 patients were randomly assigned to e i t h e r transdermal clonidine or chlordiazepoxide. On study entry bot~ groups were s i m i l a r regarding demographics, alcohol withdrawal symptoms (AWS), histories of p r i o r alcohol use, physical findings and abnormal lab results associated with alcohol dependence. Once in significant withdrawal as measured by the AWS scale, the patients started on their respective study medications and then had observations made every 12 hours. S t u d y scales administered were the AWS, the Cognitive Capacity Screening Exam, the Brief Psychiatric Rating Scale, the Hamilton Anxiety Rating Scale, the Hamilton Depression Rating Scale and subjective self-rating scales. Clonidi~e was well tolerated with no patient experiencing major adverse drug reactions. No patient in either study group progressed to delirium tremens. Analysis of the study data demonstrated more favorable AWS scores, Cognitive Capacity Screening Examscores, blood pressure, pulse, restlessness scores and quality of sleep for clonidine over chlordiazepoxide. In a l l the remaining comparisons, clonidine was shown to be as efficacious as chlordiazepoxide. These results corroborate the e a r l i e r report on oral clonidine that an alpha9 agonist may represent a new, and possibly even superio~ pharmacologic treatment in the managementof acute alcohol withdrawal syndrome. Transdermal clonidine has important implications in the compliance of outpatient alcohol withdrawal treatment. William S. Hall Psychiatric Institute, P.O. Box 202, Columbia, South Carolina, 29202, U.S.A.

311

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32.03.13

GROUP THERAPY AND PROPRANOLOL FOR BENZODIAZEPINE WITHDRAWAL C. H a l l s t r o m , G. C r o u c h , M R o b s o n 24 b e n z o d i a z e p l n e d e p ~ e ~ t p ~ n t s were randomly treated as out-patients with either coginitive group therapy or non-specific group therapy, for tranquillizer withdrawal. Patients were also given either propranolol, placebo or no a d d i t i o n a l p i l l s . T h e y w e r e t r e a t e d f o r a 10 week programme and followed-up after one year. 8 patients stopped their tranquillizers, 10 achieved a substantial reduction and 6 managed l e s s t h a n a m o d e s t r e d u c t i o n in m e d i c a t i o n . Cognitive therapy was shown to be significantly be.tter t h a n n o n - s p e c i f i c g r o u p t h e r a p y f o r stopping tranquilizers. S~ptoms remained relatively constant throughout tranquilizer withdrawal. M e d i c a t i o n r e d u c t i o n in b e n z o d i a z e p i n e s d e p e n d e n t p a t i e n t s c a n be a c h i e v e d w i t h o u t a d e t e r i o r a t i o n of t h e i r c l i n i c a l c o n d i t i o n .

DEPENDENCE LIABILITY OF THE BENZODIAZEPINE HYPNOTICS QUAZEP~M AND TBIAZOLAM IN CATS E[_Ongini, M. Marzanatti, C. Barzaghi and A. Monopoli A clinically important withdrawal syndrome has been reported to occur after abrupt discontinuation of long-term treatment with benzodiazepines (BZs). We designed a study to assess physical dependence liability of the BZs quazepam (0) and triazolam {T). Cats were given Q or T orally once daily for 21 days at m dose 5-fold that used clinically (Q = 1.25 mg/kg; T = 0.04 mg/kg). Two approaches were used: {I} precipitated withdrawal test upon administration of the BZ antagonist flumazepil {F), 5 mg/kg ip; (2) spontaneous withdrawal after stopping BZ treatment. Selected behavioral items and sleep-waking patterns were recorded during dosing period and at withdrawal. During treatment period, Q produced mostly sedation. T induced marked ataxia, hyperactivity, and unusual aggressive responses. Signs of withdrawal (staring behavior, muscle stiffness, pupil dilation and appetite suppression) were precipitated by F after stopping treatment with both BZs. RE~ sleep decreased and waking increased. In the spontaneous withdrawal test, no behavioral changes were observed after stopping Q treatment. Sleep-waking patterns ~radually returned to baseline. Conversely, at discontinuation of T treatment there were moderate withdrawal signs, mostly limb tremors and altered behavior. The data indicate that the two BZs have different withdrawal-producing properties, being T, but not Q, effective in the spontaneous withdrawal approach. Moreover, with T the most impressive behavioral changes were observed during the dosing period rather than at cessation of treatment. Research Laboratories, Essex Italia, I-2OO60 Comazzo, Milan Italy.

32.04.01

POSTER PRESENTATION 32.04

Methodology of Drug Studies and Classification of Psychiatric Disorders

312

A DOUBLE-BLIND CONTROLLED STUDY OF CM6912 (ETHYL LOFLAZEPATE) ON NEUROSIS USING PLACEBO A. Morl, M. Murasakl, K. Ohara, K. Kamijlma, K. Hase~awa~ Y t Hada, S. Mizushlma, G. Yagl, M. Kurihara, S. M/ura A double-bllnd controlled trial on CM6912, a long-term antlanxiety drug, comparing with placebo in the treatment of neurotic patients, was conducted. CM6912 was administered on a fixed schedule of one 2 mg tablet once a daily after supper. The observation period was 4 weeks. Both PNRS which was designed in Japan and Hamilton Anxiety Scale were utilized for the evaluation of symptomatological parameters. The subjects of the trial consisted of 241:121 cases of CM6912 (CM group) and 120 cases of placebo (P group). I~ overall evaluatlon, CM group was significantly superior to P group by U-test concerning to final global improvement rating (P<0.001). As to improvement rate, "Markedly improved" results were obtained in 18% of the cases for CM group -and 6% for P group, "Moderately improved or more" results in 46% for CM group and 22% for P group and, "Slightly improved or more" results in 68% for CM group and 52% for P group. The statistical analysis for each of these improvement rates reached at significant levels of P
32.04.02

32.04.03

EFFECTS BY REPEATED TESTING ON HALOPERIDOL-INDUCED EFFECTS ON TREADMILL PERFORMANCE ~ND ON STRIATAL DOPAMINE TURNOVER Hillegaart, S A~lenius, 0 Ma~nusson and CF Fowler

METHODOLOGICAL CONSIDERATIONS FOR THE ASSESSMENT OF DOSEEQUIV~ OF BENZODIAZEPINE AGONISTS AND ANTAGONISTS IN NORMAL VOLUNI'~S.

In previous experiments we have shown that repeated treadmill testing of rats, treated with haloperidol, enhance the duration of the effect, in comparison with the effect seen in animals tested once only, at the various time intervals. Initial biochemical experiments did not indicate any difference in striatal dopamine (D~) turnover between animals of the two test procedures at the time of maximal ~ehavioral difference, 2h after haloperidol, 0.32 mg.kg- i.p. As expected, there was a marked increase in striatal D~ turnover by the haloperidol treatment , and testing of the animals immediately before sacrifice produced a further increase in the D~ turnover in the two groups alike. In the present experiments we omitted the last test immediately before sacrifice. The animals were tested on the treadmill 30 and 60 min after the haloperidol injection, and sacrificed for biochemical evaluation of striatal DA turnover at 2h. Under these conditions we found a significant increase in DA turnover in the group tested repeated times (30 and 60 min), in comparison with animals not tested for treadmill performance, 2h after haloperi8ol. In conclusion: Our previous findings showed an enhanced duration of haloperidol-induced effects on treadmill performance by repeated testing, and increased DA turnover by treadmill exercise in haloperidol-treated animals. The present results demonstrate short-term changes in pre- or post-synaptic dopaminergic mechanisms since, omitting the last treadmill test before sacrifice, it was still possible to see an increase in striatal DA turnover 2h after haloperidol treatment in animals tested at 30 and 60 min after the drug administration.

C. Gorenstein, V. Gentil and S. Tavares Dose is a critical determinant of the intensity and duration of the effects of hypnotics. Usually doseequivalence is determined in relation to latency, total sleep time, nLm~ger of a ~ k e r ~ , and sleep quality. As an alternative we suggested the comparison of peak sedative effects in normal volunteers and the determination of dose-equivalence by a bioassay statistical method. This will be exemplified with data frc~ our experiments with triazol~n, flurazepam and zopiclone. Problems with the experimental design (parallel ~roups, crossover and incomplete design) will be discussed. Dose-equivalence studies for benzodiazepine antagonists face additional problems such as the need to assure the same level of sedation to be antagonized and the possible intrinsic agonistic or ~ r s e agonistic effects. Results of a study in normal volunteers ~ t h intravenous titrating doses of Ro 15-1788, Ro 15-3505 and placebo, following a 2rag i.v. dose of flL~nitrazepam will be presented to illustrate these phenog~na. Grupo de ?sicofisiologia Cl~n/ca, Instituto de Psi~diatria, Hospital das Clinicas, Caixa Postal 8091, Sao P~4/o, Brazil

Research and Development Laboratories. As~ra Alab AB. 3151 85 Sodert~iJe, Sweden.

32.04.04 A TOLERANCE AND PSYCHOMETRIC S'TtH)u OF SETASTINE, A NEW ANTIHISTAMINE. R.F. Coen, M. Kenny~ R. Lambe, F. Goer~eenyi~ M.I.K. Fekete~ A. Darragh. Setastine is a new antihistamine which is structurally related to clemastine with a similar activity as H1 antagonist. In animal experiments its sedative effects are considerably weaker than those of clemastine. In clinical trials setastine (i and 2mg t.i.d.) was well tolerated and was effective in the treatment of allergic rhinitis and allergic skin diseases. The present study was undertaken to investigate tolerance (including possible sedative effects) of single rising doses when administered orally to healthy volunteers. This was a double blind, placebo controlled study in 2 groups of 8 subjects, with 2 subjects in each group randomly assigned to placebo thronghout. The remaining subjects received placebo, 2mg and 6mg setastine or placebo 4mg and 8mg setastine on 3 separate o~casions. Effects of setastine on mood and performance variables were investigated using Digit Symbol Substitution, a Computerised Vigilance / Reaction Time Task, Saccadic Eye Movement, Wright-Codoc Ataxiameters and the Bond and Lader Mood Rating Scale. Colour vision was assessed using the Farnsworth Munsell lO0-Hue Test. Setastine was well tolerated at all dose levels. There were no adverse reactions of any clinical significance, and no clinically significant changes in laboratory or ECG parameters. While evidence of sedation was detected this occurred only at the highest (Smg) dose level and was mild in nature. Colour vision was not affected by setastine and no impairment of performance or mood occurred at those doses which have demonstrated therapeutic efficacy. Institute of Clinical Pharmacology (Irl.) Ltd., Sir Patrick Dun's Hospital, Lr. Grand Canal Street, Dublin 2, Ireland. ~Egis Pharmaceuticals, Budapest Hungary.

32.04.05 EFFICACY (im L ~ DOSES OF T~ICYCLIC$ L. ~qmaronatti,C" Burrai, L. Tcr~, G.F. Floris, P.P. Pani ~hile the antidepressant efficacy of Tricyclics is well known there ex&st many arguments about the correct therapeutic dosage. In fact ttere is a diootcmy between doses ~ in literature m~d real doses used in clinical prentice. ~ t r o l l e d observations of the effectiveness of low doses of Tricyclics performed by psychiatrists end practitioners stimulated interest for a more controlled research cn this topic. Fc~ this prc~ an open study v~s carried (m/t on patients wil/ndia~nc~is of M~jc~ Depressive Disorder, Bipolar Disorder, Depressive or Dysthymic Disorder. Each patient wee treated with 50 rag/dieof Amitriptyline, Clomiprmmine and Imiprmmine either orally or e.v. In order to prevent sideeffects such as m~nsea, vomitirg &nd o ~ t a t i c ~/potansian e.v. doses were increased gradually over a few days. Clinical statos was evaluated weekly from To "to T2B with H[~S. Pla~natic levels of the ~ ~ monitored. Results show that e.v. 1~'ea~m~nthad both more efficacy and improvement latency. !aprowmant ecctrred within ~ ~-~ee weeks and no. important side-effects were detected. After ten days of therapy ere patient became manic and required medicaticn with leptics &nd 'Lithium. 9b_ile the results concerr~ ~ne icwest effective dose for Tricyclics disagree with previous data they nonet#~less confJ_rm ttmt low doses of trdcyclics are effective in a percentage of c~ses greater tt~n is the placebo. In conclusion low doses of Tricyclics appear to be effective in those patients either never treated before or after a lorg time from dneir last antidepressant trea~mmlt. It is su~gestsd that dxing antidepressant t ~ a mcdificaticn of the sensitivity of m o n c ~ c receptcrs may occur requirin~ a higher dose of drq6.

Clinica Psichiatrica [biversi~ di Cagliari Via Liguria 13 , 09127 ~_gliari, ITALY

313

32.04.06

32.04.07

JAPANESE PSYCHIATRISTS PRESCRIBE LOWER DOSES OF NEUROLEPTICS AND UTILIZE HEAVY POLYPHARF~CY M__~. Tateyama, M__~.Kamisada, M_~. Tokuno, G_~_.Yaqi, M. Barrels and H. Heimann There were arguments whether Asian schizophrenics require lower doses of neuroleptics than Caucasians. The 1984 admission records of i00 schizophrenics (ICD-9:295) in both Japan and W. Germany were reviewed for number, type, initial dose, and max. dose of prescribed neuroleptics. Patients displaying similar severity of illness were randomly chosen from university psychiatric hospitals. Doses were converted to chlorpromazine equivalents (Davis 1974) and corrected for body weight. Results showed: 76 (76%) W. German patients were prescribed single neuroleptics as opposed to only 30 (30%) Japanese patients [p<0.01]; No W. German patients were prescribed over three kinds of neuroleptits whereas 30 (30%) Japanese patients were; Concomitant use of anti-Parkinsonian drugs was more prominent in Japanese patients (94 versus 21, p<0.01); Mean initial daily dose was higher in W . German schizophrenics than in Japanese patients (777 mg versus 449 mg, 11.93 mg/kg versus 8.18 mg/kg). Since Sramek et al (1986) found no significant difference in neuroleptic dosage requirements for Asian and Caucasian psychiatric patients we concluded that Japanese schizophrenics don't require lower neuroleptic dosage but Japanese psychiatrists display a clear trend for prescribing lower dosage & utilizing polypharmacy. Dept. of Neuropsychiatry, Keio University, 35 Shinanomachi Shinjuku-ku, 160 Tokyo, Japan

EMOTIONALITY-ASSESSMENT FOR THE TIME COURSE OF PHARMACOLOGICAL TREATMENT, EXPERIENCES ON THE FENFLURAMINE TEST F.M. Reischies, B. MOller-Oerlinghausen The emotional response especially in the acute trial of psychotropic medication can be assessed only very poorly.

Following the concept of Izard 1977, we therefore developed and tested an emotionality assessment, which can, after an instructio% be answered quickly in the time course of a psychopharmscological t r i a l . The intensity of 14 emotional qualities are evaluated on visual analogue scales in 3 categories of assessment: present state, emotional responsiveness and expression. Normdata were obtained from n=97 subj. and a first validation study involved n= 89 successively admitted psychiatric outpatients (ICD-9 giagn.). A disariminant analysis demonstrates the diagnostic power for healthy subj. (76 to 87% correct classifications), endogenous depression (78 to 100%), anxiety disorder (50 to 71%) and acute schizophrenic pat. (50 to 67%) on the basis of the 3 categories of assessment. We will report on the emotionality assessment in the time course of the acute administration of fenfluramine, a substance which is known for 5-HT depletion; furthermore an antidepressant effect is discussed for the acute medication of this substance. Psychiatrische Klinik und Poliklinik der Freien Universi-

t a t Berlin, Eschenallee 3, 1 Berlin 19, West Germany

32.04.08

32.04.09

SUCCESS AND FAILURE AT INPATIENT HEROIN DETOXIFICATION L. San. J. Cam[. J. M. Peri, R. Mats. M. Porta Predictors of either detoxification success or failure were evaluated during an inpatient randomized controlled clinical trial that compared the efficacy of methadone, clonidine and guanfacine for rapid heroin detoxification. The analysis of such predictors was stimulated by the fact that in order to achieve 90 patients who completed the study (30 in each group), a total of 170 patients had to be included. Of 80 detoxification failures, 10 occurred in the methadone group, 32 in the guanfacine group, and 30 in the clonidine group. There were not statistically significant differences with regard to sociodemographic characteristics and drug addiction among patients in the three groups who completed detoxification with success or failure. The treatment drug, the type of schedule and the score obtained from the Symptom Checklist-90/Revised were the only predictors of either detoxifioation success or failure. The main cause of detoxification failure was the subject's decision to discontinue detoxification therapy. Adrenergic agonists show limitations in the retention of patients when compared to methadone. Inpatient opioid detoxification appears to be a useful strategy for patients with more severe psychological symptoms, because successes were distinguished from failures by having higher symptom levels as measured by the SCL-90/R. Differences were significant in seven of the nine subscales as well as in the general symptom index (p<0.05). Hospital del Mar and Institut Municipal d'lnvestigaci6 M~dica. P. Maritim 25-29. 08003 Barcelona, Spain.

EFFICACY OF CLONIDINE, METHADONE AND GUANFACINE IN THE RAPID DETOXIFICATION OF PATIENTS DEPENDENT ON HEROIN J. Cam[. L. San. J.M. Peri, R, Mata. M. Porta The efficacy of methadone (MTD), clonidine (CLD) and guanfacine (GFN) in rapid detoxification of heroin inpatiens was assessed. Signs and symptoms of abstinence and the presence of side-effects were analyzed in all 90 heroin addicts (30 in each group) successfully completing a 12 day randomized controlled clinical trial. All patients fit DSM-III criteria for opioid dependence. 80.1% were males, the age range being 18 to 36 years. Mean length of heroin use was 5.1 years (SD 2.3). Mean daily street heroin dose was 473.7 mg (range 100-1500 rag/day). All three drugs were effective in controlling abstinence; however, the course of abstinence was different in the MTD group as compared to the adrenergic-agonists: while mean number of withdrawal signs and symptoms was significantly lower during days 2 to 5 in the methadone group (p< 0.01 in all cases), adrenergic agonist were more effective at the end of the trial. Incide0ce of side-effects was closely related to the dose administered. Hypotensive action of adrenergic agonists was more marked in orthostatic position. In this respect, guanfacine appeared to have some advantage over clonidine. These findings suggest that new strategies for rapid heroin detoxification, such as starting with methadone during the first 2-3 days and then switching to guanfacine, need to be considered. Hospital del Mar. Institut Municipal d'lnvestigaci6 M~dica. P. Marftim 25-29. 08003 Barcelona, Spain.

314

32.04.10

32.04.11

SERUM GLUT~4ATE AND PSYCHOTIC SYMPTOIIS IN SCHIZOPHRENIC PATIENTS G. Alfredsson, and F-A. Wiesel Serum glutamate was measured in acutely i l l schizophrenic patients before and during s u l p i r i d e treatment. The study lasted f o r 6 weeks and included 24 patients who were treated with 400, 800 or 1200 mg s u l p i r i d e , according to a randomized schedule. Glutamate and s u l p i ride levels were measured once a week and p s y c h i a t r i c ratings were performed before and a f t e r I , 3, 4 and 6 weeks of treatment using the Comprehensive Psychopathological Rating Scale (CPRS). From the CPRS items three subscales were made, one f o r a wide range of psychotic symptoms (ZIO), depressive symptoms (ZDep) and a u t i s t i c symptoms (ZA). Before treatment there was no s i g n i f i c a n t c o r r e l a t i o n between glutamate levels and p s y c h i a t r i c r a t i n g scores. During treatment, however, there were s i g n i f i c a n t correlations betw#en the changes in glutamate levels and the ratings of morbidity. The changes in serum glutamate were negatively and s i g n i f i c a n t l y correlated to the ZIO, a f t e r 3 and 6 weeks (r=-0.43"; r=-0.56") to the ZA a f t e r 3 and 4 weeks (r=-0.43"; r=-0.53") and to changes of the ZDep a f t e r 3 and 6 weeks (r=-0.49 ; r=-0.47 ).Thus, cJlnlcal improvement was related to an increase of serum glutamate. I t could not be established i f the r e l a t i o n s h i p between the i~crease of the glutamate level and improvement was a r e s u l t of s u l p i r i d e treatment, since there was no correl a t i o n between s u l p i r i d e levels and changes of serum glutamate nor was there any r e l a t i o n s h i p between the d i f ferent s u l p i r i d e doses and glutamate l e v e l s . Department of Psychiatry and Psychology, Karolinska Hospit a l , S-I04 Ol Stockholm, Sweden.

A NEW METHODOF SINCLE CASE EVALUATIOn! OF DRUG STUDIES: HTAKA-MODELL E.M.Steinmeyer,H.-J. N~LLER Mod~n~isTica~o~hes to the analysis of single cases are at present s t i l l seldem employed in p s y c h i a t r i c therapy research.Using the evaluation of the effects of antidepressant medication as an example,the results of a new kind of time-series-analysis performed according to Hierarchical-Trend-Segment-Component-Analysis(HTAKA) are presented. The aim of the HTAKA-model is to c r i t i c a l l y review the i n f e r e n t i a l l y - b a s e d aspects in i n d i v i d u a l time-series analyses with respect to t h e i r c l i n i c a l relevance. Regarding t h e i r a p p l i ' c a b i l i t y for therapy,cumulative processes and trend a l t e r n a t i n g parameters w i l l receive special a t t e n t i o n , t o g e t h e r with the v a l i d a t i o n procedures to spec i f y differences in growth curve l e v e l s . The analysis model suggested above can be u t i l i z e d f o r both experimental plannina procedures as well as f o r nonexperimental a p p r o a c h e s ( c l i n i c a l l y the f a r more frequent case).In non-experimental settinos,no influencing phases are calculated in advance.Considering such a s i t u a t i o n , the task arises how to simultaneously f i l t e r possible and optimal curve sections from the l o n g i t u d i n a l data and then to analyse i t according to aspects of level or trend a l t e rations. HTAKA is-a new form of time-series analysis,combining the advantages of trend and ARIMA analysis.With regard to the p r a c t i c a b i l i t y of this approach,it is important to emphasi, ze that HTAKA,which u t i l i z e s non-parametric significance tests,requires considerably fewer continous measurements over time than is the case f o r the ARI~'A-models. Abtl. Psychiatrie der Medizinischen Einrichtungen der Rheinisch-Westf~lischen Technischen Hochschule Aachen, Pauwelsstr.,51 Aachen

32.04.12

32.04.13

CONSTRUCTION AND VALIDATION OF AN ANX_rETY SCALE, T ~ F.A.R.D. (Ferreri Anxiety Rating Diaaram)

METHODOLOGICAL ASPECTS IN CLINICAL EVALUATION OF MIGRAINE PROPHYLACTIC AGENTS I. Simonidesz-Vermes, Gy. Papp, E. FGrizs, H. Kov~cs, I. Jelencsik, K. Kov~cs and J.I. Sz~kelv GYKI-32 594 (1-me• ~ -thiazolin-2'-vl/-amide bimaleinate) is a new migraine prophylactic agent. During its phase II. clinical evaluation GYKI-3~ 594 was compared to placebo and pizotilen (Sandomigran -Alkaloida Works, Hungary) in a double-ollnd cross-over study. In the course of the statistical processing of clinical data the methods used in evaluation of antim~graine agents had to be reexamined. The multiplex statistical analysis has led to the following COnClusions: Unless the c l i n i c a l t r i a l s and the subsequent s t a t i s t i c a l processing are c a r e f u l l y designed, the genuine migraine attacks might be e a s i l y confounded by various forms of i n t e r v a l headache wich are not r e l a t e d to genuine mtgraine; - The migraine prophylactic agents decrease the frequency and i n t e n s i t y of migraine attacks but they do not modify t h e i r duration; The e~ficacy of antimigraine agents can be detected abo~e a l l by examining separately the most severe attacks'. Comparing the a c t i v i t i e s of GYKI-32 594 and p i z o t i f e n in g~neral the former has been found more e f f i c i e n t . Nevertheless, in a subgroup of patients (unresponsive to Sandomigran) GYKI-32 594 proved to be superior.

R. yon Frenckell, M. Ferreri, S. Tawil, D. Bonnet, J.P. Girre and J.M. Alby The authors have first applied to a sample of 81 patients with generalized anxiety disorders (following DSM-III) a set of 14 items previously defined by pools of General Practitioners and psychiatrists. The list was based on the more frequent items in arxiety, speaially related to the influence of anxiety ~tate on daily living. Of the first list of 14 items, 12 were extracted as pertinent by the way of a factor analysis with retained 4 factors (64.5 % of variance explained). The authors called these factors, which polled 3 items each, somatic, relational, cognitive and vigilance dimensions so it was possible to represent the global information on a diagram. T~ese results were confirmed on two other samples, one rated by General Practitioners (250 cases) and the other one rated by Specialists (150 cases). The studies showed that the scale was particularly valid, sensitive, reliable and easy to complete by G.P. or Specialists. T~is new scale is characterized by a predominance of ter~ion/irritability items over somatic items as compared to the Hamilton Anxiety Scale. University of Liege, Neuropsychiatry Unit, Centre Hospi;aiier Universitaire (B 35), B-4000 Liege Sart Tilman, Belgium.

I n s t z t u t e for Drug Research, Szabads~gharcosok d t j a 4T-49. H-1045 Budapest, Hungary.

315

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32.04.15

THE MUNICH STUDY GROUP: "PSYCHOTROPIC DRUGS IN PRIVATE MEDICAL PRACTICE": METHODOLOGICAL ASPECTS. Blaschke D; Laakmann_G. Many drug trials have been done in the last years in order to determine the efficacy and tolerability of newly developed psychotropic drugs. In many of these studies the authors found no difference between the standard and the new compound. Possible reasons for these results can be that either there is actually no difference between the tested drugs or that these studies did not consider a number of methodological aspects which could have proved real differences or a differential efficacy between the two drugs. The following will discuss these problems partly based on own studies: I. Sample size too small: To statistically substantiate the equality of two drugs (exclusion of the ~-error, i.e. false acceptance of equality) using the standard parameters.(i.e. HRDS: sd=10; a=0,05; 5=O,30;mean difference=5) one needs at least 50 patients per group. 2. Responder-definition: A score reduction of 50% is normally used to measure response. It can, however, be shown that a change of response-level (i.e. 25% or 75%) leads to a drastic change in the results. For example, with a response-level of less than 30% there is a threefol~ increase in the proportion of placeboresponders. 3. Differential efficacy depending on severity of psychic illness: The assessment of Alprazolam vs. Amitriptyline showed no differences in the total group, whereas significant differences in favor of Amitriptyline where seen in the group of severely ill patients. 4. Differential efficacy depending upon the type of depressive syndrome: The assessment of Fluoxetine vs. Amitriptyline showed no difference in the total group. There were, however, differences in favor of Amitriptyline in the group of patients with a retarded depressive syndrome, and in favor of Fluoxetine in the group of patients with a vitally disturbed depressive syndrome.

EXPERIENCE OF A DSMIII-BASED EXPERT SYSTEM (ADINFER). J. Fondarai, G. Vallat, M. Ohayon The authors present the DSMIIl-Based Expert. system Adinfer (9 M.Ohayon, 1984). The knowledge basis includes the DSM-III critena for all adult mental disorders on axis I. The computer displays its questions in the very wording of DSMHH (French translation, mini DSM4~I), following the decision trees. Moreever,~e clinician has to give the ten main symptoms and his own dignos~, freely expressed, according to his nosographiu referencies and habits. The d;nical and computer diagnoses are strictly independent, This experI system was used in mufticont~'ic c~inical an'ddepressive drug tdaJs. among GP as well as PsychiatrLsts. The authors present the results of the comparison between the spontat)eous and Expert-system diagnoses and discuss the interest of such systems in drug trials: Adinfer provides a non-biased DSMIII diagnosis and ensureS therefore the homogeneity of diagnostic subclasses, espe~ally in depressive disorders. Moreover, the simultaneous free diagnostic and symptom list may confirm this homogeneity. Th!s is particulady useful in clinical drug experimentations aiming at the definition of specific target samples. Laboratoire de Traitement des Connaissances, CHU Sainte-Marguerite, 270, Boulevard de Ste-Marguerite, 13009-Mareeille (FRANCE)

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32.04.17

THE CLASSIFICATION OF DEPRESSIVE DISORDERS IN DIFFERENT DIAGNOSTIC SYSTEMS W. Mombour, W. H i l l e r Most p s y c h i a t r i s t s w i l l be in agreement on the diagnosis of a depressive syndrome.But they often do not correspond on the subdivision of depressive disorders i n t o discrete nosolog~caI groups. Depending on the nosological system used the number of these groups and the c r i t e r i a f o r inclusion or exclusion vary to a considerable e x t e n t . The world-wide use of ICD-8 in the years 1970-1980 concealed these discrepancies which again appeared a f t e r the i n t r o duction of recently developed systems l i k e DSM-III, DSMI I I - R and ICD-IO. The use of d i f f e r e n t diagnostic systems at the same time makes comparing diagnoses between count r i e s and i n s t i t u t i o n s d i f f i c u l t and requires a poIydiagnostic approach. Accordingly a considerable "migrazion" of patients between nosological groups can be shown i f one diagnostic system is replaced by another (e.g. ICD-9 by DSM-III-R). Empirical data on o u t p a t i e n t depressives, diagnosed according to ICD-8/9 and DSM-IIIR/ICD-IO are presented. The category of "major depression" in DSM-III-R subsumes a great number of depressives formerly given multiple other diagnoses according zo ICD-8/9. Many of the neurotic depressives and the adjustment reactions with depressive symptomatology according to ICD-8/9 were diagnosed as a "major depression" in DSM-III-R or did not receive any specific diagnoses; only a few of them retained the corresponding diagnosis of dysthymia or adjustment disorder. Manipulation of psychiatric diagnosis in therapy and research through the choice of a "suitable" diagnostic system could be one consequence of the actual s i t u a t i o n ,

A NEW STRUCTURED INTERVIEW FOR THE DIAGNOSIS OF SENILE DEMENTIA ALZHEIMER-TYPE AND MULTIINFARCT DEMENTIA (ACCORDING TO ICD-IO AND DSM-III-R) IN OUTPATIENT CARE M. Zaudig, J. Mitte]hammer and W. Mombour By far the most commoncauses of cognitive decline in older persons are dementia of the A1zheimer-type (SDAT) and to someextent multiinfarct dementia (MID). Detecting the presence of the disorders (diagnosis) and their stages (severity) is central to any clinical study of SDAT and MID. Up to date, SDAT is a disorder of unknown etiology and no specific treatment. However, with the marked interest recently manifested in this disorder,our knowledgeand understanding are rapidly increasing. Consequently, methods shou]d be developed for earlier detection and diagnosis of the illness and should result in rationa] treatment approaches. Many rating scales assessing behaviour and stages of the disorder have been developed using lengthy psychometric tests. But almost no diagnostic instruments have been developed supporting physicians in rapidly detecting SDAT and MID. In addition there is need for a comprehensive but short diagnostic assessment in view of the d i f f i c u l t y testing dementedpeople with lengthy psychometric ba~cteries. The authors describe a structured interview (SIHP) for a standardized assessment of SDAT and MID according to the diagnostic c r i t e r i a of DSM-III-R and ICD-IO. The instrument can easily be utilized by physicians~nd clinidans. The average time for the interview is about 20-40 minutes. Scores for the Mini Mental State (Folstein et aI. 1975) and the modified Hachinski-Score (Rosen e t a ] . 1980) are included. Preliminary results indicate a good r e l i a b i l i t y , results of the test-reteststudy and other statistical data are discussed. The SIHP was found to distinguish diagnostic categories amongolder subjects with a wide range of cognitive defects. These advances have immediate relevance with respect to the choice of therapy and pharmacological treatment t r i a l s .

316

32.04.18 A DIAGNOSTIC CHECKLIST FOR CLINICAL USE BASED ON THE CRITERIA FROM THE CLASSIFICATION SYSTEMS DSM-III-R and ICD-IO W. H i l l e r , M. Zaudig, W. Mombour, J. Mittelhammer R. Rummler, M. von Bose Structured diagnostic instruments (serving as guidelines f o r the evaluation of psychiatric signs and symptoms) are needed when c l i n i c i a n s refer to c r i t e r i a and to operat i o n a l ] y defined diagnostic categories as provided by the new c l a s s i f i c a t i o n systems DSM-III-R and ICD-IO. Covering both systems the Munich Diagnostic Checklist (MDCL) have been developed as a polydiagnostic instrument for routine use in outpatient evaluations, s p e c i f i c a l l y designed f o r both diagnostic and s c i e n t i f i c purposes. A t o t a l of 15 sections covers 33 of the most prevalent and common psyc h i a t r i c disorders. Psychopathological findings based upon the c l i n i c i a n ' s judgement ( f o l l o w i n g a c l i n i c a l i n t e r view) can-be structured and standardized to a high degree. The instrument constists of approximate]y 1000 items representing symptoms as wel] as c r i t e r i a defining present status, course and outcome of specific disorders. Of spec i a l re{evance are present status and l o n g i t u d i n a l ( l i f e time) findings. Diagnoses are given with the aid of a compute~program. Using MDCL in diagnostic e x p l o r a t i o n , the c l i n i c i a n checks in a systematical and comprehensive mann@r for a number of most relevant possible diagnoses, asks e x p l i c i t e l y for the c h a r a c t e r i s t i c s of the p a t i e n t ' s present status and c o l l e c t s a l l information pertaining to a psychiatric diagnosis. Usual modalitJes of i n v e s t i gation may be maintained so that time requirements can be kept within t r a d i t i o n a l l i m i t s . In contrast to the a p p l i cation of c l i n i c a l interviews the c l i n i c i a n can immedia t e l y focus on the most predominant symptoms and is f l e x i b l e to use the checklist under conditions when pat i e n t s show acute symptomato]ogy (e.g. states o{ d i s o r i entation, delirium, a g i t a t i o n , i n t o x i c a t i o n , mutism). F i r s t data about the evaluation of the MDCL are presented.

32.05.01

POSTER PRESENTATION 32.05

Miscellaneous

INFLUENCE OF CYTOSTATIC T R E A T ~ N T ON EEG ACTIVITY-HYPOTk~T!CAL EFFECT OF NOOTROPIC PREPARATIONS ON TBU~ TOXICITY OF CYTOSTATICS HoTONDLOV~, JoBASTECKY, K.HYNEK~ O.ANDRYSEK Psychiatric Unit,Railway Hospital and Outpatient Clinic ~ Deptoof Psychiatry,Postgraduate ~edical and Pharmaceutical Inst. ; Dept. of Psychiatry,Charles University; Clinical Ontology Center, UnivoHospital, PraEae It follows from our ebservations that some cytostatics evoke symptoms of organic brain damage on EEG.These changes probably play their part in the etiopathogenesis of the organic psychosyndrome and of the impairment of cognitive functions in cancer patients. The aim of ~he present study, concerned with lO cancer patients /without brain metastases/ treated with ;~ifferent cytostatic drugs~ was to demonstrate the side effects of these drugs on the EEGo 9_fTer 6 weeks of cy~ostatic treatment, a significant decrease of alpha,beta and gama activity was found in the parietooccipital region; on the other hand,an increased beta activity was ascertained in the frontocentral region~ changes are indicative of an inhibition:of brain electrogenesis resembling EEG changes in acute drug intoxications. The paper goes on To discuss the effect of cinnarizin /STUGERUA/on These changes in some patients. A randomize~-~rial project aimed at searching for the ~roi~hylactic action of some nootropic drugs /meclophenoxate, piracetam/ on EEG side effects of cytostatic treatment has been elabora~edoln this cop_nec~ion,an ex~eaaive screening examination of patients suffering Erom moHodkLu ~nd CA mamma is under -;;ay,-~'ith a view to arrive aV a more accurate E}
317

32.05.02 E F F E C T OF S U B C H R O N I C A D M I N I S T R A T I O N OF P C P A A N D / OR I M I P R A M I N E ON 5 H T - S T I M U L A T E D I N O S I T O L - I - P H O S PHATE A C C U M U L A T I O N IN RAT E I P P O C A M P U S . M. MIKUNI, I. K U S U M I and K. T A K A H A S H I Recently, it has b e e n s h o w n that the b i o c h e m i c a l e f f e c t o r s y s t e m of 5HT-2 r e c e p t o r i n v o l v e d i n c r e a s e d p h e s p h o i n o s i t i d e ( P I ) h y d r o l y s i s in rat cerebral cortex, but not in h i p p o c a m p u s . It has been also d e m o n s t r a t e d t h a t c h r o n i c t r e a t m e n t of m i a n s e r i n c a u s e d a s i g n i f i c a n t r e d u c t i o n , but chronic P C P A t r e a t m e n t h a d no s i g n i f i c a n t e f f e c t upon the m a x i m a l PI r e s p o n s e to 5HT. In the p r e s e n t study, r i t a n s e r i n , a s e l e c t i v e 5H T-2 antagonist, i n h i b i t e d 5 H T ( ! 0 u M ) - s t i m u l a t e d i n o s i t o l - l - p h o s p h a t e ( I P - l ) a c c u m u l a t i o n in rat h i p p o c a m p u s w i t h a Ki v a l u e of 2 5 n M , i n d i c a t i n g the a c t i v a t i o n of 5HT-2 r e c e p t o r p r o d u c e d PI h y d r o l y s i s in the h i p p o c a m p u s . 1 0 - D a y t r e a t m e n t of P C P A ( 3 0 0 m g / k g ) r e s u l t e d in a m a r k e d i n c r e a s e in the r e s p o n s e of IP-i a c c u m u l a t i o n in the hippocampus, w h e r e a s this t r e a t m e n t had no s i g n i f i cant e f f e c t u p o n the d e n s i t y of 511T-2 b i n d i n g sites in c e r e b r a l cortex. P C P A c a u s e d 98% r e d u c ~ tion in-5KT c o n t e n t and 40% r e d u c t i o n in NE levels. T h e s e o b s e r v a t i o n s u g g e s t e d t h a t lowering of 5HT and NE s y n t h e s i s i n d u c e d i n c r e a s e in 5lIT m e d i a t e d PI h y d r o l y s i s w i t h no s i g n i f i c a n t e f f e c t u p o n the n u m b e r of 5HT-2 receptor. 10-Day t r e a t m e n t of i m i p r a m i n e h a d no s i g n i f i c a n t effect on 5}IT s t i m u l a t e d IP-I a c c u m u l a t i o n in the h i p p o c a m p u s f r o m the rats w i t h or w i t h o u t co-adm i n i s t r a t i o n of PCPA. T h e s e r e s u l t s i n d i c a t e d that f u n c t i o n a l b i o c h e m i c a l c h a n g e s did not r e l a t e d to the c h a n g e s in the d e n s i t y of 5HT-2

receptors. Div. of Ment. Dis. Res., Natl. I n s t i t u t e of Neuroscience, NCNP. 4 - 1 - 1 , O g a w a h i g a s h i , Kodaira, Tokyo, 187, J a p a n

32.05.03 L~LORPRONAZIt~E I ~ I B I T S

PHOSPHATIDYLINOSITOL TU2JIOVER I N

THRO~IN-SYIMULATED HUMAN PLATELETS H. Wakatabe, T. Tsukahara, J. Ishigooka and S. Miurs Chlorpromazine (CPZ) inhibits secretion and aggregation responses in human platelets stimulated by thrombin. This indicates that CPZ might inhibit the liberation of araehidonie acid from membrane phospholipids which is induced by activation of phospholipase A2. On the other hand, platelet activation has been known to involve phosphatidylinosltol (PI) turnover which is initiated by activation of Pl~specific phospholipase C, resulting in the transient formation of 1,2-diacylglycerol(DG) and the formation of phosphatidic acid (PA). This response might be followed by the specific activation of the protein kinase C that phosphorylates a 40,000-dalton protein. In the present study, the effects of CPZ on PI turnover and successive phosphorylation of endogenous proteins by protein kinase C were investigated using human platelets. The results were as follows: (i) When [3HI arachidonatelabeled platelets were incubated with thrombin (0.3U/ml) at 37~ the radioactivity of DG was increased within 15 sec, and was then progressively decreased with further incubation. A marked enhancement of radioactivity in PA, converted from DG by DG kinase, followed a concurrent decrease in radioactivity in DG. This transient formation and successive degradation of DG were partially inhibited by CPZ (IO0~M), while the formazion of PA was blocked. (2) The degradation of phosphatidylcholine and the liberation of arachidonic acid possibly by phospholipase A2 were blocked by CPZ. (3) In [32p] phosphate-labeled platelets the phosphorylation of a 40,O00-dalton protein reached ~o the maximum within 60 sec, and was inhibited by CPZ. These findings indicate that initial changes in PI turnover may be inhibited by CPZ. Department of Psychiatry, Kitasato University School of Medicine, 863-1 Asamizodai, Sagamihara, Kanagawa 228, Japan.

32.05.04

32.05.05

DRUG TARGETS ADENYLATE CYCL~Ss Ah~ PROTEIN KINASE C: MORPHOLOGICAL BASIS FOR "CROSS-TALK" IN HIPPOCA~US Jurgen Deckers* and Martin B. Jorgensen# Two of the major second messenger systems in the mammalian CNS are the cAMP system and the diacylglycerol/IP3 system. Using radioligand probes for components of these two second messenger systems we studied adenvlate cvclase [3H]Forskolin binding sites) and protein kinase C ([3HI Phorbol-12,13-dibutyrate ester binding sites) four days after selective depletion o{ CAt pyramidal cells in rat hippocampus by transient cerebral ischemia in a quantitative autoradiographic study. Results in fmel/mg dry tissue weight: ~3H~Forskolin control ichemia CAI region 54+3 13+3" CA3 region 156512 137~15 [3H]Phorbol-12,13-dibutyrate ester control isehemia CAI region 1671+35 1091+85" CA3 region i171556 i087~63 (mean + SEM: n = 5/group; * = p <0.05). The reduction of both [3H]Fnrskolin and ~3H~Phorbol-12,13dibutyrate ester binding in the CAI region strongly suggests that adenylate cyclase as well as protein kinase C and thus both second messenger systems are localized in CA1 p~ramidal cells of hippocampns. Drugs acting at a compoAent of one of the two second messenger systems are therefore likely to affect the other system via "crosstalk" in CAt pyramidal celIs. i: PEAS USA 83, 4053-4057, 1986; 2: Acta Neural Scand 66, 536-546, 1982. 9Universitats-Nervenklinik, Fuchsleinstr. 15, D-8700 Wurzburg and #Institute of Neuropathology, Frederik V's vej Ii, DK-2100 Copenhagen

AIIACHMENI ~ F::~Z~XI~AL SLEZP: EFFECT OF ANTI-DEPRESSANTD~L3S M. DhayonI B. Cy-ui~ik and J.C. Fady The basic hyo~-esis states that the suppression of paradoxical sleep leads to major c;9=i:i.e troubtes, in particular as regards acquisition pre~s=e-a. In the animal, the cognitive processes are of major importance ! ~ ~ a certain period called the sensitive ~ericd. During this period, attachment processes are established and develop. We therefore wa~ed :o verify whether paradoxical slee'p, in an essential or =ajc~ ,ay, doesn't sustain the attachment processes that intervene during :me sensitive period in the young animal. This is catted the i~pri~t ,nose constitution is probably related to an ~ypeememory phenomenon. Their demonstration ,as greatly facilitated.by the existence of very specific behav~ora: ano neurobioiogical references. Given : i) the existence of specific behavioral and neurobiological references enaoli~g the study of the process 2) the effects of t r i o y c l i c antidepressants, true "chemicat scalpels" suppressing paradoxical sleep, we f e l t that i t was possible to test : i) whet~er there is a correlation between sensitivity to events and the amount of ~aradoxical sleep, 2) the hypothesis e-f a !ink between paradoxical sleep and attachment processes.

~he experiment ~as carried o u t on f~ur groups of kittens : clomipramine, viloxezine, =aprotiline and untreated controls. The protocol includes social tests, "familiar objects" tests, tests of new socially explo*ed situations, tests of new situations explored

alone and an analysis of the vocalizations emitted during the test situations. The tests presented in this poster were carried out between week two and wee~ eight, lhe results are provided For each compound used and enable verificationc~ t~e i n i t i a l hypotheses. taboratoire de Traltewent de Connalssances (Director : M. Ohayon), CHU Sainte Marguerlte. 270, boulevard de Ste-Marguerite, L3OOg MARSEILLE ~FRANCE)

318

32.05.06

32.05.07

BEHAVIOL~AL "DESPAIR" IN MICE: INFLUENCE OF 5-HT FUNCTION M.Maling#, M. Bourin, M.C. Colombel. Mice and rats respond differently to antidepressants (ADS) when tested in the swimming model; 5-HT function does not seem to play a critical role in ADS effects in rats (R.D. Porsolt, Eur. J. Pharmacol. 57, 201, 1979). Ue examined its influence in the mouse procedure. Groups of 6-12 male Swiss mice were subjected to a forcedswim (R.D. Porsolt, Arch. Intern. Pharmaeodyn. 229, 327, 1977) 30 min after I.P. injection of the following drugs (mg/kg): methysergide and ketanserin (.5-8), 5i~eODMT and 8-OH-DPAT (.5-4), citalopram (2-16), indalpine and fluvoxamine (4-32). Immobility duration was timed during the last 4 min of a 6-min swim (statistics: Kruskall-Wallis test, * p(O.05, ** p(O.Ol). Methysergide, ketanserin and 5-MeODMT were inactive; the putative 5-HTI agonist 8-OH-DPAT was active between 1 and 4 mg/kg (~*~) as were 5-HT uptake inhibitors, the first active doses of which were: citalopram 8 (**), indalpine 8 (*), fluvoxamine 16 (*). However, methysergide (2) and the 5-HT2 blocker ketanserin (8) given 45 min before testing increased the effect of the ~-agonist clonidine (i mg/kg at 30 min pretesting) from 44 and 52 % to 1 and 13 % of controls respectively (**). Conversely, a subthr2sfiold dose of clonidine (.06 mg/kg at 45 min) made 'effective 8-OH-DPAT .5, citalopram 2, indalpine and fluvoxamine 4 (** in all cases) but not 5-MeODMT. 5-HT mechanisms may thus account in part for ADS-induced reversal of immobility in mice and stimulation of ~ receptors due to NA uptake inhibition is presumably increased by blockade of 5-HT2 receptors. Moreover, additive or synergistic interaction would occur between direct or indirect ~-stimulants and agonists of the 5-HTI receptor subtype. Lab. Pharmacologie, U.E.R. M~decine 44035 Nantes C~dex France.

ACTIVE AND PASSIVE AVOIDANCE LEARNING IN NEONATALLY 6-0HDA-TREATED RATS. M. TAKASUNA and T. IWASAKI To examine the effects of neonatal dopamine (DA) depletion on aversive learning performance, we used two kinds of active (shuttle and rearing) avoidance and one passive avoidance tasks. On days 2 and 4 after birth, each rat of F344 strain received bilateral intraventricular injections of 70Ng 6-hydroxydopamine (6-OHDA) or vehicle solution after desmethylimipramine (20mg/kg, IP) pretreatment. From 90 days of age, each rat was trained in one of the three avoidance tasks. 6-OHDA-treated rats showed significantly less avoidance responses in the shuttle avoidance, but performed as well as control rats in the step-through passive avoidance task. Their impairment on shuttle avoidance performance was not due to motor deficit, since they were hyperactive iN the open-field test. Rather the impairment seemed to be derived from the predominance of inappropriate escape responses such as rearing and jumping. The evidence that in another kind of task, the rearing avoidance, their performance was not significantly different from that of control rats may support our notion. Analysis of brain catecholamine contents using HPLC proved selective DA depletion in striatum, hippocampus and cortex. These results were discussed in terms of motor response hierarchy, CS-US association, and memory. This kind of comparative analysis of aversive learning performance serves a useful tool for drug studies. Institute of Psychology, University of Tsukuba, [-l-I Tennodai, Tsukuba-city, Ibaraki 305, Japan

32.05.08

32.05.09

CHOLLNERGIC DYSFUNCTION AFTER HALOPERIDOL TREATMENT: PROTECTION BY GANGLIOSIDE GM1. S.P. Mahadik, A. Korenovsky, H. Laev and S.E. Karpiak. We have shown that the haloperidol treatment of rat alters the CNS cholinergic system. After short-term (7-21 days) treatment both cholinergie marker enzymes (choline acet'),ltransferase, CHAT; acetylchollnesterase, ACHE) were mcreased in hippocampus and in str/atum. After chronic (40-60 days) treatment the levels of both cholinergic enzymes were decreased. There were also morphological changes determined by immunohistochemical analysis of ChAT in both brain areas. Cortical changes were marginal Also, no chemical or morphological changes were detected fullowing treatment with either clozapine, a drug with low incidence of motor dysfunction or with imipramine, an antidepressant. The changes in cholinergic enzymes indicated that the short-term haloperidol treatment caused a hyperarousal of the cholinergic system (considered essential for antipsychotic action of haloperidol) and long-term treatment caused a hypocholinergic state in striatum (probably contributlng to motor dysfunction) and in hippocampus (probably contribute to negative symptoms associated with chronic treatment). Since ganglioside GM1 treatment of rat has been shown to protect the haloperidol treatment associated dopamine receptot~ supersensitivity in striatum and also striatal dopzmlrfergic structure/function following CNS injury we have examined its protective effects on the levels of cholinergac enzymes in striatum, hippocampns and cerebral cortex. Rats were divided in four groups: control; haloperidol (2rag/ks/day, ira.); ganglioside GM1 (10mg/kg/day, ira.) and halopendol/GM1 for 8 and 40 days. After 8 days of treatment the increases in both t h e enzymes were not changed significantly by treatment with GM1. However, after 40 days of treatment the decrease in the ChAT activity was protected in all brain areas tested. The data su,,~,est that GM1 treatment may protect cholinergic vutneral3~'~ty from toxicity associated with potent neuroleptic treatment. NY State Psych. Inst. & Col. Univ. New York, NY. 10032.

~ A L BY RO 15-1788 OF THE SEDATIVE, AT/E~TIONAL AkD AMNESTIC ~ b C T S OF LORAZEPAM IN MAN. G.C. Preston, M. Traub r C. Ward, P. Broks & S.M. Stahl. It has been suggested that the memory deficits produced by henzodiazepines ane resistant to the effects of the benzodiazepine antagonist Ro 15-1788 (Hammer, Breier, Paul, Davis & Weingartner, ACNP proceedings, 1986), whereas the anxiolytic, sedative and attentional actions of the drugs are antagonized by Ro 15-1788. Such a dissociation would imply that the amnestic propert/es of benzodiazepines are independent of their other actions, particularly their production of sedation. In this study ~ investigated the effects of lorazepam (2.0 mg p.o.) on various aspects of m~ory, attention, and sedation in normal healthy volunteers. We found that, relative to placebo, lorezepam produced deficits in verbal secondary memory, which accompanied changes in choice reaction time perform~nnce, critical flicker fusion, sustained attention and self-rated alertness. It also produced changes in the accuracy, but not the speed, of ballistic ~ t s . In addition, on three ~_perate occasions the subjects were given the same dose of. lorazepam (2.0 mg p.o.) followed by one of three doses of Ro 15-1788 (0.3, 1.0 and 3.0 mg i.v.). ql%e RO 15-1788 showed dose-related antagoni~ of the amnestic effects of lorazepam, blocking deficits in the total ntmS~r of items recalled, the cc~sistency of recall and the ntm83er of intrusien errors. It also showed a monotonic dose-dependent reversal of the changes in sustained attention, choice reaction time and self-rated sedation. Only the effects on critical flicker fusion and on perfon~anee on the ballistic ~ t task were spared by the antagonist. Frc~ these data it is not possible to dissociate amnesia from sedation, and it remalns feasible that the amnesia produced by benzediazepines are a consequence of their sedative action rather than a primary effect of the drugs. Merck Sharp & Dohme, Terlings Park, Harlow, Essex, U.K~

319

32.05.10

32.05.11

THE EFFECTS OF ~-BLOCKERS ON THE PSYCHOMOTOR FUNCTION, - WITH SPECIAL REFERENCE TO MULTIPLE SLEEP LATENCY TEST M. Uchiumi, M . Murasaki, J. Matsumoto, Y. Fukuyama and S. Miura The effects of atenelol and pindolol-R on the psychomotor function were studied in a double-blind placebo-controlled trial. The drugs studied were atenolol 50 mg, pindolol-R 20 mg and placebo. All experiments were performed using 6 male healthy volunteers. The subjects were tested three times(stepl-step3), each step period lasting 3 days. In the step i study, all subjects were given placebo once-daily for 3 days. On the third day of the experiment, MSLT(Multiple Sleep Latency Test), SSS(Stanford Sleepiness Scale), SAM were repeated every 2 hours after drug-administration. In addition to these tests, three psychomotor functional tests(kraepelin test, reaction time test and flicker fusion test) and equilibrium test were performed between MSLTs. In the stay 2 and the step 3, the subjects were randomly assigned to be ziven either atenolol or pindolol-R in a cross-over manner, and all tests were carried out in the same schedule as in the step !. SSS and SAM shewed that general fatigue was increased by pindoloi-R. MSLT reveald that atenolol significantly increased sleep tendency, while pindolol-R decreased, The effects of atenolol on psychomotor function were more favorable than those of pindolol-R. These two ~-blockers did not significantly affected the equilibrium tests. It has been reported in o t h ~ clinical studies that sleep disturbance and other advers effects of CNS were higher with lipophilic 8-blockers than with hydrophilic ones and were thought to be related to intrinsic s ~ p a t h o m i m e t i e activity. The result in the present study using MSLT and other psychomotor functional tests supported the above findings. Department of >sychiatry, Kitasato University School of Medicine, 863-1 Asamizedai, Sagamihara, Kanagawa, 228, Japan

THE CHANGES OF B E H A V I O R AND BRAIN AMINE LEVELS AFTER REPEATED ADMINISTRATION OF 6 - P H E N Y L ET~YLAMINE AND METHAMPHETAMINE M.YAMADA, M.HASHIMOTO, Y.KIUCHI, K.OGUCHI and Y.YASUHARA In t h i s s t u d y , w e c o m p a r e d the response to acoustic stimulation (AS) a n d t h e c h a n g e s of brain amine levels after repeated administration of ~ - p h e n y l e t h y l a m i n e (PEA) and methamphetamine ( M A P ) in r a t s . For inducing reverse tolerance, rats wereadmlnistered PEA (50mg/kg) i.p. o n c e d a i l y f o r 10 d a y s or M A P ( 2 . 5 , 5, 7 . 5 a n d 10 m g / k g ) i.p. t h r e e t i m e s d a i l y o n d a y I, 3, 5 a n d 7, r e s p e c tively. The response to A S by b u z z e r w a s o b s e r v e d on d a y 2 a n d I, 2 a n d 4 w e e k s a f t e r t h e drug administration using open field apparatus. The contents of a m i n e s a n d t h e i r m e t a b o l i t e s in the b r a i n r e g i o n s w e r e m e a s u r e d 4 weeks after the l a s t d o s e u s i n g H P L C - E C D ~ s y s t e m . Both drugs induced and maintained reverse tolera n c e of s t e r e o t y p y for 4 weeks after withdrawal of d r u ~ s . In P E A a n d c o n t r o l groups, the increase in a m b u l a t o r y activity by AS and its suppression after AS were remarkable. In M A P group, however, this response to A S w a s n o t ebvieus up to 4 w e e k s a f t e r a d m i n i s t r a t i o n . The increase in t o t a l n o r e p i n e p h r i n e (NE+MHPG) in c e r e b r a l cortex (CX) a n d 5 - H T t u r n o v e r in hypothalamus in P E A g r o u p a n d t h e d e c r e a s e in total 5-HT (5-HT+5-HIAA) in CX a n d m i d b r a i n in MAP group were observed. These data suggest that the different response to AS o b s e r v e d between PEA and MAP group may be associated w i t h t h a t of the c h a n g e s of a m i n e s in t h e b r a i n . D e p t . of P h a r m a c o l o g y , S c h o o l of M e d . , Showa University, Tokyo 142 J a p a n .

32.05.12

32.05.13

"The ~echas ~f the T=anb-S':~z~tz: E:~r !n]ury I~ 7ransient Ischemla an/ tn~ P r e a c h , ' ! : ( of ~ts Preventives"

ell t~y

Fyuya Kogure, ~.D.,C.v.5::

DEPRESSIVE STATES IN PATIENTS WITH ACUTE SPINAL CORD INJURIES AND THEIR TREATMENT IN COURSE OF REHABILITATION. H. Piatkowska

Tsutomu ~cakl, M.S.

Z~DIO Oga~awar~, M , S . Department o f Neurology Tohoku Univecszty Schobl of b~edic!ne I-I Seiryo-n~cEl, Sen~l ~ 0 Japan

The.mechanisms of acute neuronal ~eath, maturatlonal deatz, delayed death, and survival of the Dcst-ischemic selectively vulnerable brain cells were found to be similar. The dying process starts with the perturbatlonal ion gate opening at the qlutam~te receptor sites and the size of the pores settles the fate of the neurons. However, the ischemia-indueed ion channels can bemodified by pharmacological means. Chemicals reported to block the clutamate effect and the cal~--ium effect-, and to facilitate re-synthesis of the membrane lipids, arid c h e m i c a l s reported to enhance the effect of irinibitory neurotransmitters, effectively prevented the iszhemiainduced neuronal death. A few other chemicals such as ergotamlne, vincaloids and its relative co~pounds, also exhlblted certaln protective effects, although the mode of action of those drugs !s not yet fully understood. We also found many other compounds which may act merely as a plug or a coat for the perturbed ion chanmels can prevent those selectively vulnerable neurons to die in ischemia injury. A common denominator obtained from a computor-assisted analysis of those molecules suggested that an inert structure featured with a large and a small hydrophobzac moieties connected by a hydrophilic, flexible short chaln can be an ideal compound as a preventive of the ischemia-induced Draln cell necrosis.

320

ANALYSIS OF DEPRESSIVE STATES AFTER ACUTE SPINAL CORD INJURIES AND THEIR PHARMACOLOGICAL T R E A T MENT IS PRESENTED THE VERY IMPORTANT INFLUENCE OF LUDIOMIL IS DISCUSSED. Department of Psychiatry, Warsaw, Poland

32.05.14

32.05.15

SHORT-LATENCY EEG EFFECTS and PLASMA CONCENTRATION of :HENOBARBITAL 50- or 100 mg SINGLE ORAL DOSES in HEALTHY VOLUNTEERS

A CLINICAL PHARMACOKINETIC DATABASE FOR ALPRAZOLAM USING LIMITED SAMPLING C.L. DeVANE, T.H. GRASELA, Or., and E.J. ANTAL I n t e r i n d i v i d u a l differences in drug response are c r u c i a l considerations in designing dosage regimens. Pharmacok i n e t i c v a r i a b i l i t y , a major determinant of drug response, is frequently evaluated in pre-marketing studies designed to c o l l e c t the maximum amount of drug d i s p o s i t i o n information on i n d i v i d u a l subjects. We tested an a l t e r n a t i v e to t h i s t r a d i t i o n a l approach of k i n e t i c data evaluation. A database consisting of demographic, p s y c h i a t r i c , and drug d i s p o s i t i o n data was collected for 100 inpatients (mean age 46 +/- 15 years) who were receiving alprazolam for a v a r i e t y of c I i n i c a ] i n d i c a t i o n s . Each p a t i e n t had a blood sample c o l l e c t e d at a random time during 2 d i f f e r e n t dosage i n t e r v a l s . Plasma was assayed for alprazolam concentration by a newly developed HPLC method. The NONMENcomputer program wa~ used to c a l c u l a t e pharmacokinetic parameters for comparison with data collected in pre-marketing clinical trials. The mean (SEM) alprazolam clearance (CL), volume of d i s t r i b u t i o n and absorption rate constant'was 0.07 (0.006) I / h r / k g , 0.7 (0.1) I / k g , and 1.2 (0.4) hr-1, r e s p e c t i v e l y . CL was 30% slower in males (p 0.01); however, neither an e f f e c t due to age nor smoking s t a t u s was detected. These pharmacokinetic parameters, estimated from a diverse population of patients, are s i m i l a r to those determined from rigorous p r e c l i n i c a l studies. These results suggest t h a t aIprazolam's primary pharmacokinetic parameters have a r e l a t i v e l y small v a r i a b i i i t y across a heterogeneous p a t i e n t population. They also confirm the u t i l i t y of using a population k i n e t i c database for seeking variables in i n d i v i d u a l patients which may a f f e c t drug d~sposition and, therefore, c l i n i c a l response. University of Florida, Box 0-486, GainesviIle, F l o r i d a , 32610 U.S.A.

WG S a n n i t a Single

L Maggi

G Rosadini

50- and 100 mg doses

E Sottofattori of

phenobarbital

or m a t c h i n g p l a c e b o were given orally to 8 healthy subjects. M u l t i - l e a d EEG samples were recorded prior t:, and at regular intervals w i t h i n the 2 hrs f o l l o w i n g administration; the s i g n a l was p ~ o t e s s e d by p o w e r s p e c t r a l analysis, and b i d i m e n s i o n a l color maps were produced. The drug plasma c o n c e n t r a t i o n was assessed concomitantly; plasma peaks were 3.38+/-I .29 and 4.09+/-1 .24 ug/ml at the 50and 1 0 0 - m g d o s e s r e s p e c t i v e l y . D e s p i t e the low drug plasma c o n c e n t r a t i o n , a systematic and s i g n i f i c a n t power increment o c c u r r e d in the EEG fast f r e o J e n c y ( 1 2 . 5 - 3 2 . 0 Hz ) band after a d m i n i s t r a t i o n of the 100-mg dose; it was evident from the 30 min postdrug control, and was t o p o g r a p h i c a l l y restricted to the anterior scalp areas. The drug plasma concentration was s i g n i f i c a n t l y c o r r e l a t e d ( Kendal's c o e f f i c i e n t ) with the increment in fast f r e q u e n c y po~er only on the ( anterior ) e l e c t r o d e derivat';ons where it was s y s t e m a t i c across subjects and a t t r i b u t a b l e to d r u g a c t i o n , w h i l e no c o r r e l a t i o n was o b s e r v e d w i t h the EEG v a r i a t i o n s on p o s t e r i o r scalp areas. Center for N e u r o p s y c h o a c t i v e Drugs, I n s t i t u t e of N e u r o p h y s i o p a t h o l o g y , and I n s t i t u t e of Pharmaceutical Sciences, University; Center for Cerebral N e u r o p h y s i o l o g y , C.N.R.,I-16132 Genova, Italy

32.05.16

32.05.17

M E A S U R E M E N T OF P L A S M A ANTI-DOPAMINE, ANTI-NORADRENERGIC AND ANTI-SEROTONIN ACTIVITIES OF SHIZOPHRENICS RECEIVING NEUROLEPTICS M E D I C A T I O N T.YamamototT.HaradatT.Takeda,M.Sato* and S.Otuki Most of neuroleptics have not only antidopaminea(Da) activities, but also antinoradrenergic(NA) and anti-serotonin(5HT) activities. We measured plasma activities {anti-Da, anti-NA and anti-5HT activities) of schizophrenics receivig neuroleptic m e d i c a t i o n using radio rece~ter assay(RRA).We used in the RRA the folloing j H - l i g a n d , d i s p l a c e r and brain region: D2 recepter: InM 3H-(-)-sulpiride, 100nM haloperidol and rat striatum. NA r e c e p t e r : 0.anM 3 H - p r a z o s i n e , 200nM prazosin a~d rat frontal cortex. 5HT recepter: InM ~H-ketanserine, 500nM" p i p a m p e r o n e and rat f r o n t a l cortex. Schizophrenics were divided into the following two groups: group 1:maintenance treatment group c o n t a i n i g 42 r e m i t t e d o u t p a t i e n t s . group 2:aute treatment group containing 18 hospitalized patients at the f i r s t o n s e t or w i t h a c u t e exacerbation. Their clinical s y m p t o m s were rated by physicians using BPRS. Most of all were treated with monopharmacy, respectively in group I n=34(81%), group 2 all(100%).Furthermore, we investivated relationship among the mentioned three plasma activities, plasma drug concentration, clinical effect and patients' profiles. Department of Neuropsychiatry, Okayama University Medical School, 2-5-I Shikata-cho, Okayama 700, Japan *Department of Psychiary,Tohoku University, School of Medicine,l-1 Seiryo-cho, Sendal 980, Japan

CONJUGATED AND UNCONJUGATED LEVELS OF CLOMIPRAMINE AND ITS HYDROXYLATED AND DEMETHYLATEDMETABOLITES IN PLASMA AND URINE OF DEPRESSED PATIENTS, M.Pays,O.Varoquaux,O.Morin,J.Plas,S.Brion,C.Advenier Clomipramine (CMI) and i t s 8-hydroxy (8-OHCMl),2-hydroxy (2-OHCMl),den~thyl (DMC),8-hydroxydemethyl (8-OHDMC) and didemethyl (DDMC) metabolites were determined by HPLC with coulometric detection. Both unconjugated and codJ~ugat4d compounds ( a f t e r S-glucuronidase h y d r o l y s i s ) were determined in the same sample of plasma or urine: I ml,buffered at pH 9.8 is extracted with 20% e t h y l a c e t a t e in n-heptane. After back e x t r a c t i o n i n t o an acid phosphate buffer(pHa.4) 20 ~I were injected i n t o a 5 vm C-18 IP-RP column and eluted with a mobile phase containing a phosphate buffer with tetramethylammonium c h l o r i d e and a c e t o n i t r i l e 59-41 v / v . This method was used to determine the steady-state conjugated and unconjugated plasma l e v e l s of CMI and i t s metab o l i t e s reached in patients given CMI d a i l y , e i t h e r 75 to 150 mg o r a l l y or 50-75 mg by i n f u s i o n . Following oral administraCion, DCMI is the predominant form as shown by the high steady-state concentrations. In c o n t r a s t , f o l l o w i n g repeated IV a d m i n i s t r a t i o n , plasma DCMI concentrations are only s l i g h t l y higher than those of CMI. 8-OHCMI and 8-OHDCMI plasma levels are s i m i l a r to those of CMI. At any par t i c u l a r d o s e , i n t e r - i n d i v i d u a l v a r i a t i o n s of up to f i v e fold were observed even in t h i s small sample. 2-OHCMI was not detectable in plasma. The conjugated 8-OHDMCI and 8-OH CMI were r e s p e c t i v e l y 2.5 and 3.4 f o l d higher than the respective unconjugated compounds. Steady-state 24 h u r i nary levels of CMI and metabolites of 6 iV treated pat i e n t s showed a high proportion of conjugated compounds being 300 ( f o r 2-OHCMI), 20.8 (8-OHCMI), 7.9 (8-OHDMC) and 1.8 (CMI) fold higher than the respective unconjugated compound in the same urinary sample.Conjugated and unconjugated CMI metabolites amounts are very high. These unconjugated metabolites may be taken i n t o account in metabolic and pharmacological studies. Departement de Biochimie et Pharmacologie, Centre Hospital i e r de V e r s a i l l e s , H6pital A Mignot F-78 157 Le Chesnay.

321

32.05.18

32.05.19

T H E M O R E S T A B L E D R U G L E V E L T H E BEq~FER CLLNICAL OUTCO~ D L ~ I N G TREAqS~[ENT ~ T } I DEPOT h~UROLEPTICS ? B. L i p s k a ~ L. W e l b e l

HALOPERIDOL K I N E T I C S IN C H R O N I C S C H I Z O P H R E N I C PATIENTS WITH ACTIVE PSYCHOTIC SYMPTOMS. T.Itaya a K.0guri, K . S h i o z a k i _ _L K . K o b a z a s h i , M . N a k a s h i m a K.Ohara W e s t u d i e d pharmac'okinetics of h a l o p e r i d o l in chronic schizophrenic patients with active psychotic symptoms despite usual neuroleptic treatment after oral administration. These patients under continuous oral treatment with h a l o p e r i d o l ( d a i l y d o s e 9-24 mg) p a r t i c i p a t e d in the s t u d y on a i n f o r m e d consent. S e r u m level of ha loperidol were determined by radioimmunoassay. Previous studies have shown that the mean lag time after oral a d m i n i s t r a t i o n of p s y c h o t i c p a t i e n t s w a s 1.3 • 1.1(SD)hr and the t e r m i n a l h a l f life(tl/2) w a s 1 8.1 +_ 4.5 hr (Y.F.Cheng et al., Psychopharmacology, 91,410-414,1987). T m a x w a s r e p o r t e d to be 3-I 0 h r ( G . Y a g i et al., S e i s h i n igaku,2~,1149-1157,1980 in J a p a n e s e ) . In o u r study, however, the mean lag time after oral administration w a s 0.36 + 0.38 h r a n d t i / 2 w a s 5.0 _+ 2.6 hr. T h e p e a k s of t h e s e r u m l e v e l w e r e t w o p o i n t s w h i c h w e r e 0.9 + 0 . 6 h r a n d 2.8 _t 1.6 hr. T h e l a g t i m e , T m a x a n d t i / 2 w e r e s h o r t e r than responding schizophrenic patients. Serum l e v e l of h a l o p e r i d o l / d a i l y d o s e / b o d y w e i g h t in ~ r e a t m e n t r e s i s t a n t p a t i e n t s w a s 27 + 7 % as compared to responding patients. It m a y b e s u g g e s t e d that b i o a v a i l a b i l i t y of h a l o p e r i d o l in t r e a t m e n t r e s i s t a n t p a t i e n t s w a s l o w e r t h a n that in responding patients. We have to consider the methods of a d m i n i s t r a t i o n in chronic schizophrenic patients with active s y m p t o m s d e s p i t e the c o n t i n u o u s oral t r e a t m e n t with haloperidol. Department of Psychiatry and Neurology, H a m a m a t s u U n i v e r s i t y S c h o o l of M e d i c i n e , 3600 H a n d a H a m a m a t s u , 431 -31, Japan.

T h e a i m of o u r s t u d y w a s to c h e c k if sertun levels provide information in practical management of s c h i z o p h r e n i a . 121 c h r o n i c s c h i z o p h r e n i c s w e r e o b s e r v e d . ~"ne d o s e s in single injection given every 23 days for 6-~2 m o n t h s were: f l u p e n t h i x o l d e c a n o a t e 2 0 - 6 0 mg, c l e p e n t h i x o l d e c a n o a t e 2 0 0 mg, p i p o t h i a z i n e p a l m i t a t e 2 5 - 1 5 0 mg, p e r p h e n a z i n e e n a n t h a t e 100 mg, f l u p h e n a z i n e e n a n t h a t e 1 2 , 5 - 5 0 mg. M e n t a l s t a t e w a s a s s e s s e d b y B P R S ~ extrapyz-am i d a l s y m p t o m s b y Simps@n-A-ngus scale. R e s p o n d e r s h a d r e d u c t i o n of B P R S s c o r e ~ 5 0 % at the e n d of t r e a t m e n t . T h e R R A w a s u s e d to measu~'e s e r u m n e u r o l e p t i c a c t i v i t y o n the d a y 7 a f t e r the i n j e c t i o n / m a x / a n d p r i o r to the n e x t o n e /mill/. Max./min r a t i o s 8/id c o e f f i c i e n t s of v a r i a t i o n /c.v.~/ w e r e a n a l y z e d . L i n e a r c o r r e l a tion ~as found between c.v.~ values and clinical r e s p o n s e / ~ S / f o r p i p o t h i a z i n e / r = - O . 90, p 0. O01/, c l o p e n t h i x o l / r = -O. 61, p
32.05.20

32.05.21

PLASMA HALOPERIDOL AND LORAZEPAM LEVELS IN ACUTELY SCHIZOPHRENIC PATIENTS AND THEIR RELATION TO THERAPEUTIC SUCCESS AND INTENSITY OF SIDE EFFECTS

LEOIC-Lz2~S' CLASSIFICATION OF CHRONIC SCHIZOPHRENIA AND PSYCHCTROPIC DRUG TREATMENT RESULTS G.A.A.M. Wetzer, A.J.M. Loonen, C.H. Doorschot A cohort of 157 schizophrenic patients (DSM-III), selected from a chronic psychiatric in-patient population (N=602), were classified according to the principles of K. Leonhard and their reactions to former psycho~ropic drug treatment were assessed. In order to distinguish three main categories, each with two subtypes, of Leonhards' classification, a set of criteria was developed and a group of 8 psychiatrists and 3 psychologists were trained in its usage. Former drug therapy benifit was classified as having been considerable, moderate, slight or absent on the achieved level of social functioning. Vulnerability to negative drug effects was classified into three categories upon the level of interference of adverse reactions with daily functioning. Results: - 59 (~8~) patients were classified hebephrenic, 32 (23-~) catatonic and 66 (42%) paraphrenic. Within each category about 1/5 of the patients were considere~ to belong to the non-systematic sub-classes. - 132 (84,1%) patients, equally distributed over each (sub-)class, were currently under drug treatment. - Non-~'stematic subclassified patients had generally sh~wr, more drug-induced improvement than systematic type. Within the latter sub-groups, somewhat less (40~ vs 52% and 58%) paraphrenic type schizophrenics had shown at least moderate improvement. - Systematic-type patients were considerably less vulnerable to (extrapyramidal?) side-effects with very few differences between hebephrenic, catatonic and V~aphrenic type schizophrenics. Psych. Hosp. Voorburg, P.O. Box 10150, NL-5260 GB Vught The Ketherlands

G.Pfab-~-dlk!ein, A.Nshal, R.Wiegsnd and H.J. Gaertner The psychopathologic status of newly admitted acutely schizophrenic patients on haloperidol (20-40 mg/day) and lorazepam (0-5.5 mg/day) was recorded weekly using BPRS rating and GAS; intensity of the extrapyramidel-motoric side effects was assessed with the Webster and Simson scales. At this time, plasma haloperidol and lorazepam levels were determined by gas chromatography (Forsman et al. 1974, Greenblatt etal. 1978). At assessmen~ the intensity rating of the scales was considered and the patients correspondingly elassifled according to whether haloperJdol treatment could be continued or whether, because of side effects or inefficacy, they should be changed over to another drug. The quest}on is whether adjunct administration of lorazepam influences the intensity of the side effects of haloperidol and whether the course of the psychopathologic disturbance can be related to plasma levels. Forsman, A., E. Martensson, G. Nlberg, R. 0hman: Naunyn Schmiedebergs Arch Pbarmacol (1974) 286, 113-124 Greenblatt, D.J.,K. Franke, R.J Shader: J Chromatogr. (1978) 146:311-320 Department of Psychiatry (Director: Prof Dr H Hetmann)~ University of T~bingen, Osianderstr. 22, 74 TQblngen

322

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32.05.23

DIFFERENT THERAPEUTIC WINDOWS OF HALOPERIDOL IN SCHIZOPHRENIC PATIENTS AS A FUNCTION OF THE TIMESPAN OF THE ILLNESS. J. L. Santos. J. A Ramos. C. V~zauez. I. Almoeuera. F. Fuentenebro. and J / k Cabranes Levels of hatoperidol were determined by radio-immunoassay (RIA) in 30 schizophrenic patients (DSM-Ill), who were treated with fixed-dose of this neuroleptic for a period of 21 days. An inverted "U-shaped" relationship was found between the percentage of improvement observed in the BPRS global score and the steady-state of halopertdol. An interval of effective concentrations of haloperidol was set between 12.0 and 35.5. ng/rnl. However, the limits of that type of interval found in the subchronic schizophrenic subgroup (SS) ranged from 7.4 to 24.9 ng/ml whereas in the chronic schizophrenic subgroup (CS) ranged from 14.8 to 38.5 ng/ml. These findings suggest that the interval of effective concentrations may vary as a function of the number of years of evolution of the subjects illness. This may be compatible with [ ~ development of tolerance in the mesolimbic and/or mesocortical dopaminergic systems as a response to prolonged neuroleptic treatments.

SERUM NEUROLEPTIC

Hospital Universitario San Carlos. 28040-Madrid.

32.05.24 A.hITR_rPTYLINE MONITORING AND CLINICAL OUTCOME IN D E P R E S S I C ~ G.L. Corona, M.L. Cucchi, P. Frattini, G. Santagostino, S. Schinelli, F. Zerbi~aod _E,~Savoldi ~he interactive relationship anong the antidepressant main tenance dose, steady-state plam~a l ~ e l s and clinical outcome is highly variable and impredictable (P. Baumann, Int. ~_in.Psychopharm. 1,89,1986)'; hence it has been suggested tZ-mt the antidepressant plasma levels monitoring may impro_ ve t_ha safety and efficacy of the therapy. We searched for a relation between amitriptyline (AMT) and nortriptyline (}~) plasma concentrations and clinical response in 59 female depressed inpatients [D~M III: (I) major depression: .%~ 296.20 n=14 and B: 296.30 n=31; (~J dysthymic disorders 300.40 n=14] treated with ~4T (100 mg/day i.m.) for 4 we4~s _No correlations between steady-state AMT or N T plasma levels and clinical response, evaluated by percent Improven~_nt (PI) criterion, ~ s found in the patient sample as a -~nole. Significant correlations between clinical outcome acn~ plasma levels of ~ (r= -0.66 P < O . O ! ) and of n ~ {~=_ -<2.58 P50, n=41) versus the nonrespontiers (~=18). Significant higher levels of NT (t= 2.88 P < O.O1, df. 34) and of AMT+NT plasma concentrations (t=-2~I P_--56yrs.) respect to lounger (21-45 yrs. ) subjects. Corrected side effects in older patients were also significantly reduced (t=2.37 P < O . O 5 ) . O ~ data do not give a satisfactory answer about the rela*_tonship between plasma level/clinical response hut they confirm that monitoring can be useful in managing depressed pauients by allowing a maintenance of drug plamua level at a safer range. ir~t.Phazmacology Univ.Pavia V.Taramelli 14-27100 PAVIA (I)

LEVILS MIASUKED

BY RADIOD.,, m-Ach ) AND CLASSIFICA-

PdSCZPTOR ASSAY ( D9

TION OF SCHIZOPHRE~IA ~ S. Nakajima, S. Kamba, T. inomata, H. Koshikawa, G. 7agi and R. Kato In recent years, many s~udies concerning about serum neuroleptic levels measured by radioreceptot assay have been report@d. But in these reports, examination of clinical significance is mainly about D~ levels and regardless of classification of scEizophrenia. And the meaning of D~ / m-Ach ratio in relation to the effects of n~uroleptics has been discussed in many reports, but it remains little-investigated subjects. In this study, we divided the patients into subgroups of schizophrenia in several ways, measured not only D~ levels but also D I and m-Ach levels and examined the clinical s~gnificance of DI, D~, .m-Ach levels an~ D o / m-Aeh ratio etc. SubjeCts are 52 schizoph~enTcs receiving longterm neuroleptic treatment. As one way of classification, patients were divided into two groups, patients who cannot respond favorably to any kind of neuroleptics and in any dosis ( group i ), and patients whose psychiatric conditions could be suitably adjusted ( g r o u p l I ). D o ~evels were in very wide range ( 2 - 340 n~ / ml HPD-~ ). Althou~h D~ levels of group i were generally high, there w~s the tendency that D> levels of group !Z wer~ concentrated in the r~latively narrow range of 2 - 20 n g / ml HPI!. Together with the 9 results . of D.and m-Ach, J . Classification of schlzophrenza ( includlng subtyping of longitudinal process ) and neuroleptic maintenance therapy will be discussed. Tokyo Musashino Hospital. 4-11-11Komone, ftabashi-ku, Tokyo, 173 JAPAK.

32.05.25 HABITS OF CONSUMPTION OF TRANQUILLIZERS ~ HEALTHY

SWISS

MEN

OVER

13

HYP-NOTICS IN

YEARS

R. Battegay, H.R. Wacker, C. Schl6sser In 1972/73 4082 randomly selected 20 years old Swiss military recruits were interviewed with a standardized questionnaire about their consumption of tobacco, alcohol, tranquillizers, hypnotics and illegal dregs. In addition standardized questions about sociod-~mographic characteristics, physical well-being, physical complaints and health behavior were asked. In 1979 and in 1985 1658 respectively 1554 men out of the original sample were asked similar and identic questions in postal interviews. 843 men took part in all three surveys.The results concern this sample9 In 1985 41 (4,9%) reported to take tranquillizers seldomly or repeatedly. In 1972 there were 69 (8,2%) consumers of tranquillizers (p
323

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32.05.27

LONG TERM P H E N O B A R B I T A L T R E A T M E N T INDUCES E N D O C R I N E CHANGES R E V E R S I B L E U P O N DRUG D I S C O N T I N U A T I O N IN E P I L E P T I C PATIENTS. R.Manni,G.Murialdo~ Palma~ U.Filippi ~ and A . T a r t a r a A l t e r a t i o n s of a d e n o p i t u i t a r y function and sex steroid peripheral p a t t e r n have b e e n r e p o r t e d in epileptic patients. However, the c o n n e c t i o n s b e t w e e n h o r m o n e s , e p i l e p s y and a n t i e p i l e p t i c drugs (AED) are far from complete elucidation. We have p r e v i o u s l y d e m o n s t r a t e d that ii e p i l e p t i c male patients in remission, u n d e r g o i n g long term p h e n o b a r b i t a l (PB) treatment, showed b a s e l i n e and G o n a d o t r o p i n R e l e a s i n g Hormone s t i m u l a t e d levels of serum L u t e i n i z i n g Hormone (LH) s i g n i f i c a n t l y lower than normal male controls. Since these p a t i e n t s were seizure free and w i t h normal EEG recordings, their endocrine c h a n g e s have b e e n ascribed to PB treatment. In order to c o n f i r m this hypothesis, 7 subjects of this group have been retested 1 y e a r after complete PB withdrawal; p a r t i c u l a r l y , L H p u l s a t i l e secretion throughout a six hour p e r i o d (15 min sampling intervals) has been studied. In fact h i g h e r m e a n LH l e v e l s , e n h a n c e d s e c r e t o r y areas under the curve and increased f r e q u e n c y and amplitude of the LH peaks have been o b s e r v e d after drug d i s c o n t i n u a t i o n in u n r e l a p s e d p a t i e n t s These findings c o n f i r m a role of PB in i n d u c i n g the endocrine changes observed in our e p i l e p t i c patients. o Institute of Internal Medicine, U n i v e r s i t y of G e n o v a and Epilepsy Center, N e u r o l o g i c a l I n s t i t u te, U n i v e r s i t y of Pavia, 27100 Pavia, Italy

PSYCIIOTROPIC D R U G S U T I L I Z A T I O N I N CZ~CIIOSLOVAKIA J,.~lis! O . V i n a 9 r L . ~ t i k a ~ K o E l i s o v & In the f o u r t h p h a s e of the e l i n l o a l e v a l u a t i o n of a n e w l y i n t r o d u c e d drug, the b e n e f i t of the n e w d r u g is e v a l u a t e d in the r o u t i n e m e d i c a l p r a c t i c e . One s i m p l e m e a s u r e of this b e n e f i t is the a m o u n t of the d r u g p r e s c r i b e d in c o m p a r i s o n to the o t h e r d r u g s w i t h s i m i l a r p h a r macological properties which already have been on the m a r k e t . In C z e c h o s l o v a k i a such s t u d i e s hove one of the longest traditiom and psyohotropie drugs have b e e n a m o n g the f i r s t one i n v o l v e d . S y s t e m i c s t u d y of t h e i r u t i l i z a t i o n b e g a n a l r e a d y in 1965 incl. s t u d i e s on the p r e s c r i b i n g b e h a v i o r and on the p o s s i b i l i t i e s to i n f l u e n c e it. T h e m e t h o d of d e f i n e d d a i l y d o s e s (DDD) e n a b l e d c o m p a r i s o n of the p s y o h o t r o p i e d r u g u t i l i z a tion in C z e c h o s l o v a k i a a n d S e a n d i n e v i a n countries o L o n g i t u d i n a l t r e n d s of p s y c h o t r o p i c d r u g s u t i l i z a t i o n in C z e c h o s l o v a k i a a n d r e s u l t s of s u c h c o m p a r i s o n w i l l be p r e s e n t e d . S t a t e I n s t i t u t e of D r u g C o n t r o l ~ ~ r o b & r o v e 48, 110 00- P r a g u e 10, C z e c h o s l o v a k i a

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32.05.29

LACK OF Ah~ICHOLINERGIC ACTION OF MIDALCIPRAN COMPARED TO AM!TRIP~fLINE IN NORMAL SUBJECTS. C, Serre*, M. Elohick*, D. Orahame-Smith§ C. Moret~and M. Briley*. One of the most common undesirable effects of tricyclic antidepressants is their an~icholiner~ic action. Midalcipran, a new non-tricyclic ~ntidepressant has been shown and in vitro in animals to be devoid of any antioholinergic activity (Moret et al., Neuropharmaool. 24, 1211, 1985 ; Stenger et el., Psychopharzacol. 91, 147, 1987). This study compares, in healthy volunteers, the anticholinergic effects of midalcipran with those of amitriptyline and placebo. Eight healthy male volunteers were administered a single clinically equivalent oral dose (half the average daily-dose) of midalcipran (50mg), amitriptyline (75mg) and placebo in a double-blind three sequence cross-over paradigm. Salivation 2 h after drug administration was measured by absorption onto preweighed dental cotton wool rolls. Blood samples were taken at 2 h for analysis of drug plasma level and the inhibition of muscarinic receptor binding (3H-QNB) to rat cerebral membranes. The volunteers were asked to mark a visual analogue scale of "dryness of mouth" and to report any adverse effects during the study and in the following 24 h. In midalcipran-treated subjects saliva secretion was increased by 4%, while under treatment with amftriptyline it was significantly decreased (- 30%, p<0.05) as compared to placebo. Neither inhibition of 3H-QNB binding by plasma samples nor visual analogue scale were significantly different between treated and control groups. Thus that amitriptyline showed a significant anticholinergic effect as measured by the inhibition of salivation whereas midalcipran showed no anticholinergie effect and even had a non-significant tendency to increase salivation. *Centre de Recherche Pierre Fabre, 81100 Castres, France. +Radcliffe Infirmary, Oxford. England.

EFFEC!5 OF HEMICHDLINIiJM-% SEPTO-HIPPOCAHPAL NEURONS IN TH[ qmT.

324

ON

IDENTIFIED

M.H. BASSANT~ ~. JOBERf and Y. LAMOUR The medisl septal area contains neurons ~nich project to the hippocampal formation. A sizeable proportion of these septo-hippocampal neurons (SHNs) are ~ho]~oergic. About 40% o f them also d~splay a characteristic discharge p a t t e r n in rhythmic b u r s t s . We hypothesized that 5HNs with s rhythmically bursting activity (RBA) are the cholinergic ones. To test this hypothesis, we studied the effects of acetylcholine synthesis blockade by hemicholinium-5 (HC-3) on the properties of the SHNs. HC-3 (16, 32 or 6& pg) or saline were injected in the lateral ventricles if adult male Sprague Dawley rats anesthetised with urethane (n = 24 animals). Extracellular recordinos from SHNs in the medial septal area were-obtained within hours after HC-5 injections. Theta activity in the hippocampal formation was abolished even after the smallest dose tested (16 ~g). Choline chloride (lO0 mg/kg i.v.) did not reverse the effect of HC-3. No significant change in SHNs conduction velocity or spontaneous activity was observed at any dose of HC-]. The percentage of SHNs with RBA was unchanged either. In contrast the mean frequency of the RBA #as decreased by HC-5 in a dose-dependent fashion. The mean frequency was lowest within the first 3 hours after injection. These results suggest that acetylcholine synthesis blockade by HC-3 leads not only to the disappearance of the 4Hz theta hippocampal activity in urethane-anesthetized animals, but also to a decrease in the frequency of the rhythmically bursting activity of the SHNs. Since the 4Hz hippocampal theta is atropine sensitive, the results provide indirect evidence that the septo-hippocamDal neurons with rhythmically bursting activity are the cholinergic SHNs. INSERM U 161. 2, Rue d'Al@sia 75014 PARIS France.

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32.05.31

DISCRIMINATIVE STIMULUS PROPERTIES OF THE MUSCARINIC AGONIST RS-86 IN THE RAT J. De VrT, D.G. Spencer Jr. and J. Traber Male Wistar rats were trained to discriminate a combination of RS-86 (2-ethyl-8-methyl-2,8-diazaspiro(4,5)-deean-l,3-dion hydrobromide; 0.45 mg/kg) and N-methylscopolamine (NMS; 1.25 mg/kg, i.p., t - 15 min) from saline in a standard two-lever food-reinforced procedure. The dose-response curve obtained with RS-86 was not affected by co-administration of NMS, although NMS, when given alone, induced partial generalization (36%). Among the musearinic agonists tested, pilocarpine completely generalized, whereas oxotremorine and areeoline partially generalized (67 and 50%, respectively). The nicotinic agonist compounds nicotine, anabasine and cytisine induced saline-appropriate responding. Tetrahydroaminoacridine (THA) and physostigmine induced intermediate (50%) and saline-appropriate responding, respectively. Co-administration of lecithin failed to increase the extent of generalization to THA. The discriminative effects of RS-86 were virtually antagonized by scopolamine (0.32 mg/kg), but were unaffected by mecamylamine. It is concluded that the discriminative effects of RS-86 are mediated by a muscarinic cholinergic mechanism, although further work is needed to elucidate its central and/or peripheral nature. The data additionally suggest that the discriminative properties of muscarinic agonists are heterogeneous in nature. Neurobiology DepartmentdTroponwerke , Neurather Ring i, 5000 Cologne 80, FRG

M A G N E T I C ~7~IO M O D U L A T I O N OF NqCOTLNqC ACETYLCHOLLA~E RECEPTOR Ft]NC]qON C. Chiles, E. Hawrot, J. Gore, and R. Beck Although itis ~dely held thatthe magnetic fields encountered during

Magnetic Resonance Imaging (MRI) and other procedures have no discernible effect on biologic systems, we found that the rate of binding of the neurotoxin alpha-bungarotoxin to nicotinic acetylcboline receptor was significantly reduced in a constant 2.0 Tesla magnetic field. Alpha-bungarotoxin (BTX) obtained from elapid snake venom is a high affinity, competitive antagonist of the well-characterized nicotinic acetylcholine receptor (AchR), derived from Torpedo californica electric organ (M.P. McCarthy, et al., A. Rev. Neurosci., 9: 383; 1986). The kinetics of AchR-BTX interaction are distinguished by a relatively slow association rate (J. Schmidt and M.A. Raftery, J. Neurochem., 23: 617; 1974). AchR contains transmembranous, alpha-helical segments which are a c o m m o n c o n f o r m a t i o n o f membrane proteins and are known to produce an electrostatic dipole (W.G.J. Hol, Prog. Biophys. Molec. Biol., 45: 149; 1985). It is conceivable that AchR contains one or more magnetic dipoles within the receptor which m a y make the conformation of the r e c e p t o r vulnerable to a strong magnetic field and that this effect is revealed in an alteration of functional activity such as ligand binding. Formation o f the receptor-ligand complex was initiated by the addition of 125I-BTX (final concentration 0.4nM) to affmity purified AchR (0.37 gg/rnl) at 25~ Half the samples were held in control conditions and half were placed in a 2.0 Tesla, 31 c m horizontal bore, superconducting magnet (Oxford Instruments Ltd). The amount of 125I-BTX bound to AchR was measured by a DEAE filter-disc assay (J. Schmidt and M.A. Raftery, Analyt. Biochern., 52: 349; 1973). After 45 min of exposure to the magnetic field, the initial rate of association was reproducibly reduced relative to unexposed control and the effect persisted at 90 min of exposure. The mean + g E M of radiolabelled toxin (tzbI-BTX) specifically bound to nicotinic AchR in the exposed samples relative to controls was 0.85 + 0.02 at 45 min and 0.82 + 0.03 at 90 min (n=I3). The rate o f association for samples exposed to the magnet differed significantly from the rate of association of those samples kept under control conditions (p < 0.0005). Yale University School of Medicine, Sterling Hall of Medicine, 333 Cedar Street, New Haven, CT 06510, USA

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32.05.33

COMPAP~SON OF THE BEHAVIORAL AND BIOCHEMICALS EFFECTS OF THE N)~DA RECEPTOR ANTAGONISTS, ~ - 8 0 1 AND PRENCYCLIDINE M. Hiramatsu and A. K. Cho ~-801, (+)-5-methyl-10,11-dlhydro-5-H-dibcnzo[a,d] c y e l o h c p t e n - 5 , 1 0 - i m i n e maleate, was d e s c r i b e d p r e v i o u s l y as a potent antlconvnlsa~t drug. More recent studies have shown that it binds with high affinity to sites proposed for other non-competitive N ~ A antagonists such as p h e n c y c l i d i n c (PCP) and related d r u g s . PCP p r o d u c e s a complex behavioral syndrome in the rat that is mediated

SIMULTANEOUS DETERMINATION OF URINARY METHAMPHETAMINE AND PHENYLETHYLAMINE IN PATIENTS SUFFERED FROM METHAMPHETAMINE PSYCHOSIS

via various neuronal systems but little information is a v a i l a b l e on mechanisms of ~K-801 b e h a v i o r a l a c t i v i t y . T h i s s t u d y compares t h e b e h a v i o r a l p r o f i l e of ~ - 8 0 1 and i t s e f f e c t s on monoamine m e t a b o l i s m w i t h t h o s e f o r PCP. When administered to rats, ~ - 8 0 1 and PCP produced hyperactivity, ataxia and stereotyped behav ior that included sniffing, head-weaving, turning and backpedalling. Forward l o c o m o t i o n , s n i f f i n g and h e a d weaving induced by }~-801 i n c r e a s e d in a d o s e - d e p e n d e n t manmer when 0.125 and 0.25 mg/kg w a s a d m i n i s t e r e d b u t at 0.5 mg/kg, a s e v e r e a t a x i a prevented the these behavioral responses. more

severe

The ataxia induced by MK-801 at 0.5 mg/kg was than that induced by 7.5 mglkg of PCP.

ME-g01 produced t u r n i n g and b a c k p e d a l l i n g b e h a v i o r s s i m i l a r to PeP, b u t t h e s e e f f e c t s were weak compared to PeP and n o t d o s e - d e p e n d e n t . ~ - 8 0 1 (0.5 mg/kg) i n c r e a s e d c o r t i c a l DOPAC and HVA l e v e l s 60 min a f t e r i n j e c t i o n , b u t dopamlne, s e r o t o n i n and fi-HIAA l e v e l s were u n a f f e c t e d . Striatal dopaminc l e v e l s were d e c r e a s e d u n d e r t h e s e c o n d i t i o n s , b u t l e v e l s of t h e o t h e r monoamines and t h e i r m e t a b o l i t e s were unchanged. Thus, a l t h o u g h PCP i n c r e a s e s the

neuronal

activity

of

both

dopaminergic

and

n e u r o n s , MK-801 o n l y i n c r e a s e d dopamine This d i f f e r e n c e in b i o c h e m l c a l d a t a may account f o r t h e d i s s i m i l a r b e h a v i o r a l p r o f i l e between MK-801 and PCP. U n i v e r s i t y of C a l i f o r n i a , Los A n g e l e s , Medical C e n t e r , serotonergic turnover.

Department of Pharmacology. 10833 Angeles, California 90024-1735

Le Conte Avenue.

Los

S.Yamada~ Y.Mine~ M.Ishibashi~ T.Yokoyama~ T.Koga~ H.Kojima~ K.Miki} T.Inokuchi~ S.Nishiland K.Inanaga 2 A sensitive gas chromatographic chemical ionization mass spectromatric assay has been developed to measure the urinary contents of methamphetaine(MAP) and phenylethylamine(PEA) of patients suffered from MAP psychosis. These amines were isolated by Extrelut (R) column. Our method was capable of measuring 200 pg/ml of urinary PEA and MAP, simultaneously. Urinary concentration of PEA in normal volunteers was 35.4 • 12.5 ~g/g creatinine (mean • S.D., n=12) and that in patients was 11.4 • 10.4 ~g/g creatinine (mean • S.D., n=11) which was significantly lower than that of normal volunteers (t=3.88, P
325

32.05.34 NEUROPHARMACOLOGY OF C A D M I U M V. .. N. .. P. u. r. i. . .and . . . . .G .. .S .h .a .n .k .e .r C a d m i u m is an e n v i r o n m e n t a l toxicant.Psychophar m a c o l o g i c a l e f f e c t s of this m e t a l h a s not b e e n evaluated,therefore an a t t e m p t w a s m a d e to s t u d y the e f f e c t s of c a d m i u m a c e t a t e on m a l e C. D . R . I . b r e d a l b i n o m i c e on v a r i o u s p s y c h o p h a r m a c o l o g i c a l s c r e e n s . M a l e m i c e ( 2 5 - 3 0 gm) w e r e p r o v i d e d p e l l e t d i e t and w a t e r ad l i b i t u m 0nd h o u s e d in t e m p r a t u r e c o n t r o l l e d r o o m 2 3 + 2 C. Cadnium was injected intraperitcmeally(~.p) in d o s e s of 0 . 1 . 0 . 3 , 1 . 0 m g / K g and b e h a v i e r a l d a t a was r e c o r d e d as d e s c r i b e d by C a n p b e l l and R i c h ter(!967).Cadmium (0.I m g / K g i.p) did not p r o d uce s i g n i f i c a n t c h a n g e s , c o m p a r e d to s a l i n e tre ated controls.However m i d d l e ( 0 . 3 m g / K g i . p ) and higher(l.0 mg/Kgi.p) doses produced'central ner v o u s s y s l e m d e p r e s s i o n as c o m p a r e d to c o n t r o l s . C a d m i u m p r o d u c e d d e c r e a s e d in l o c o m o t o r a c t i v i ty and d e c r e a s e d r e a c t i v i t y to t o u c h and sound. C a c m i u m did not p r o d u c e i a t a x i a , p u o s i s or c a t a l e p s y in m i c e . I m p o r t a n t f i n d i n g o b s e r v e d w a s th at c a d m i u m p r o d u c e d d o s e and t i m e d e p e n d e n t hy o o t h e r m i c r e s p o n s e in m i c e . E D . ~ of 1 . 0 + 0 . 3 8 , 0.70~0.20,0.75t0.29,0.68~0.23 ~/Kg i.p-follow i n g ~ l , 2 , 3 , 5 h o u r s r e s p e c t i v e l y w e r e o b t a i n e d on inzraperitoneal cadmium administration in c o n s c ious m i c e . T h e s e r e s u l t s i n d i c a t e t h a t c a d m i u m may be h a v i n g s o m e a t y p i c a l n e u r o l e p t i c p r o f i l e B a s e d on the i n f o r m a t i o n p r o v i d e d , r o l e of cad n i u m in p s y c h i a t r i c i l l n e s s e s and t h e r a p y s h o u !d be e v a l u a t e d . D i v i s i o n of P h a r m a c o l o g y . C e n t r a l D r u g R e s e a c h institute.Lucknow 266001.1ndia.

32.05.35 1231-SPIPERONE AS A LIGAND FOR DOPAMINE RECEPTORS: IN VITRO AND IN VIVO EXPERIMENTS J.A. Van der Kro~t r O.J.S. Buruma~ P.A.P.M. Van Doremalen~ E.K.J. Pauwels~ C.F.M. Van Valkenbur~ and G. Wijnhoven Nowadays there is great interest in the development of positron or single photon emitting radioligands for imaging neuroreceptors in the living human brain. In the present study we evaluated the dopamine receptor binding properties of the potential SPECT ligand 123I-spiperone (SPI). 123I-labelled SPI was prepared by radioiodination at the N-phenylring and purified by BPLC. Specific activity was in the order of i000 Ci/Imnole. Binding properties of 123I-SPI were compared with those of 3H-SPI in parallel in vitro and in vivo experiments. In vitro binding to rat striatal membrane preparations was studied in two types of experiments: saturation experiments (applying 0.i - 5 nM labelled SPI) and competitio~ experiments w i t h (+)- and (-)-butaclamol (I0-i0 - 10-4M). No specific binding of 123I-SPI was observed in these experiments. For in vivo binding studies 0.1-0.2 nmole labelled SPI was administered to rats via'a jugular vein cannula. After 2 h the animals were killed and radioactive contents of dissected brain regions were measured. Binding to cerebellum was used to reflec~t non-specific binding. For 123I-SPI a striatal/ cereb~llar ratio of 1.8 was found. By pretreatment of the rats with i mg/kg haloperidol i.v. this ratio was reduced to i.I. For 3H-SPI the ratio was 3.5. In conclusion, although we did not found evidence of specific binding of 123I-SPI to rat striatal membranes in vitro, in rive clearly specific accumulation in rat striatum was seen. Probably, homogenization of brain tissue unmasks a large amount of non-specific 123I-SPI binding sites. The extent of in vivo striatal accumulation, however, is too small for SPECT studies. Department of Pharmacology of the University of Leiden, Wassenaarseweg 72, 2333 AL, Leiden, The Netherlands.

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32.05.37

PROLONGED ELECTROSHOCK CH.&NG=~. q Tk~ COUPLING BETW'EEN ~- AND 2- ADILENOCEPTORS IN RATS A,y~ic. I. Naleoa. J.Vetulani. Stimulation of ~-adrenoceptors is regarded as a main cause of increase in cyclic AMP formation in brain slices exposed to noradrenaline. However, in the rat, a specific ~-adrenoceptor agonist, iseprmterenol is less efficacious than neradrenaline, a mixed o-and s agenist. This action of isoproterenol is potentiated by coadministration of an ~-adreneceotor agonist- 6-fluoronoradrenaline (6-FNE), suggesting t~--~=ta coupling between ~and 2- adrenoceptors favors the formation of the second messen- ger. Treatment of rats with electroconvulsive shock once daily for 7 days wms without influence on the isoproterenol-iaduced cyclic ~ accumulation, however the accumulation of the second messenger induced by either noradrenaline alone, or in combination with 6-FNE was markedly (by about 50%) reduced. That result resembles our earlier data on different antidepressant drugs treatment (Pilc and Enna, Life Sci, 1985,37, 1183) therefore We suggests that the possible target of antidepressant treatment might be. the coupling of ~- and 2-adreno~eptors rather than the ~-adrenoceptors alone. Since the function of ~,-adrenoceptors, as measured by the nor~dreDm!ine - induced inositol t r i s phosphate accumulation was not changed by prolonged electroshock it may b~ inverted that antidepressant treatment changes the coupling between 2- and ~ subtype Institute of Pharmacology. Polish Academy of Sciences, 12 Smyrna Street, 31-843 Krakow, Poland.

APOMORPHINE INDUCES INTENSE GROOMING BEHAVIOUR IN MICE TREATED WITH DISCRIMINANT BENZAMIDE DERIVATIVES. M. VASSE and P. PROTAIS Grooming behavlour evaluated by a scoring method in mice was dosedependently increased by the selective D-1 agonist SK&F 38393 (1.87-30 mg(kg, s.c.) whereas it was dose-dependently decreased by the selective D-2 agomsts RU 24926 (2.5-10 mg/kg, i.p.) or LY 171555 (0.4-1.6 mg/kg, i.p.) alone or associated with SK&F 38393 (s.c.) as well as by apomorphine (0.39-6 mg/kg, s.c.). The inhibitory effect of 0.75 mg/kg apomorphlne (s.c.) on grooming behaviour was not modified by SCH 9.23390, chlorpromazine, clozapine and thiorldazine. In contrast, it was antagonized by 8 other tested dopamine antagonists. Nevertheless, whereas with flupentixol, haloperidol, metoclopramide, thioproperazine and tlapride, a restoration of a grooming score lower or roughly similar to that determined in control mice was only observed, a score higher than that determined in control mice was observed in mice treated with ( _ ) sulphide, amisulpride or RIV 2093. Furthermore, of the six dopaming antagonists tested against SK&F 38393 (1.87 reg.&g, s.c.), only chlorpromazlne and clozapine antagonized SK&F 38393-induced grooming behaviour, whereas the effects of thioridazine, metoclopramide, haloperldol and amisulpride in SK&F 38393-treated mice paralleled their effects in control mice. Fin~llly, RU 24926 (5 mg/kg, Lp.) did not induce grooming behaviour in mice treated with haloperidol, metoclopramide, ( _ ) sulphide or amisulprlde, whereas SCH 23390 (20 ug/kg, s.c.) antagonized apomorphine-induced grooming in mice treated with amisulpride, ( _ ) sulphide or tiapride. These data ~i) conforte the potential role of D-1 dopamine receptors in the expression of grooming behaviour, (ii) indicate from the intense grooming behaviour induced by apomorphine in mice treated with the discriminant benzamide derivatives [(• sulpiride, amisulpride and RIV 2093] that the dopamine receptors involved in the i-hlbition of grooming could be of the D-4 subtype , (iii) reveal the D-1 antagonist properties of chlorpromazine and clozapine, and (iv) suggest that the modulation of apomorphine-induced grooming behaviour by dopamine antagonists in mice could be a test for their classification according to their activity at the different dopamine receptor subtypes. Laboratoire de Physiologie (U.A. CNRS 2170), U.E.R. de M#decine-Pharmacie de ROUEN, B.p. 97, 76800 Saint Etienne du Rouvray, France.

326

32.05.38

32.05.39

SIMULTANEOUS EVALUATION OF 5 BEHAVlOURS IN MICE AS A TEST FOR A RAPID FIRST CLASSIFICATION OF DOPAMINE ANTAGONISTS. P. PROTAIS, M. VASSE and A. C H A G R A O U I

QUANTITATIVE AUTORADIOGRAPHY AS A TOOL TO STUDY DISTRIBUTION AND REGULATION OF CENTRAL NEUROTRANSMITTER RECEPTORS; FURTHER EVIDENCE FOR DOPAMINERGIC RECEPTOR HETER0-REGULATION. F. Trovero, D. Herv4, G. Blanc, J. Glowinski and J.F. Tassin.

We have tested in mice introduced in cylindrical cages with vertical metal bars (climbing cages) the effects of increasing doses of 12 dopamine (DA) antagonists on the behavinurs spontaneously displayed by naive mice (climbing, sniffing, gnawing and grooming) and on the behaviours induced by 0.75 mgfkg apomorphine (APO)(climbing, sniffing, licking, gnawing and grooming). The IDs0 determined on spontaneous behaviours allow to classify DA antagonists in at least two groups: those which decrease the scores of all spontaneous behavioars at similar doses (SCH 23390, ehlorpromazine, clozaplne, thioridazlne) and those which decrease grooming behaviour at higher doses than other behaviours (others). The ID50 determined on APO-induced behaviours allow to classify DA antagonists in at least 3 groups: those which antagonize climbing and sniffing with similar IDs0 and which do not promote grooming behaviour (SCH 23390, ehlorpromazine, elozapine, thlondazlne), those which antagonize climbing and sniffing with similar IDso and which promote relatively low scores of grooming (flupentixoi, haloperidol, thioproperazine, metoclopramide and fiapride) and those which antagonize sniffing with an [Ds0 higher than that determined on climbing, which potentiate licking and gnawing behaviouss and which promote high scores of grooming (sulpiride, amisulpride and RIV 2093). These data suggest that the simultaneous evaluation of five behaviours in control mice and in APO-treated mice could be used as a test for a rapid first classification of dopamine antagonists according to their activity at the different DA receptor subtypes: (i) DA antagonists acting preferentially at D-1 receptors which decrease all spontaneous bchaviours with similar IDS0 and which do not promote grooming behaviour in APO-treated mice (SCH 23390, chlorpromazine, dozapine), (i.i) DA antagonists acting preferentially at D-2 receptors which decrease spontaneous grooming bchaviours at higher doses than other behaviours, which antagonize with similar IDs0 APO-induced climbing and sniff'rag behavlours and which promote low scores of grooming in APO-treated mice (flupentixol, haloperidol, thioproperazine, metoclopramide and tiapride) and 0il) DA antagonists discriminating D-2 and D-4 receptors which decrease spontaneous grooming bchaviour at higher doses than other behaviours, which antagonize APO-indueed climbing with an IDs0 lower than that determined on APOinduced snlffmg, which potontiate APO-induced licking and gnawing behaviours and which promote intense grooming behaviour in APO-..a~ated mice (sulpiride, amisulpride and RIV 2093). Laboratoire de Physiologic (U.A. CNRS 1170), U.E.R. de M4decine-Pharrnacie de ROUEN, B.P. 97, 76800 Saint Etienne du Rouvray, France.

INSERM U. 114, C o l l ~ g e de France, Marcelin Berthelot, 75231 Paris France

Ii Place cedex 05,

The distribution of the dopaminergic (DA) receptors positively c o u p l e d to the a d e n y l a t e c y c l a s e (DI r e c e p t o r s ) , c l o s e l y r e s e m b l e s that of the DA innervation in the prefrontal cortex. Different mechanisms of r e g u l a t i o n of these r e c e p t o r s can be shown in the rat central n e r v o u s s y s t e m f o l l o w i n g e i t h e r d e s t r u c t i o n of a f f e r e n t fibers or b l o c k a d e of heterologous receptors: I) A c o r t i c a l s e r o t o n e r g i c (5-HT) d e n e r v a t i o n obtained.by an i n j e c t i o n of 5,7 DHT into the m e d i a n and d o r s a l r a p h e nuclei, induces, five weeks later, a small but s i g n i f i c a n t d e c r e a s e of the D A - s e n s i t i v e a d e n y l a t e c y c l a s e a c t i v i t y m e a s u r e d in h o m o g e n a t e s of m i c r o d i s c s p u n c h e d out frem the m e d i a l p r e f r o n t a l c o r t e x (-25%). 2) T h e , b l o c k a d e of s e v e r a l a m i n e r g i c r e c e p t o r s by an i r r e v e r s i b l e ligand, EEDQ (i), may a l l o w to study some of the m e c h a n i s m s responsible for ~ the regulation of the D1 receptors. Indeed, the d o s e - d e p e n d e n t d e c r e a s e of 3 H - S C H 23390 binding observed by quantitative autoradiographic analysis in the s t r i a t u m and the p r e f r o n t a l c o r t e x was d i f f e r e n t from the dose-dependent decrease of DA-sensitive adenylate cyclase activity in the same structures. We propose that these differences are r e l a t e d to the s i m u l t a n e o u s d e s t r u c t i o n of o t h e r non DA receptors, a phenomenon which might interfere with the coupling of DI r e c e p t o r s to the a d e n y l a t e cyelase. (i) Hess 1987, 31,

et col., 50-57.

Molecular

Pharmacology,

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POSSITIVE INTERACTION BETWEEN ALPHA-ADRENERGIC AND D2 DOPAMINE (DA) RECEPTORS IN LOCOMOTOR ACTIVITY OF NORMO AND SUPERSENSITIVE MICE M. Rubinstein, A. Schinder, O. Gershanik and F. Stefano Stimulation of both nl and D2 DA receptors is necessary 9 o induce locomotor responses in normosensitive animals whereas under supersenslt~ve conditions the separate administration of either D1 or D2 agonists is enough to produce an adequate locomotor behavior. However, in these conditions,pretreatment with alpha-methyl-ptyrosine(AMPT) inhibits D2 hut not D1 agonist-induced responses. In order to study The apparently crucial role of the D1 receptor in supersensitive mice (reserpine I mg/kg/day,s.c., for 5 days), we analyzed the effect of the DI antagonist SCH 23390 (0.05 mg/kg,s.e.) on responses elicited by the combined use of a D1 agonist SKF38393 plus a D2 agonist LY 171555 (4 mg/kg,s.c., each) or by the mixed DI/D2 agonist pergolide (2 mg/kg,s.c.). A bimodal pattern of responses was found: a subpopulation of mice did not show reversion of reserplne-induced akinesia while the other showed normal locomotor scores. In both cases AMPT (200 + I00 mg/kg, i.p., 3 and 1 h before) abolished DA agonist-induced locomotor responses suggesting a possible noradrenergic parti~ ipation.;Clonidine (CLO, 2 mg/kg,i.p.) also showed a himodal pa;tern of responses in the reversal of aklnesia in chronic reserpinized mice but it did not induce locomotion in acut~ reserpinized mice (5 mg/kg,s.c., 2 h before). In . these~last conditions, CL0 + SKF (2 mg/kg,l.p. + 8 mg/kg, s.c.) did no~-reverse akinesia but CL0 + LY (2 mg/kg,i.p. + 8 mg/kg,s.c.) did. The responses induced by CLO + LY were not prevented either by SCH23390 or by AMPT but were abolished by the separate use of prazosin (0.5 mg/kg,i.p.) or yohimbine (2.5 mg/kg,i.p.). These results suggest that clonldine could mimic, interacting simultaneously with alpha-1 and alpha-2 adrenergic receptors, the effects of D1 stimulation necessary t o generate DA-mediated locomotor responses. Instituto de Investigaciones Farmacol6gicas (CONICET). Jun~n 956 - 5~ 1113 Buenos Aires. Argentina.

E F F E C T S OF S E L E C T I V E D-I A N D D-2 D O P A M I N E ANTAGONISTS ON METHAMPHETAMINE-INDUCED BEHAVIORAL SENSITIZATION ~UiiketT.Onoue,K.Akiyama and S.Otsuki In this study we a i m e d at c l a r i f y i n g effects of s e l e c t i v e D-I and D-2 d o p a m i n e a n t a g o n i s t s on the d e v e l o p m e n t of b e h a v i o r a l s e n s i t i z a t i o n p r o d u c e d by r e p e a t e d m e t h a m p h e t a m i n e (MAP) administration. M a l e S.D. r a t s w e r e d i v i d e d into four groups. Each group received daily injection of s a l i n e (control group), MAP 4 m g / k g (MAP group), YM 09151-2 0.5mg/kg + M A P 4 m g / k g ( Y M + M A P group) or SCH 23390 0.5mg/kg + MAP 4 m g / k g (SCH+MAP group) for 14 days. A f t e r abstinence period of 7 d a y s , all groups received a challenge d o s e of M A P ( 2 m g / k g ) . Repeated MAP administration produced a progressive augmentation in l o c o m o t o r and stereotyped behavior, whereas concomitant administration of Y M 0 9 1 5 1 - 2 a n d S C H 2 3 3 9 0 completely abolished progressive behavioral a u g m e n t a t i o n by r e p e a t e d M A P a d m i n i s t r a t i o n . Challenge of MAP (2mg/kg) resulted in reproduced hyperlocomotion and intense stereotyped behavior only in M A P group. However both YM+MAP group and SCH+MAP group s h 6 w e d only h y p e r l o c o m o t i o n and no s t e r e o t y p y which were similar to t h o s e observed in control group. These results indicate selective D-I a n t a g o n i s t as w e l l as s e l e c t i v e D-2 a n t a g o n i s t not o n l y r e v e r s e d M A P - i n d u c e d motor effects but also prevented the development of behavioral sensitization i n d u c e d by r e p e a t e d MAP administration. Department of N e u r o p s y c h i a t r y , Okayama University Medical School, Shikata-cho, O k a y a m a 700, J a p a n

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CHRONIC EFFECT OF A SELECTIVE D-2 ANTAGONIST, YM-09151, ON DOP~41NE AGONIST-INDUCED STEREOTYPY IN RATS S. Usuda,M. Terai,T. Yamaquchi,F. Wanibuchi and K. Hidaka Chronic administration of neuroleptic drugs a l t e r i n g D-2 receptor s e n s i t i v i t y produces tolerance to t h e i r acute effects in animals. Recently, a combination of D-I and D-~ agonists was reported to enhance stereotypy in rats. A novel benzamide, YM-09151 (YM) exhibits a potent and sel e c t i v e D-2 antagonistic a c t i v i t y , as compared with haloperidol (HPD) (Terai et a l . , Japan. J. Pharmacol., 33, 749, 1983). In the present studies, f i r s t l y , the homologus tolerance of YM and HPD to the i n h i b i t i o n of apomorphine-induced stereotypy (gnawing and l i c k i n g behaviors) in rats was tested a f t e r chronic oral administration of YM or HPD for 21 days. Chronic treatment with HPO at both doses of 1 and 3 mg/kg decreased i t s anti-stereotypic effect. On the other hand, reduction of the i n h i b i t o r y effect of YM was observed a f t e r chronic administration of YM at a dose of 3 mg/kg, but not at l mg/kg, suggesting that YM wa~ less in producing the tolerance than HPD. Secondly, the cross tolerance from YM to HPD (D-2 antagonist) and SCH23390 (D-] antagonist) and behavioral supers e n s i t i v i t y to dopamine agonists were investigated a f t e r chronic subcutaneous i n j e c t i o n of YM, 0.1 mg/kg, for 14 days in r a t s . The chronic i n j e c t i o n of YM reduced i t s anti-stereotypic effect and produced the cross tolerance from [M t o both HPD and SCH23390. The threshold dose of apomorphine for inducing stereotypy such as gnawing and licking behaviors in pretreated rats was lower than that in non-pretreated animals. A D-I agonist, SKF38393, which did not induce stereotypy in non-pretreated rats, induced stereotyped b i t i n g and grooming behaviors in pretreated rats. These results emphasises the i n t e r a c t i o n between D-I and D-2 systems in mediating stereotypy. This further suggests that the tolerance by chronic i n j e c t i o n of a D-2 antagonist may be associated, in part, with a functional change in D-I receptor. Central Research Laboratories, Yamanouchi Pharmaceutical Co. Ltd., Azusawa I - I - 8 , Itabashi-ku, Tokyo 174, Japan

CENTRAL PHARMACOLOGICAL EFFECTS OF 5-HT, B RECEPTOR AGONISTS. ~CHO/NACKA-u A.K~ODZINSKA. J . ~ m-Triflusromethylphenylpiperazine (TFMPP) add m-chlorep~enylpiperazine
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THE INHIBITION OF NEUROTRANSMITTER RECEPTOR BINDING TO HUMAN BRAIN PREPARATION BY PSYCHOTROPIC DRUGS M. Toru, H, Shimizu, N. Hata and H. Ogata The inhibition of dopamine D2, adrenaline aI,~2, muscarinic cholinergic and serotonin 5HT2 receptor binding to human brain by various psychotropic drugs was studied. Human putamen was used for I>2 and cerebral cortex was used for other receptor binding assay. 3H-spiperone was used for labeling D2 and 5h~2 receptors, 3H-WB4101 for al, 3H-idazoxan for a2, 3H-quinuclidinyl benzilate for musucarinic cholinergic receptor binding. Antipsychotic drugs assessed were: chlorpromazine, levomepromazine, clozapine, thioridazine, propericiazine, perphenazinc, zotepine, haloperido!, timiperone, bromperidol, carpipramine, clocapramine, oxypertine, sulpirid~, YM-09151, etc. Antidepressants were: imipramine, clomipramine, desipramine, trimipranine, lofepramine, amitriptyline, nortriptyline. amoxapine, maprotiline, mianserin, dosulepine, etc. Antiparkinsonian drugs were: promethazine, trihexyphenidyl, biperiden, piroheptine, profenamine, etc. There were some antidepressants which inhibited D2receptor binding as strong as antlpsychotic drugs, al-receptor inhibition of phenothiazines was generally stronger than butyrophenones. Of all antidepressants, mianserin most strongly inhibited both a2 and 5HT2 receptors.

5-HT BINDING SITES IN POST-MORTEM HUMAN BRAIN S.C. Cheetham, Y. Yamaquchi and R.W.Hcrton Receptors for serotonin (5-HT) have been classified into 5HTI, 5HT2 and 5HT3. 5HTI sites have been shown to be heterogeneous and have been further sub-divided into 1A, B, C, and D. We have used 3H-5HT (3 nM, non-specific binding defined with 5xl0-4M unlabelled 5HT) to label 5HT binding sites in post-mortem human brain and have studied the displacement with sub-type selective drugs. In frontal cortex, 5HTIA selective drugs (8-OH DPAT buspirone, ipsapirone, spiperone and 5C~ displaced from a similar proportion of sites (35-53%) with high affinity (KD 7-200 nM) and the remaining sites with low affinity (4-69 ~M). TFMPP (5HTIB selective) was only a weak displacer (32% inhibition at 10-5 M) . Ketanserin (5HT2 selective) displaced from 70% of the sites with low affinity (KD 1.6 ~M). GR 38032F and M D L 72222 (SHT3 selective) only displaced from 31% and 15% of sites respectively at 10-4M. 8-OH DPAT displaced with high affinity from a similar proportion of sites in the amygdala (43%) as in the frontal cortex (42%) but a higher proportion (63%) in the hippocampus. RU 24969 (equivalent affinity for IA and IB sites) displaced from a higher proportion of sites than 8-OH DPAT in the hippocampus (90% v 63%), amygdala (70% v 43%) and frontal cortex (61% v 42%). The results demonstrate the selective labelling of 5HTl-like sites by 3H-5HT in the human brain with little or no labelling of 5HT2 or 5HT3 sites, and indicate a higher proportion of 5HTIA sites in the hippocampus compared to the frontal cortex and amygdala. Department of Pharmacology, St. George's Hospital Medical School, London SWI7 ORE.

Department of Psychiatry, Shinshu University School of Medicine, 3-i-1 Asahi, Matsumoto, Japan 390

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CHARACTERIZATION AND LOCALIZATION OF D O P A M I N E AND S E R O T O N I N U P T A K E S I T E S IN H U M A N B R A I N J.M. Maloteaux, J.N. Octave, M.A. V a n i s b e r g , E.C. L a t e r r e and P.M. L a d u r o n * ~ H - G B R 12935 binds w i t h a h i g h a f f i n i t y (Kd: 3.2 nM) to d o p a m i n e u p t a k e sites in human striatum (Kd: I.I nM in rat). ~H-GBR 12935 s p e c i f i c b i n d i n ~ was i n h i b i t e d by s e v e r a l d o p a m i n e u p t a k e b l o c k e r s in the s t r i a t u m and t h e r e was o n l y a very low b i n d i n ~ in n o n - d o p a m i n e r E i c areas. The subcellular profile of the specific binding revealed a principal synaptosomal localization which is q u i t e d i f f e r e n t from that of d o p a m i n e D~ receptors. The ~ H - G B R 12935 s p e c i f i c b i n d i n E is a ~ood m a r k e r of d o p a m i n e r ~ i c n e r v e e n d i n g s in h u m a n s t r i a t u m and has been used for the study of the dopamine uptake sites in extrapyramidal disorders. ~H-parox~tine specifically recognizes the s e r o t o n i n u p t a k e sites w h i c h are c o n c e n t r a t e d in subcortical structures of human brain whereas both serotonin S, and S~ receptors were concent!ated in the cerebral cortex. The Kd v a l u e of ~ H - p a r o x e t i n e was of 0.15 nM in h u m a n putamen (Kd: 0.22 in rat). The subcellular distribution profile of ~ H - p a r o x e t i n e s p e c i f i c bind%ng revealed the a s s o c i a t i o n of s e r o t o n i n uptake sites with the m i t o c h o n d r i a l f r a c t i o n s and the s y n a p t o s o m e s . B o t h ~ H - p a r o x e t i n e and ~ H - G B R 12935 w e r e found a s s o c i a t e d , to a lower extent, to microsomal structures s~gesting the presence of amine binding sites which are s p e c i f i c but not f u n c t i o n a l in the m i c r o s o m e s . Laboratoire de Neurochimie, Universit~ de Louvain, B-1200 Brussels, Bel~ium and *RheneP o u l e n c Sant@, C e n t r e de R e c h e r c h e de Vitry, F - 9 4 4 0 7 Vitry sur Seine, France.

TEE DIEYDROPYRIDINE C~LCIUK CHANNEL ANYAGORIST NI~ODIPINE ~S &N &~TIDEPEESSANT DRUG A. Czvrak. E. Mo~inlcka. I. Mal ~imDdipine (NI~), a calcium antaEonist is a vasodilator with a preferential action on central vessels. Apart from cerebral vascular effects, NIM has also been show1~ to possess some central pharmacoloEical effects. Recently, we de~nstrated that ~IM reduces the mouse immobility in the behavloural despair test (MoEilnlcka et el,, 1987). At present we found that various antidepressants (imlpra~Ine, amltriptyline, mianserin, cltalopram), used at doses which are not effective themselves, facilitate the immobilityreducln S effect of ~I~ in the despair test when they are administered jointly with this drug. Purther behavioural experiments demonstrated the effect of NIX (2.5, 5, i0, 20 m~/kg p.o.) in other tests for antidepressant activity. NIM antagonized the hypothermla induced by a hish dose of apomorphlne (16 mg/kg) in mice. It potentiated ~he action of L-DOPA in mice (Everett's test) aud reduced the clonidine-induced sedation in rats. The reserpine- and clonidineninduced hypothermias in mice wer~ not chan~ed by NI~. In blochemical experiments the effect of NIM on the uptake of 5-hydroxytryptamine (5-HT) and noradreualine (NA) ia vivu (protection aEainst the H~-~/~ [4,alpha-dlmethylmeta-tyramine]-Induced displacement of 5-HT and NA) was inves~isated. NI~ sisnificantly reduced (by about 30%) the H~,~m-induced displacement of 5-HT, but not of ~A, in the rat brain cortex. These results indicate that in some tests NIM in its profile resembles antidepressant dru~s; moreover they support the idea that concominant administration of antidepressants and dlhydropyridlne calcium channel antagonists may result in a steerer therapeutic efficacy. 9Mo~ilnicka E., Czyrak A. and MaJ I. Eur. 1. Pharm~col. 1987, 138, 413-416. Institute of Pharmscolosy, Polish Academy of Sciences, 12 Sm~tna St., 31-343 Krakow, Poland

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]3e ~ D ~ S 8 1 1 / E

32.05.49 P ~ I ~

(A d o u b l e - b l i n d p l a c e b o controlled study in general practice) L. C R O C 0 t, P. BUGARD*, Ph. BOUHOURS** Ritanserin is a selective, potent and centrally acting serotonin-S 2 antagonist. Ritanserin was studied in d y s t h ~ i c disorders (DSM XII) in a d o u b l e - b l i n d p l a c e b o controlled ~ultJcentric general practice trlal. The dosages of ritansezin were 5 mg b.~.d, and 10 mg b.i.d. The treatment duration was 4 Weeks. The evaluation was made by using the #~s~e~mia ~ l e of C ~ and BUCkleD. This scale is divided in 15 clinical items: Presentation and cantact, language and oral expression, general condition, appetite disturbances, sleep disturbances, sexual ~isorders, muscular fatigue, intellectual fatigue, sensitivity to the external world, cephalic and sensorial s~,mptoms, somatic distress, psychic anxiety, depression, disturbance of character, hypochondria. This scale is evaluated by a Global Severity score and a symptom-sum of the 15 clinical items. 134 patients entered the study and 121 patients were finally analyzed, 13 patients were excluded fzo~ the efficacy analysis for insufficient data. 39 received I0 m~ ritanserin, 42 received 20 mg ritanserin aod 40 received a placebo. Results : l ~ g ritanserin at Week 2 was more effective than plBcebo on the global severity evaluation (MWU-test); at Week 4 the global severlty is also significantly improved ( M ~ - t e s t ) a~d the item intellectual fatigue improved at a significant level (p<0,01). The global severity evaluation of 20 mq ritanserin was better than p l a c e b o at Week 2 but not at Week 4 ( ~ U - ~ e s t ) . At Week 2 and Week 4 analysis the results showed no statistically significant difference between 10 mg and 20 mg ritanserin. If the intezgzoup comparison was m~de separately for male and female patients, global clinical improvement on :itanserin was found better in male patients. PatieRt's Visual A~alog Scales (present state, sleep, fatigue): there was a~significant difference between I0 ~ ritanserin and placebo for the present state ltem, There was no difference between i0 mg and 2 0 mg ritanserin. At Week 4 (final evaluation), 8 1 % of patients were considered cured or improved with I0 mg ritanserin; 80 % with 20 mg ritanserin and 54 % with placebo. Side effects were minimal and tolerance was generally excellent in the three groups. Based on these results a new trial using lo~er doses of ritanserin will be implemented in dysthymic disorders. * G~oupe d'E~udes de la Fatique (G.E.F,), 2 square du Cro[slc, 75015 PARIS =* Leboratoires JANSSEN, 5 r@e de Luback, 75116 PARIS

RELATIONSHIP OF HUMAN PLATELET AND BRAIN MAO: STUDIES BY ISOELECTRIC FOCUSING (IEF) P. K o r o n a k i s , J. F r i t z e , P. R i e d e r e r MAO has been c h a r a c t e r i z e d a c c o r d i n g t o substrate and i n h i b i t o r specificities. A l t h o u g h MAO-B has been i d e n t i f i e d in human brain by such biochemical and also i m m u n o l o g i c a l means, only few is known of w h e t h e r the enzyme is i d e n t i c a l in brain and platelet. IEF has proved to be a very sensitive method to detect p r o t e i n heterogeneities. Therefore, MAO was labeled by 3 H - p a r g y l i n e (0,i VM) in both tissues, s o l u b i l i z e d by Triton x-t00 (0,5 %; v/v) and s u b m i t t e d to IEP. In platelets, l a b e l e d m a t e r i a l f o c u s e d at pH 6.4 w i t h o u t i n t e r i n d i v i d u e l d i f f e r e n c e s . In the 9 brain regions studied, the m a t e r i a l focused between pH 5.7 and pH 6.4 w i t h o u t r e v e a l i n g distinct bands within this range. 3 H - p a r g y l i n e a f f i n i t y . l a b e l i n g in the p r e s e n c e of various r e v e r s i b l e and i r r e v e r s i b l e i n h i b i t o r s shewed the m a t e r i a l to r e p r e s e n t MAO-B. MAO-A from human placenta was not labeled under the conditions used. Thus, the h e t e r o g e n e i t y of brain MAO-B in IEF is p r o b a b l y due to lipids still attached to MAO. M o d i f i c a t i o n s of the s o l u b i l i ration p r o c e d u r e should f u r t h e r clarify this topi~. Klinische N e u r o c h e m i e , U n i v e r s i t ~ t s - N e r v e n klinik WOrzburg, F O c h s l e i n s t r . 15, 8700 WOrzburg, FRG

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POSTER PRESENTATION 33.01

Schizophrenia - Basic and Clinical Aspects

THEP~fIC P R I N C I P I ~ AI~ PRACTICE IN 8055 P A T I ~ OF A I~/N-ICIPAL PSYCHIATRIC DEPARE~='~T Gy..~k~in~ and I. Gy. Magyar yor 7 years, the data of every acut and chronic relapsed cases we_re processed and analyzed by C-128 c c ~ u t e r program /ICD-9, AFDP system, specialized drug subroutine codes 1-9/. In this evaluation, 4 patients' group were assessed /DgM-III, ICD-9; 295, 296, 300, 301/ to make graphs for yearly cmmparison /1981-87/ with their "first adjustment" of drug regime. In schizophrenics -acut and cbm-onic relapsed- the first choice of pharmacotherapy was tr• /6 years/. Its use was revalry with butl~rophenons which turned to be favoured only last year in reduced doses or instead of that more frequently given milder antipsychotics /thioridazid, perfenazin, chlorprotixenl. In affective psychoses, the "hospitalization index" revealed an increased rate. Because of severe psychotic episodes, the neuroleptics, tricyclics, Li and "antiepileptic antima_nic" drugs /CARB/ were added more frequently. qhe admission of neurotics, -rsDst of thegn with grave anxiety and depression, increas<~d in the last 3 years. The gravity of the slm~ was "c/r=Tracterized" by raising first choice of tricyclics, neuroleptics with milder tranquillation, added to anxiolytics in spite of intensified psychotherapy. At last, personality disorders observed for 7 years seemed ~ to show "breakless increase". The difficulties in socialization, family and/or work place adaptation, stress situation were challenging the hospital to intervene in crisis by drugs /anxiolytics, milder antipsychotics and ~-ithdra%,-=l therapy/, qhe hospit~%lization and therapy of the heteroger~us subgroups with affective and sociopathic sy~t~irs indicated significantly negative predictor variables /drug abuse, suicide behavior etc./.

Hospital "Istvan" /Mer@nyi/ Dept. ">f Psychiatry H-1097. Budapest, Gy~li u. 17. Hungary.

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33.01.03

ABSTRACT Schizofrenia: The Brief Psychiatric Rating Scale (BPRS), Reliability and Validity studies.

IS FAMILY HISTORY PREDICTIVE FOR TREATMENT RESPONSE OF AFFECTIVE AND SCHIZOPHRENIC PATIENTS J. Hallmayer, W. Maier Valid predictors of treatment response on affective disorders and schizophrenia are rare. A large number of psychopathological or clinical features has been tested but only a small number of them were found to be predictive (e.g. delusions in depression for an unfavorable response to antidepressants). However familial loading with psychiatric disorders of patients has only been proved in a few studies for its predictive power for treatment response; this is especially the ease for treatment with tricyclic antidepressants and neuroleptics. To evaluate utility of family history for treatment response to tricyclic antidepressants and neurolepties we carried out a family study in inpatients with depressive and/or psychotic disorders. 40 patients with a current major depressive disorder (RDC) and 40 patients with schizophrenic/schizoaffective disorders (RDC) will receive standardized tricyclic treatment for depression and standardized neuroleptic treatment for productive symptomatology during a period of 4 weeks after admission to the hospital. First degree relatives are interviewed personall~ using the SADS-L. Preliminary results from this ongoing study do not support the hypothesis that patients with sporadic occurrence of the disorder are bad responders to treatment. Psychietrische Klinik der Johannes Gutenberg-Universit~t Mainz, Untere Zahlbacher Str. 8, D - 6500 Mainz 1

Andersen John, Korner Alex, Jens Knud Larsen, Vilhelm Schultz, Bjarne Meyer Nielsen, Ebbe Munk-Andersen, Kirsten Behnke, Niels Bjerum. 103 patients (32 women, 71 men), 19 to 59 years of age (median 35 years), fullfilling the DSM-III criteria for schizofrenia were rated with the BPRS once weekly between 8.15 to 9.00 a.m. from august 1984 till july 1987. In the used version of the BPRS each item is graduated from 0 to 4 with an explicit definition of each grade. The group of raters consisted of 7. Each rater has seen no less than 50 and no more than 79 (median 73) of the 103 patients. 31 of the patients were, furthermore, on the same morning as the BPRS took place, rated globally by a consultant using the Clinical Global Impressions (CGI). The consultant did not attend the weekly co-ratings. The inter observer reliability (Rs) for the BPRS is 0.82 (0.74 to 0.88), for the B~RS 10 item schizofreniasubscale;it is 0.85 (0.80 to 0.89). The concurrent validity, the Global-rating versus the BPRS: R=0.64. The Global-rating versus The BPRS schizofrenia-subscale: R=0.66. The B PRS item 6 (tension) and 16 (blunted affect) are responsible for disagreement between 5 and 4,respectively, of the 7 raters. On 9 items there was agreement among all the raters. By comparing earlier interim results with the final result it is demonstrated that co-rating increases the inter-rater-reliability-coefficient for the scale as a whole as well as the agreement on the more specific schizofrenic symptoms comprising the BPRS subscale.

330

33.01.04

33.01.05

SUBGROUPS OF SCHIZOPHRENIA, CLINICAL . ~ PHARMACOLOGICAL ASPECTS M. Jarema

CLIniCAL SYMPTOi~TOLOGY,NEUROLEPTIC RESPONSE A}~ SERUM DOPAk~NE-BETA-HYDROXYLASE ACTIVITY IN FAMILIAL A ~ SPORADI~ SCHIZOPHRENIA Gy. Bartk6,Gy. Z~dor,~&Arat6,Sz.Horvdth The characteristic psychopathologic features, the neuroleptic response at the last episode, serum dopamine-beta-hydroxylase /DEH/activity were studied in 32 schizophrenic patients possessing a first degree relative with history of schizophrenia and 49 patients without a family histozoj. The family history positive patients characterized by a more severe positive symptoms at admission.There was no significant difference in the severity of negative symptomatology between the two patient groups.Schizophrenics with positive family history showed a nonsignificant tremd for greater improvement over the 28 day neuroleptic treatment.There was significant reduced serum DEg activity im the patients with positive family history in comparison to patients with negative family history.The results support the validity of familim!/sporadlc distinction in schizophrenia.

Different therapeutic response to neuroleptics in schizophrenia may be caused by heterogeneity of schizophrenic population. The use of more detailed classification of schizoplnrenic psychoses may reveal more homogenous subgroups of patients. A cohort of patients who met the D~{-III-R criteria for schizophrenia has been s~adied. Negative/positive symptoms scale and DCR Nashville (Ban et. al, 1987) has been used. DCR (Diagnostic Criteria for Research) is based on European classification of functional psychoses (Leonhard's classification, French and Scandinavian schools of psychopathology). Therapeutic response to neuroleptics as well as many individual and social factors (i.e. familial risk for schizophrenia, duration of illness, length of present episode, season of birth, number of previous hospitalizations, occupafional activity, and others) has been compared among schizophrenic subgroups. The differences bet,r various schizophrenic subP9PUlations has been discussed. Department of Psychiatry, Medical Academy, Bronlewskiego 26, 71-460 Szczecin, Poland.

National Institute for Nervous and ~ental Diseases, t 2 9 1 Budapest Pf.1.,Hungary

33.01.06

33.01.07

THE -JTILITY OF -~ZOPERIDOL PLAS:L~. ZE~.-s AFTER A TEST DOSE TO 7F-DiCT THE CLINICAZ RvSPONSE OF ACUTE SC~ZO_=---~_=!~C PATIENTS TO I---=&2>~NT. N. R. LouzR Zero*. F. Xiiller-Spai~-n. E. RGther~ J. Scherer Plasma level monitoring plays an =-portant role in psychiatric care. Besides its use during lit thium and antidepressant therapies, there are numerous investigations about the relationship between neuroleptic plasma levels and clinical response to vreatment with controversial results (Baldessarini e t a l . Arch Gen Psychiatry 45:79-

SIGNIFICANCE OF PLASMA AND CSF HVA IN PSYCHIATRIC PATIENTS BEFORE AND AFTER TREATMENT. J.l. Javaid, R. Sharma, K. Fault, and ~.M. Davis

9~, 1988). In a double-blind study the plasma level of haloperidol (EL) after a single test dose (0.05 mg/kg) was used to predict the resnonse of acute schizophrenic patients (n=20, 7~C) to treatment with a low (O.15 mg/kg) and a high (0.40 mg/kg) f~xed-dose of HL. Clinical response was evaluated 8 and 30 days after the beginning of the treatment with the BPRS (Overall & Gotham Psychol Rep 1C:~99-812, 1962); _~ plasma level was measured ~.#_th Eadioimmunoassay. The EL plasma level after the test ~ose had a significant relationship (r=0.69, u{D.O3) with the clinical improvement after 8 d&Vs of treatmentfonly for the low-dose group. ~ e improvement after 30 days could not be ore~icted from the HL plasma level after the test dose. These results could be due to the different rate of the d~ag-induced clinical -'__-provement, which decreases along the treatment (~avis et al. Psychopha-r~-acol Bull 21:48-5~, ~ E f ) . Psychiatric Clinic University of Zunich. Nussbaumstrasse 9 , 8000 ~t[uchen 2. FP.G *D#~D-Ee!low. lnstitut of Psychiav_~, 7niversity of S~o Paulc, ~razil.

Measurement of 3-Methoxy-~-hydroxy-phenylacetic acid (HVA) has been used as an index of dopamine (DA) turnover. Recent evidence suggests that changes in plasma HVA may reflect central dopaminergic activity. We studied plasma and CSF HVA in i7 psychiatric inpatients (11 schizophrenics, 3 schizoaffectives, 2 bipolars, 1 paranoid disorder). After a washout period of 19 days ( + 6 days), all patients underwent a baseline lumbar puncture. Nine schizophrenics and three nonschizophrenic patients underwent a second lumbar puncture after /4 weeks of treatment. The schizophrenic patients were all treated with trifluoperazine. Blood was drawn 15 minutes prior to each lumbar puncture. Plasma HVA was measured by HPLC-EC and CSF HVA was assayed bY GC/MS.

Although there were no consistent changes across patients, alterations in CSF HYA after pharmacological treatment strongly correlated with changes in plasma HVA ( N= l l , r = 0.7/4, p = 0.009). The baseline plasma and CSF HVA did not eorreIate with baseline clinical measures. However, there was significant correlation with a decrease in both CSF and plasma HVA and clinical improvement in schizophrenic patients. These results suggest that improvement in certain psychotic symptoms after /4 weeks of treatment may be associated with a reduction of DA turnover in the central nervous system. Illinois S t a t e Psychiatric Institute and Department of Psychiatry, University of Illinois at Chicago, 1601 W. Taylor Street~ Chicag%Ii 60612.

331

33.01 .O8

33.01.09

INDICATION OF PSYCHOTIC AND PSYCHEDELIC STATES BY IMPAIRED BINOCULAR DEPTH INVERSION H.M. Emrich, M.M. Weber, A. Wendl and J. Zihl A three-component-model of the neuropsychological basis of psychotogenesis is presented: it consists of Ist) a sensualistic; 2nd) a constructivistic, and 3rd) a "censor"-component of the system. It is assumed that in psychotogenesis the "censor-function" in relation to the constrnctivistic component is weakened. Measurements of binocular depth inversion using a stereoscopic slide projection with polarized light were performed in schizophrenic patients and in healthy volunteers under cannabis. Since binocular depth inversion represents an illusion occurring in the perception of objects with semantic relevance projected in a 3-D inverted fashion, the hypothesis can be tested that psychosis represents a state in which the human CNS is unable to correct implausible perceptual hypotheses. The data demonstrate a strong impairment of binocular depth inversion in productive schizophrenia as well as in a cannabis-induced psychedelic state. Max-P]anck-lnstitut ffir Psychiatrie, Kraepelinstr. 10, D-8000 Mfinchen 40

DEPRESSIVE SYMPTOMS IN THE ACUTE PHASE OF SCHIZOPHRIINIA AS PRI~ICIZIRS FOR RESPONSE TO ~ L E P T I C q!~FATME~T Y. L a m e r t T. Tl~l~t, N. Tamarin Data regarding the relationship between depressive symptoms in schizoyhrenia and response to neuroleptics is scarce and conflicting. Kolakowska et al. (Psychol. Med. 10, 335, 1980) found the subgroup of poor responders to have lower depression scores. Becker et al. (J. Clin. Psychiatry 46 (11, Sec 2), 26, 1987), on the other hand, claim that the depression that occurs in the course of schizophrenia is associated with poor response to neuroleptic treatment. In the present study, 46 randcmly admitted patients who met RDC definite criteria for schizophrenia were rated on the BPRS, Hamilton Depression Scale, and the EPI Scale, at admission, and after six weeks of hospitalization. Neuroleptic treatment was prescribed by the therapist independently of two blind raters. Patients were divided according to their basal Hamilton soores into two subgroups: schizophrenics with depression (Hamilton>18) and those with few or no depressive symptoms (Hamilton <18). The tw~ groups of patients did not differ as to their basal BPRS scores, but at six weeks, the depressive schizophrenics scored higher on the BPRS. There was no difference between the two groups on the exti-apyramidal rating score, neither at admission nor at six weeks. The results support our previous findings (Lerner et al., Lithi~n CombLned with Haloperidol in Schizophrenic Patients. Brit. J. Psychiatry, accepted for publication) that the presence of depressive sympton~ during the acute y~ase of schizophrenia correlates with poorer response to neuroleptic treatment.

33.01.10 DES-~qKhwHAL~~ORPHIN A N I ~ C ACTIVITY

33.01.11 : FdPrIHER EVIDENCE OF ITS

J.M.A. Sitsen and A.M.L van Delft Ever since the isolation and the identification of the endorl~ many investigators have been intrigued by their physiological and pathological functions. A role for these neuropeptides has been claimed in several psychiatric disorders, in particular schizophrenia. Des-enkephalin-gamma-endorphin (Org 5878) is the shortest amino acid sequence derived from gamma~r~hin retaining the behavioural activity, e.g. the facilitation of extinction of active avoidance behaviour in rats. Since antipsychotic drugs such as haloperidol exhibit the same pharmacological effects, des-enkey~nlin-gamma-endorphin has been investigated in schizophrenic patients. In a trial comparing placebo, i, 3 and i0 mg of this peptide per day in acutely exacerbated schizo~enic patients on standard maintenance treatment, the patients receiving i0 mg showed a significantly larger reduction in CPRS (Comprehensive Psychopathological Rating Scale) scores than the other groups after 4 ~ e k s of treatment. A second cxmmparative trial of Org 5878 (3 mg i.m. per day) versus haloperidol (5 mg p.o. twice daily) in schizophrenic patients not taking other antipsychotic medication showed a similar reduction of CPRS and BFRS (Brief Psychiatric Rating Scale) scores. No side-effects that could be attributed to des-enkeyhalin-ganma-endoc~in ~ r e observed. In the second comparative trial patients treated with the endorphin had clearly less movement disorders than the haloperidol-treated patients. The lack of sedative effects and the need for parenteral administration of Org 5878 are disadvantageous in the treatment of acutely psychotic patients. However, the former and the absence of extrapyramidal side-effects may ~ i i prove to be improvements on existing maintenance treatment for schizophrenic patients. Scientific Development Group, Organon International B.V., P.O. Box 20, 5340 BH Oss, ~ Netherlands.

332

~UROLEPTIC-INDUCED HYPOTHER~ffA : A PERIPHERAL IALPHA-ADRENERGIC IhWOL%U~NT G. Boschi t N. Launay and R. Rips Although neuroleptics are generally administered peripherally, their hypothermic effect has been said to involve the central nervous system, and more precisely t h e hypothalamus. However, the few data which provide information regarding hypothermia produced by intracerebral administration of neuroleptics are controversial. We have therefore studied twelve neuroleptics belonging to five chemical classes for their ability to produce hypothermia when administered ~utraperitoneally (ip) or intracerebroventricularly to mice. The phenothiazines (chlorpromazine, levomepromazine, thioproperazine, prochlorperazine, perimetazine and piportil) produced the strongest hypothermia. The butyrophenones (haloperidol and droperidol), the thioxanthene (flupentixol) and the diphenylbutylpiperidine (pimozide) decreased the rectal temperature to a lesser extent. The benzamides (sulpiride and sultopride) did not modify the temperature except for sulpiride which produced hypothegmia at a dose inducing toxic effects (rigidity, convulsions). Surprisingly, none of the neuroleptics administered icv induced hypothermia at doses which did not :produce toxic effects, suggesting that neuroleptics act to elicit hypothermia via a peripheral, rather than a central mechanism. Since most neuroleptics possess alphs-adrenolytic properties, we attempted to antagonize the hypothermia with phenylephrine which activates peripheral alpha-adrenoceptors. Indeed, the concomitant injection of phenylephrine (6 mg/kg ip) and chlorpromazine (2.5 mg/kg ip) or haloperidol (4 mg/kg ip) suppressed the hypothermia supporting the view that peripheral alpha-adrenoceptors may mediate neuroleptic-induced hypothermia. D~SERH, Pharmacologie, 17 rue du Fer ~ Moulin, 75005 PARIS.

33.01.12

33.01.13

A NEW CLUE IN THE PRECLINICAL PREDICTABILITY OF NEUROLEPTICS Y. Okazaki, N. Anzai, M. Setoguchi, T__ t. Fukuda The clinical effects of neuroleptics are many and varied. The strong correlation between the clinical potency of a neuroleptic and its anti-dopaminergic (DA) activity has been supported by many studies. Based on behavioural-pharmacological experiments, 14 neuroleptics known to have a variety of action characteristics, relative anti-NA/anti-DA, anti5HT/anti-DA, and anti-5HT/anti-DA ratio-values adjusted to have a value equal to a chrolpromazine (CP) value of i were obtained. Values for each nenroleptic were plotted on a logarithmic coordinates' graphs with the origin at CP(1,1,1). After considering the clinical effects reported from each drug,findings important for the preclinical predictability of clinical effects in neuroleptics were observed. 1)Two significant axes crossing the origin (CP) at right angles were found and considered to characterize neuroleptics tested. 2)One axes - the anti-5HT/anti-NA axis may relate to sedative (anti-bHT>anti-NA)-disinhibitory (anti5HT
ACTION OF LOW AND HIGHT DOSE OF PIPOTIAZINE ON SCHIZOPHRENIC NEGATIVE SYMPTOMS. P. Robert, Y. Merdji, M. Touary, B. Bensmail, G. Darcourt. The aim of these study was to compare efficacy of low and hight dose of neuroleptic (pipotiazine) in DSM III-R schizophrenia catatonic type, disorganized typ~ undifferentiated type and residual type. After i0 days of neuroleptic wash out patients must present a minimal score of 75 at the scale for the assessment of negative symptoms (SANS - ANDREASEN). In these double blind study i0 patients received 0,I mg/kg of pipotiazine and I0 patients 0,5 mg/kg during 8 weeks. Clinical course was rated each week using SANS, CPRS and MJtDRS. Pipotiazine blood ratio was evaluated after 4 days, 4 weeks and 8 weeks of treatment. First results indicate that there is no signifiant difference between low and hight dose improvement rate. In the first 4 weeks action of low dose are more effective but these initial better results is cancel by signifiant worsen score noted in the last 4 weeks. Clinique de psychiatrie et de psychologie m~dicale H8pital PASTEUR - 30, avenue de la Vole Romaine 06002 NICE CEDEX -

33.01.14

33.01.15

PRESYNAPTIC DOPAMINE RECEPTOR AGONIST (B-HT 920) TREATMENT OF SCHIZOPHRENIA G.Lipka, K.Wiedemann, O.Benkert, F. Holsboer B-HT 920 was administered in a dose range from 0.3 - 1.2 mg/d f o r 21 days to 12 patients with schizophrenia, paranoid type, in order to examine whether presynaptic receptor stimulation exerts antipsychotic effects as can be assumed by therapeutic t r i a l s with low dose administration of apomorphine. From a p i l o t study which was conducted at the Research Unit of the Dep. of Psychiatry, University of Mainz, the following results emerged; In 4 patients a significant amelioration (reduction of i n i t i a l BPRS scores by more than 50~) of psychotic symptomatology was observed. 8 patients remained without any change of psychopathology. Psychomotor activation was observed in six patients which prompted termination of the t r i a l i n two cases. No other marked adverse effects of B-HT 920 were noted. In agreement with pharmacology of B-HT 920, Prolactin plasma concentrations two hours after oral application of a single dose of the drug were significantly re4uced. I t remains to be clarified whether B-HT 920 possesses antipsychotic properties. The activating properties of 8-HT 920 in o~r hand are interesting and should be inves#igated in further studies in a specifically defined subsample of schizophrenic patients where negative symptoms predominate. Department of Psychiatry, University of Freiburg, Hauptstrasse 5, r~-7800 Freiburg, West-Germany

CLINICAL EVALUATION OF YM-09151, A BENZOAMIDE DERIVATIVE ON SCHIZOPHRENICS A.Sumiyoshi, M.Murasaki, A.Mori, R.Takahashi, H.Kazamatsuri, G.Yagi, K.Kamijima, and T.Kariya YM-09151 is a benzamide derivative which has been newly developed in Japan, having a differnt chemical structure from both sulpiride and sultopride. It has been shown to have potent antipsyehotic effects in the preclinical studies. In our phase 2 study of YM-09151 on schizophrenics, a high quality of th@~inal global improvement rating (FGIR) has been obtained as shown in Table i. Table i: Final $1ohal improvement rating (%) Improvement No change Aggravation +++ -H+ 8 (7.7)

20 (19.2)

35 (33.7)

34 (32.4)

7 (6.7)

Total 104 (i00)

AS to the symptomatological parameters in BPRS, effectiveneSS Was ascertained in the terms of tention, hostility, and hallucinately behavior. Furthermore, relatively good results were obtained in the terms of anxiety, emotiona] withdraw~l, and uncooperativeness, suggesting that YM09151 might have the effect towards negative symptoms of schizophrenia, namely an activating action, as well as posit$ve symptoms. The~nogt frequently observed side effect was akathisia noticed in 15.7%. Followed by appearence of tremor, muscular rigidity, slurred speech, and drowsiness were observed in over 10% respectively. It is the fact that the incidence of the extrapyramidal symptoms is reretively low in YM-09151. The global utility rating has been evaluated better than FGIR, shoeing the fact that YM-ogI51 is superior to the conventional antipsychotics used earlier in those schizophrenic patients. Department of psychiatry, Tokiwa Hospital,3439-2 Tokiwa, Machida, Tokyo, Japan, 194-02

333

33.01.16

33.01.17

G Y K I - 2 2 441, A N E W P H E N O T H I A Z I N E ESTHER WITH LONG-ACTING NEUROLEPTIC EFFECT I. K i r ~ I y , J. B o r s y , M. T a p f e r , S. L o s o n c z y , K. R A s k y , L. T o l d y a n d I. T 6 t h In o r d e r t o o b t a i n d e p o t n e u r o l e p t i c effect the new 2-trifluoromethyl-phenothiazine esthers were synthetized by using sterically hindered acids of l i p o p h y l l i c c h a r a c t e r . Some compounds were administered intramuscularly in d e p o t i n j e c t i o n a n d t h e i r p h a r m a c o l o g i c a l efficacy were compared to fluphenazine decanoate /Modecate/ as r e f e r e n c e drug. O n e of t h e s e c o m p o u n d s , GYKI-22 441 /2-trifluoro methyl-lO-~-[4-/@-ethyl/-l-piperaziny~ - p r o p y l phenothiazine /4-chlorophenoxy/ isobutyrate/ were selected for further investigation. Its preclinical studies have already finished and the clinical trials are in progress now. In t h e p h a r m a c o l o g i c a l experiments the strong and long-lasting antiapemorphine e f f e c t s of t h e compound were verified. It e f f e c t i v e l y antagonized the apomorphine-induced hypermotility, stereotypy and turning behaviour o f r a t s a n d the apomorphine-emesis of d o g s . It h a d s e d a t i v e and cataleptegenic effect, as well as inhibited the learning performance of rats. The pharmacologica& spectra and potency of this new depot phenothiazine c o m p o u n d w e r e s i m i l a r t o t h a t o f fluphenazine decaneate. Its long-acting pharmacological effects were supported by the pharmacokinetic studies, too. Institute for Drug Research, Budapest, 1045. Szabads~gharcosok u. 4 7 - 4 9 . , H u n g a r y .

INTERACTION OF THE N E W A N T I P S Y C N O T I C R I S P E R I D O N E W I T H SPONTANEOUS AND AMPHETAMINE-INDUCED MOTILITY IN RATS A.A.H.P. Me~ens, F.H.L. Awouters, C.J.E. Nieme~eers and P.A.J. Janssen The effects of risperidone and haloperldol on spontaneous and amphetamine-lnduced motility were studied in rats. Large motor movements were significantly reduced by low doses of both risperidone and haloperidol (0.062 and 0.038 mg/kg, respectively). Progressively higher doses were required to block smaller motor movements. The dose increment, however, was much larger for risperidone (up to 2.80 ms/ks) than for haloperldol (up to 0.085 ms/MS). Also hyperactivity and stereotypy induced by low levels of amphetamine stimulation were antagonized by low doses Of the two compounds (0.02 to 0.0~ ms/ks). Normal motility was completely restored at higher dose levels of amphetamine stimulation too, but the required doses diverged. To normalize motility induced by amphetamine doses up to 5.0 ms/ks, the effective doses of risperldone had to be increased rapidly (up to 0.50 to 0.96 mE/kS) whereas a relatively small dose increment was sufficient for haloperidol (up to 0.0~5 to 0.0Zl ~ / k g ) . At still higher amphetamine doses, the dose-normalization curves of risperidone and haloperidol were virtually parallel. It is concluded that risperidone and haloperidol are equipotent in controlling a low level of dopaminerglc overactlvlty by partially occupying dopamine D2-receptors. Higher levels of functional dopamine antagonism up to saturation of the D2-receptors, however, require much higher doses of risperidone than of haloperldol. Therefore, the risk of dopaminerglc overblockade (and EPS induction) is considered to be much smaller with risperldone than with haloperidol. Department of Pharmacolo&y, Janssen Research Foundation, B-2340 Beerse, Belgium

33.01.19

33.01.18 THE

PHARMACOLOGICAL

PROFILE

OF

THE

NEW

ANTIPSYCHOTIC

RISPERIDONE C.J.E. NiemeKeers, K.H.L. Schellekens, F. Awouters and P.A.J. Janssen The in rive pharmacological profile of rlsperidone, a henzisoxazole derivative, was compared with that of rltanserln, a selective centrally actlnE serotonln S 2 antagonist, and with that of haloperidol, a classical dopamine D 2 antagonist. Rlsperidone was found, like rltanserin, to be very active in tests related to serotonln antagonism, and, llke haloperldol, in tests related to dopamlne antagonism. Peripheral serotonin antagonism was obtained at 0.0011 mE/k E sc and central serotonin antagonism at 0.01~ ms/ks sc, in tests in which tryptamine was used to induce serotonerElc overstimulation. Peripheral dopamlne antaKonism was obtained at 0.0016 mE/ks sc and central dopamlne antagonism at 0.056 mg/k E sc, in tests in which amphetamine was used to induce overstlmulation. In contras~ to ritanserln and to haloperidol, risperldone, was a potent and complete LED antagonist (0.028 mE/ks, sc). Furthermore manifestations Of dopaminergic overblockade, such as catalepsy, inhibition of food-intake, and abolition of motor activity occurred with rlsperidone at significantly higher doses than with haloperldol. The mixed serotonin S 2 and dopamine D 2 antagonism of risperld6ne is considered to be the pharmacological basis of a new type of antipsychoties with major advantaEes over classical neuroleptics, additional control of negative symptoms and EPS-free therapeutic doses. Janssen Research Foundation, B-23~0 Beerse, BelEium

334

PHARMACOKINETIC EFFECTS OF THE

PROFILE AND NEUROENDOCRINE NEW ANTIPSYCHOTIC RISPERIDONE.

~ANDEN BUSSCHE G.. HEY~_ANTS J. AND DE COSTER R. Risperidone (R 64 766) is a new benzisoxazol-derivative with potent central serotonin-S2 and dopamine-D2 receptor blocking properties. The pharmacokinetic profile of risperidone was investigated both in volunteers and in psychotic patients. In single-dose kinetic studies in volunteers with oral doses ranging from 0.5 to 4 mg, it was demonstrated that oral absorption of risperidone was very rapid, with peak plasma concentrations (measured by a direct radioirmuunoassay) attained approximately 1 h after dosing. The extent of absorption was as complete after intake of a ~ablet formulation as after a solution, and was not affected by a meal. Values of Cma x and AUC 0_ 8h increased proportionally with the dose. Terminal halflives, dependent of the dose, were between 20 and 30 h, with a mean terminal half-life of 24 h. After chronic oral administration of i mg for 20 days in volunteers, steady-state plasma concentrations were reached after 7 days, and the terminal half-life after the last 1 mg dose was 30 h. These linear pharmacokinetics were also confi-~ned in 15 chronic psychotic patients, who received increasing doses of risperidone during 4 weeks. The initial dose of 5 mg b.i.d, during the first week was increase~ with increments of 5 mg each week, until a daily dose of 25 mg was reached during the fourth week of treatment. Plasma concentrations were measured on each day o ~ dose increase, just before intake of the morning medication and 1 h thereafter. Mean peak- and trough plasma levels of risperidone increased proportionally with increasing doses. In the same study and at the same time points, the following neuroendocrine parameters were measured: plasma T3, TSH, GH, LH, FSH, cortisol and prolactin. Plasma prolactin levels increased 7-fold after the first drug achninistration and remained at this level till the end of the experiment. The other parameters were not affected by the treatment with risperidone. Janssen Research Fou/~dation, B-2340 Beerse, Belgiu/n.

33.01.20

33.01.21

RISPERIDONE IN THE TREATMENT OF BEHAVIORAL SYMPTOMS IN P SYCHOGERIATRIC PATIENTS : A ]~ILOT CLINICAL INVESTIGATION. -~synt~ens A.. Hevlen S.. Gelc]ers y.. and Vanden Bussche G.

THE IN VITRO AND IN VIVO BIOCHEMICAL PROFILE OF RISPERIDONE, A NEW ANTIPSYCHOTIC J.E. Leysen, W. G o ~ e r e n , A. Eens, D. de Cbaffoy de Courcelles, P.F.M. Janssen and P.A.J. Janssen In in vitro receptor binding and receptor mediated functional studies risperidone was compared to the serotonin-S 2 antagonist ritanserin and to the dopamine-D 2 antagonist haloperidol. The receptor binding profile revealed for rlsperidone high affinity binding (Ki-value , nM) to serotonin-S 2- (0.16), dopamine-D 2- (3.13), a- I adrenergic (0.8), histamlne-H I- (2.23) and a 2 -adrenergic receptors (7.5~). The S 2 affinity was two-fold higher than that of ritanserin and the D 2 affinity two-fold lower than that of haloperidol. Risperldone showed higher affinity than the latter drugs for the adrenergic and histamine receptors. The signal transducing system coupled to S 2 receptors, measured as serotonin induced 32p-phosphatidic formation in human platelets, was potently and specifically bloomed by risperidone and ritanserin (ICto values 0.5" and 1.6 ruM, respectively). Functional responses mediated by post- and presynaptlc D 2 receptors respectively, i.e. inhibition by dopamine agonists of evoMed release of labelled acetylcholine and dopamine from rat striatal slices, were both antagonized at nanomolar concentrations of risperidone and haloperidol. In in wive receptor labelling studies in rats, the occupation of D 2 and/or. S2 receptors in brain areas was investigated for rlsperldone, ritanserin, haloperidol, setoperone, plmoride, sulpiride and clozapine. Risperidone occupied frontal cortical S 2 receptors with an ID50 = 0.03 mg/kg, i.e. 8 times more potent than ritanserln and strlatal D 2 receptors with an ID50 = 0.63 mg/kg i.e. g times weaker than haloperidol. The in vitro and in wive biochemical properties of risperidone are in agreement with the in wive pharmacological profile. The potent S 2 and D 2 antagonism of risperidone may underlie its beneficial clinical effects on both negative and positive symptoms of schizophrenia. Department of Biochemical Pharmacology, Janssen Research Foundation, B-2340 Beerse, Belgium

~isperidone (R 64 766) is a new benzisoxazol-derivative ~ i t h potent serotonin-S2 and d o p a m i n e - D 2 receptor blocking properties. Previous single-blind trials in 120 chronic psychotic patients have demonstrated that risperidone is a potent antipsychotic, which also remarkably improves the negative symptoms of schizophrenia, without inducing acute extrapyramidal symptoms (EPS) . The present study was conceived to evaluate the effect of risperidone in a psychogeriatric population with behavioral disturbances. Fourty patients, ~eeting the DSM-III criteria for "Dementias Arising in --he Senium and Preseniura" or for psychotic disorders in ~he elderly were selected. Selection criterion was the presence of behavioral disturbances (agitation, agressiven~-ss, hostility, irritability, wandering, day and night disturbance, delusions, hallucinations), poorly responding to conventional neuroleptic therapy. Patients with major somatic diseases were excluded. The trial lasted for 5 weeks: a 1 week single-blind placebo washout period, followed by four weeks of active treatment -with risperidone. The starting dose of 0,5 mg b.i.d, was adapted whenever necessary, according to the achieved -_herap,eus effect or the appearance of side-effects. Patients were evaluated on a weekly base, using a 15-item behavioral evaluation scale, a Visual Analogue Line for the main target symptom, the Clinical Global Impression, and the Chouinard-scale for evaluation of EPS; sideeffects were assessed and vital signs checked. A pre versus post safety evaluation was performed, including ECG. At the end of the study a comparison was made with the most successful previous neuroleptic therapy. The results of this pilot investigation suggest that risperidone represents a new effective and well tolerated tool in the pharmacotherapy of behavioral symptoms in psychogeriat tic patients. ja~Issen Research Foundation,

B-2340 Beerse, Belgium.

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BEHAVIORAL PHA~,~ACOLOGICAL EVIDENCE OF 0PC-h392: A DOPAMINE AUTORECEPTOR AGO~?IST AND POSTSYDA_~UIC ZDPkMINE RECEPTOR ANTAGONIST T. Kikuchi~ S. Suzuki~ T. Hirose~ Y. Uwahodo and K. Tottori The behavioral pharmacological effects of 0Pc-L3~2 (7-{3[4-(2,3-dimethylphenyl)piperazinyl]propoxy}-2(iE!quinolinone) on the central dopaminergic system were studied in mice and rats. Dopamine (DA) autoreceDtor ar activit?:= 0PC-4392 inhibited spontaneous locomotor activity e_nd climbing behavior in mice. The effects of 0Pc-L292 were antagonized by low doses of DA antagonist which selectiVely blocks DA autoreceptors. 0PC-4392 inhibited mothamphetamine-induced locomotor activity in mice. ~ne effect of 0PC-4392 was antagonized by low doses of DA ~n~agonist. No DostsvnaDtic DA receptor ar activit)'_. 0PC-4392 did not increase spontaneous motor acr in reserpinized mice. 0PC-4392 did not enhance spontaneous ipsilateraf rotation in rats with unilateral striatal kainic acid lesions (KA-lesioned rats) and did nc~ induce contralateral rotation in rats with unilateral seriatal 6-hydroxydopamine lesions (6-0HDA-lesioned rats). Postsyna~tic DA receDtor antagonistic activity. 0PC-h392 inhibited apomorphine-induced locomotor acr in reserpinized mice and apomorphine-induced szerect~rpy in mice.,0Pc-4392 inhibited apomorphine-induced rc~azion in KA-le~ioned rats and 6-OKDA-!esioned rats. The results suggest that OPT-h392 acts as an agcnist on DA autoreceptors, does not act as an agonist on pcs~si,-~_.eptic normosensitive and supersensitive DA receptors, an~ acts as an antagonist on these DA receptors. Third Tokushima ~nst. of Hew Drug Res., Otsuka ~na.~--_aceutical Co., Ltd., h63-i0 Kagasuno Kawauchi-cho Uc~ashima 771-01, Japan

A DOUBLE-BLIND, CROSS-OVER, COMPARISON OF CONTROLLED RELEASE AND IMMEDIATE RELEASE FORMULATIONS OF REMOXIPRIDE D. Tench, S. Semi and T. Ashwood Thirty years of clinical experience have proved beyond doubt the efficacy of neuroleptics in controlling the symptoms of acute schizophrenia and in maintaining the patients symptom free. One of the major problems with neuroleptic treatment is the high rate of non-compliance amongst the schizophrenics for maintenence therapy. The introduction of depot neuroleptics obviated this difficulty but carried with it other problems associated with prolonged action and complications at the site of injection. One way of overcoming non-compliance without relinquishing the advantages of oral medication such as ease of clinical control, is to use controlled release (CR) formulations which need to be administered only once daily. Remoxipride is a substituted benzamide which in clinical trials of the oraI immediate release (IR) formulatiop appears to be effective in the treatment of acute schizophrenia. 3t follows, therefore, that to improve compliance, a CR formulation would he of immense benefit in the long-term treatment of schizophrenics. This parer describes a study comparing the pharmacokinetics of a CR formulation of remoxipride with a convention~l (IR) formulation. The study was a double blind, cross-over comparison of the two formulations in stabl~, chronic schizophrenic inpatients resident at Prestwich Hospital. A preliminary analysis of the data showed that the fluctuations in the plasma concentration of remoxipride were less for the CR formulation than the IR formulation. Remoxipride CR appeared to fulfill the kinetic rationale for a CR formulation end from a kinetic point of view the drug can be g~ven once daily. However, clinical studies have to determine if there is a benefit regarding severity and frequency of adverse events during treatment with the CR formulation. Prestwich Hospital, N~nchester, U.K.

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EX VIVO RECEPTOR OCCUPATION BY RITANSERIN AND RISPERIDONK MEASURED USING AUTORADIDGRAPHY A.G. Schotte and J.g. Leysen Ex vivo receptor binding experiments were performed in rats with ritanserln and risperidone. Doses ranking from 0.0025 to 160 mg/kg body weight were injected subcutaneously two hours prior to sacrifice. The occupation of serotonin Sz-receptors in the frontal cortex, of el-adrenergic receptors in tbalamic nuclei and of dopamine D2-receptors in the striatum was investigated for both compounds using ex vivo autorediographical techniques. We used in adjacent horizontal 20 ~m thick brain sections: 0.2 nM [125I]7-amino-8-1odo-ketanserln (with addition of selective displacers in the incubation medium) to label S 2- and el-receptors , and 0.2 nM [125I]sulpride for measuring D2-receptors. Ritanserln showed 50 % occupation of S2-receptors at 0.02 mg/kg and a total blockade of these sites at 0.16 mg/kg, while ~i- and D2-receptors remained unoccupied until i0 mg/kg. 40 mg/kg ritanserin gave a 30 % occupation of D2-receptors and g5 % occupation of el-receptor binding. Risperidone showed a higher potency for occupying all three receptors. Dosages producing 50 % occupation were O.00Z5 mg/kg for $2- , 0.16 mg/kg for ~i- and 2.5 mg/kg for D2-receptors. 100 % occupation of the receptors was reached at 0.63, ~0 and 160 mg/kg, respectively. The findings using ex vivo autoradiography were in agreement with in vivo binding data on S2 - and D2-receptors. For the first time, demonstration of ~l-receptor occupation measured ex vivo was achieved. For the latter receptor an in vivo binding model is not available. Ex vivo autoradiography, in contrast to brain homogenate techniques, allows an investigation of receptor occupation by rapidly dissociating drugs. Janssen Research Foundation, Department of Biochemical Pharmacology, B-2340 Beerse, Belgium

LIGAND-BINDING PROFILE OF EMD 49980. A SELECTIVELY PRESYNAPTIC DOPAMINE (D2)-AGONIST WITH POTENT ACTIONS ON 5HTSYSTEMS C.A. Seyfried, H.E. Greiner, A.F. Haase and H. BSttcher In in vivo neurochemical models, EMD 49980 (5-hydroxy-3(4-(4-phenyl-1,2,3,6-tetrahydrepyridyl(1)-butyl)-indole, mesylate) proved to be a highly potent and selectively presynaptic D2-agonist with a profile very similar to that of EMD 38362 (Seyfried et el., in Dopaminergic Systems and their Regulation, ed. Woodruff, MacMillan, London, 1986), the hydrochloride of the identical base. Due to its higher solubility, we used EMD 49980 to study in vitro interactions with various ligands in rat brain membrane preparations. EMD 49980 was active in the nM range with respec~ to D2-receptors (spiperone- and ADTN-binding:IC50=5x10- M), slightly less ~ctive o n < - , 5HT2- andS--receptors and inactive (IC50>I0" M) on muscarinic and opiate receptors. Most orominent actions were observed at hippocampal 5HT-IA sites (8-OH-DPAT-binding: IC50~"I0- M); in additi?~, 5HT-uptake was potently inhibited in vitro (IC50=2xi0- M) and in vivo (ED50=0.17 mg/kg sc, inhibition of p-chloroamphetamine-induced 5HT depletion). Other 5HT-uptake inhibitors,e.g, zimelidine, were inactive in 5HT-IA-binding studies, thus the hypothalamic 5HT-transporter and the hippocampal 5HT-IA-receptor seem to have different characteristics. The possibility that the dopaminergic actions of EMD 49980 (ED50= 0.08 mg/kg so, inhibition of striatal L-dopa accumulation) are brought about by indirect effects via 5BT-systems can be ruled out since both, zimelidine and 8-OH-DPAT were inactive in the L-dopa model (ED50>I0 mg/kg sc). Furthermore, a number of structural analogs of EMD 49980 with potent dopaminergic actions are devoid of 5HT-IA-binding and 5HTuptake inhibiting effects, supporting the conclusion that in EMD 49980, dopaminergic and actions on 5HT-systems are independent properties. It is speculated that in addition to its presumed antipsychotic actions due to presynaptir inhibition of dopaminergic impulse flow, the effects of EMD 49980 on 5HT-systems might lead to beneficial antidepressive and/or anxiolytic properties in the clinic. Biolog.Res.,Dept.Neurochem., E. Merck, 6100 Darmstadt, FRG.

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TIOSPIRONE: POTENTIAL MECHANISMS OF ATYPICAL ANTIPSYCHOTIC ACTION D.P. Taylor~ D.K. Hyslop~ and J. Dekleva Clozapine has become a benchmark in the search for new antipsychotics because it has been shown to be efficacious without the short- or long-term motor liabilities associated with the "neuroleptics." One hypothesis advanced for clozapine's "atypical" profile has been its weak D-2 dopamine receptor blockade which occur~ in the presence of potent muscarinic blockade. Tiospirone (BMY 13859) is a new antipsychotic candidate which has demonstrated clinical efficacy with an atypical side effect profile, i.e., devoid of extrapyramidal symptoms (EPS; Jain et al., Intl. Clin. Psychephai-macol. 2:129, 1987). Tiospirone was identified as an antipsychotlc candidate based on its affinity for D-2 sites and in vivo activity in tests predictive of efficacy (Yevich e_!ta_!., J. Med. Chem. 29:359, 1986). However, its failure to induce catalepsy in animal testing,the preclinical predictor of EPS, was not attributable to antimnscarinic effects in vitro or in vivo. We have investigated the interactions of tios~irone and clozapine in in vitro receptor binding at other sites which have been implicated in the action of atypfcal antipsychotics. These include D-I, sigma, PCP, 5-HTI, =I, and calcium antagonist binding sites. The m~st notable affinity of both compounds is for the 5-HT 2 site. This was of interest sincebehaviorally relevant doses of tiospirone did not inhibit ex vivo binding of [3H] spiperone to D-2 sites in the rat striatum. When this radioligand was used for in vivo binding studies specific radiolabeling at D-2 sites in striatum was reduced 30% and completely eliminated at 5-HT 2 sites in frontal cortex. Similar observations have been made with clozapine. These observations suggest an important role for serotonin in the pharmacologic profiles of tiospirone and clozapine. CNS Biology, Bristol-Myers Co., PO Box 5100, Wallingford, CT 06492-7660, U.S.A.

AMPEROZIDE - A POTENTIAL NEUROLEPTIC DRUG WITH SPECIFIC EFFECTS ON LIMBIC FUNCTIONS G. A n d e r s s o n , E. C h r i s t e n s s o n , B. G u s t a f s s o n , G. P e t t e r s s o n a n d J. S v a r t e n g r e n Amperozide is a novel psychotropic drug with atypical neuroleptic properties. It is characterized by a limbie mode of action in several experimental models. Thus, amperozide significantly attenuated amphetamine induced hypermotility in mice. Furthermore, amperozide treatment caused an increased DA turnover selectively restricted to the limbic forebrain of the rat. Similar to antidepressant drugs amperozide is a very potent (0.]5 mg/kg) inhibitor of spontaneous mousekilling behaviour and the coni0ound significantly reduced the ~ b i l i t y time in the behavioural despair test. Amperozide exhibits a high affinity for 5-HT 2 receptors frcm rat cortex and these receptors are downregulated during long-term treatment. In accordance with its effect on serotoninergic nerv transmission amperozide is a potent stimulator of the pituitary-adrenocortical axis. There is, however, no stimulation of prolactin release. A ~ r o z i d e also posses~-~ed potent anticonflict (=~xiolytic) properties and of great interest is its remarkable therapeutic effect on the % ~ t i n g pig syndrome. This chronic stress bondition is most probably caused by maladaptation to environmental stressors. The pronounced limbic mode of action on emotional parameters, its total selective effect on limbic DAturnover, the absence of extrapyramidal side effects in primates and lack of stimulation of prolactin release makes amperozide an interesting novel candidate for clinical studies in schizophrenic patients with both positive and negative symptoms.

336

AB Ferrosan, P . O . B o x 839,

D e p a r t m e n t of C N S - R e s e a r c h , S-201 80 M a l m ~ , S w e d e n

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NEUROCHEMICAL C?_~CTERIZATION OF SOME NEW HALOGEN SUBST~ TUTED LYSERGOLS WITH ANTIPSYCHOTIC ACTIVITY I. Laszlovszky, F. Auth, B. Kiss, E. Lapis

KC 9172 - A NOVEL AGENT HAVING ANTEPSYCHOTIC AND ANXIOLYTIC POTENTIAL B. Costall i , A.M. Domeney i , M.E. Kelly I , D.M. Tomkins* and H. Kr~hling 2 KC 9172, a new psychotropic agent, has been claimed recently to possess antipsychotic and anxiolytic activity (Ruhland et al., and Kr~hling et al., Pharmacopsych., in press). We have investigated these potential activities in detailed tests using both rodent and primate species. Antipsychotic potential of KC 9172 w-as established using a model in which dopamine is infused persistently into the rat n. a c ~ n s to induce a phasic hyperactivity. This behaviour is sensitive to inhibition by known antischizophrenic agents. KC 9172 inhibited, without sedation, the dopamine-induced hyperactivity at doses of i00 ng/ kg to 10 ~g/kg i.p.b.d. Anxiolytic potential was assessed in a mouse aversion test, a rat social interaction test and a marmoset b , ~ n threat test. In the first of these tests naive mice are taken from a dark home environment and placed in the centre o f a white, brightly lit area of a test box having a black, darkened area simultaneously available. Vehicle treated mice spend must of their time in the black environmentf KC 9172 (0.0001 - i00 mg/kg p.o), like known anxiolys agents, increases the time spent in the white environment. This anxiolytic potential was confirmed in a rat ~est in which naive animals from separate cages are placed in an arena for measurement of time spent in social contact (e.g. grooming partner) which is increased by known anxiolytic agents, and in a human threat test where the retreat of a marmoset from the threat, associated with characteristic posturings, is inhibited by known anxiolytic agents. Thus in our tests KC 9172 presents as an atypical antipsychotic having novel anxiolytic potential.

The pronounced dopamine (DA) agonistic activity of ergolines as well as some of their 2-halogen derivatives such as bromocriptine and lergotrile are well known. Wachtel et al. (Life Sci.33:2583 /1983/) provided the first example that bromination of ergoline skeleton at position 2 resulted in a DA-antagonist (e.g. 2-Br-lisuride). A se~esof monc- (at position 2) and di-halogenated (at position 2 and 8) lysergols were synthetized and screened using nenrochemical and psycbopharmacological methods. Our attempts undertaken to develop new ergolines provided further evidence for that not only bromination but also chlorination (at position 2) could change the DA receptorial profile of lysergols. Surprisingly, the 8-halogenation of 2-halo-lysergols turned their DA antagonistic profile back co DA agonist direction. Three compounds, the DA antagonist 2-chloro-lysergol, RGH-6141 and 2,8-dichloro-lysergol derivatives as DA agonists, RGH-L455 and RGH-1430 have been selected for further deveiopment and the neurochemical action of these drugs are briefly described here. They devoid of activity on D-I reneptors (on basal and DA-stimulated adenylate cyclase activity) while all the three compounds displaced with different activity 3H-gplroperidol in D-2 binding experiments with IC-50 value in a range of 100-1000 nM. The in vitro binding studies indicated their ~-adrenergic and serotoninergic activity as well. RGH-614~, like haloperidol, markedly increased the biosynthesis and metabolism rate of DA (but not that of serotonin) in predominantly DA-ergic structures (striatum, limbie brain) while RGH-4455 and RGH-1430, like bromocriptine had the opposite action on both parameters. Interestingly, not only RGH-6141 (antagonist) but also RGH-4455 and RGH-1430 (agonists) showed antipsychotic activity in behavioural experiments. Pharmacol. Research Center, Chemical Works of G.Richter Ltd., H-1475 Budapest 10, P.O.Box 27. Hungary

1 School of Pharmacology, Bradford University, 2 Kali-Chemie AG, Pharmaceutical Division, P.O. Box 220, D - 3000 Hannover 1

BD7 IDP,UK

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ANTAGONISM OF AP-5-1NDUCED STEKEOTYPIES LINKS KC 9172 TO ATYPICAL ANTIPSYCHOTICS ~.J. Schmidt i , D. B u r ~ , S. Harrer i and H. Kr~hhling ~ In animal models KC 9172 exhibits behavioural effects predictive for antipsychotic and anxiolytic activity. However, unlike classical antipsychotics (e.g. haloperidol), KC 9172 does not induce catalepsy and does not antagonize amphetamine-induced stereotypies (Ruhland et al. and Kr~hling et al., Pharmacopsych., in press). Recently we found that not only a stimulation of dopamine activity induces stereotypies but also a blockade of g!utamatergic transmission in the striatum using the NMDA receptor antagonist AP-5 (100 nM/0.5 ~i). AP-5 induced sniffing is antagonized not only by classical neuroleptics but also by atypical ones (e.g. clozapine). Possibly, AP-5-induced sniffing may prove to be an animal model corresponding more closely to antipsychotic efficacy in man than e.g. amphetamine-induced stereotypy (Schmidt, Psychopharmacol. 90, 123, 1986). SNIFFING: KC 9172 (20, 10, 5 ~M/kg) did not change spontaneous sniffing of rats, but the AP-5-induced enhancement of sniffingwas effectively antagonized at 20 and i0 ~M/kg~ These effects resemble the effects of clozapine (30.7, 15.3, 6.1 ~M/kg). Haloperidol (0.26 ~M/kg) acts differently in reducing spontaneous and AP-5-induced sniffing. GRCOMING. (additional parameter recorded in parallel): KC 9172 neither changed spontaneous grooming nor did it restore grooming suppressed by AP-5. Here the effects of KC 9172 differ from both, clozapine and haloperidol since clozapine reduces spontaneous grooming and further suppressed grooming reduced by AP-5. Haloperidol restores AP-5 inhibited grooming. -CONCLUSION-: Sniffing induced by a blockade of glutamatergic transmission at the h~MDA receptor within the striatum is antagonized by KC 9172. The detailed behavioural profile of KC 9172 links this substance to atypical neuroleptics. 1 Biolog. Institut d. Universit~t, D - 7000 Stuttgart 80 2 Kali-Chemie AG, P.O. Box 220, D - 3000 Hannover 1

CLINICAL EFFICACY AND NEUROENDOCRINE EFFECTS OF ZOTEPINE A. WeiSbach, U. v. Bardeleben, O. Benkert and F. Holsboer Zotepine is a 2-chloro-ll-(2-dimethylamincmthoxy)dibenzo ( b , f ) - t h i e p i n e with a seven-membered central ring in contrast to conventional phenothiazines. To e l u c i date c l i n i c a l e f f i c a c y and neuroendocrine p r o f i l e the f o l l o w i n g studies were performed at the Department of Psychiatry, U n i v e r s i t y of Mainz, I ) In an open t r i a l 23 i n p a t i e n t s with schizophrenia, paranoid type (RDC). were treated with a mean dosage of 200-300 mg/day f o r at l e a s t 21 days with the most s i g n i f i c a n t improvement during week I. According to the a p r i o r i defined c r i t e r i o n f o r response (BPRS t o t a l score < 28) there were 17 responders and 6 nenresponders at day 21. There was a low incidence of dyskinesia and parkinsonism. 2)In a d o u b l e - b l i n d c o n t r o l l e d study e n r o l l i n g 40 i n patients ~ i t h schizophrenia (RDC) the a n t i p s y c h o t i c effis of zotepine was s i m i l a r to perazin, rio major imbalance concerning f r e q u e n c y of s i d e - e f f e c t s was noted. 3) In An open t r i a l in 14 i n p a t i e n t s with endogenous depression, p s y c h o t i c subtype (RDC), 9 p a t i e n t s were c l a s s i f i e d as responders supporting t h a t zote~ine may be ap a l t e r n a t i v e to combinations of neuro]ep~ics and antidepressants. 4) In 6 normal male c o n t r o l s 25 mg zotepine administered o r a l l y in the morning induced a s i g n i f i c a n t increase of plasma p r o l a c t i n l e v e l s corresponding to the a n t i dopaminerglc action. C o r t i s o l , LH, FSH, t e s t o s t e r o n e remained unaffected. Plasma growth hormone increased 6 hours a f t e r a d m i n i s t r a t i o n , p o s s i b l y due to behavioral sedation. Department of Psychiatry, U n i v e r s i t y of Freibu~g, Hauptstrasse 5, D 7800 Freiburg, West-Germany

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BECLAMIDE AS ADJUVANT IN THE NEUROLEPTIC TREATMENT C. Roptis M. Dose, D. Garcio, D.E. Bremer, M.M. Weber, and H.M. Emrich A recent study shovved the adjuvant effect of the anticonvulsont carbamczeaine in the neuroleptic treatment of acute schizophrenic psychoses (Dose & Emrich, 1987). Since other cnticonvulsonts might hove similar applications the combira~ion haloperidol-beclamide was tested in the treatment of acute paranoid psychoses. Beclamide has been long used in the treatment of grand mal epilepsia as well es in ]uverile behaviour disorders. The combination of low dose haloperidol (HPD)/beclamide (BCM) vs. low dcse HPD/piacebo was tested using a doubleblind design in 24 patients with an acute schizophrenic or schizoaffective (non-manic) psychosis who had given their informed consent. In both groups patients initially received HPD 6 mg/d and e i t h e r BCM (2 g/d i n i t i a l l y , increased by ] g/d to 3 g/d) or placebo. Every seven days the t r e a t i n g p s y c h i a t r i s t was allowed to increase HPD by 3 mg/d if ~ l i n i c s t l y n e c e s s a r y . C h l a r p r o t h i x e n e and b i p e ride~ were at ncqd as additional sedative and anticholiheroic m e d i c a t i o n . After 28 days 3CtA or placebo were discontinued under constant HPD-doses and a final of weekly r~tings by IMPS, BPRS and EPS was carried out. Results: Within 28 days the BCM- and the placebo-group improved. The 5~.'-group, however, needed only 77% of the HPD-dpsage comosred to t h e p l a c e b o - g r o u p , 46% of t h e c h l o ~ p r o t h i x e n e - and 66% o f the b i p e r i d e n - d a s a g e . Extrapyramidal as v,e!i as B C M - t y p i c a l s i d e - e f f e c t s in the BCMgroup were o n l y 72,5%, in comparison t o t h e p l a c e b o group. From =hose f i n d i n g s an a d j u v a n t e f f e c t of the anticonvu!sant ceclomide in antipsychotic treatment with n e u r o l e p t i c s is suggested, which i s , however, less p r o nounced to the a d j u v a n t e f f e c t o f acrbamczepine. Max-Planck-lnszicut f o r Psychiatrie, Kreepelinstr. 10, D-dOO0 MOnchen 40.

CARBA~ZEPINE AS ADJUNCT OF ANTIPSYCHOTIC TREATMENT M. Dose, S. Apelt, D.E. Bremer, and H.M. Emrich Anticanvulsonts have been used as adjuncts of neuroleptic treatment in patients with kEG-abnormalities or aggressive behavior and putative temporal lobe epilepsy. However, controlled studies of a combined treatment with anticonvulsonts cnd neuroleptics in acute psychotic patients without kEG-abnormalities or aggressive outbursts have not been carried out so for. Therefore, a placebocontrolled, double-blind study was designed to study the efficacy of corbomazepine (CBZ) as an adjunct of halopetidal (HPD) treatment in non-epileptic, acute schizophrenic patients without EEG-abnormalities. 34 patients were randomly assigned to the CBZ- or placebo-group. In both groups, patients initially received HPD (6 mg/d) which could be increased by 3 mg/d every 5 days according to clinical judgement by the treating psychiatrist who was not aware of the additional medication with either CBZ (200 mg/d initially, increased by 100 mg/d to serum lev61s of 8-10 pg/ml) or placebo. Biperiden end chlorprothixene served as additional medication. Within 28 days o statistically significant improvement occurred in the CBZ- and in the placebo-group. Discontinuation 6f CBZ/placebo between day 28 and 35 under constant HPD led to continuous improvement of the placebogroup while the CBZ-group deteriorated statistically significant. The CBZ-group, however, needed only 75 % of the HPD-dosage compared to the placebo-group, 44 % of the chlorprothixene- and 31% of the biperiden-dosoge. According to s i d e - e f f e c t s , extrapyramidal as w e l l as CBZt y p i c a l s i d e - e f f e c t s in the CBZ-group were only 38 % as compared t o the p l a c e b o - g r o u p . HPD serum l e v e l s in the CBZ-graup were found to be 50 % of the placebo group with equal HPD dosages. From these f i n d i n g s an a d j u v a n t e f f e c t of o n t i c o n v u l s o n t s in antipsychctic treatment with neuroleptics is concluded. Max-Planck-lnstitut f o r Psychiotrie, Kraepelinstr. 10, D-8000 MOnchen 40

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SND 919 INHIBITS DOPAMINE RELEASE IN VITRO. J. Mierau and W.D. Bechtel

V I V O AND

IN

We studied the e f f e c t s of SND 919 Y ((S)-2-amino-A~5, 6,7-tetrahydro6-propylamino-benzthiazole-dihydrochleride) on the dapamine release by means of in viva and in vitro trials. SND 919 Y exhibits a strong and dose-dependent attenuation of the alpha-methyl-p-tyrosine induced reduction of dopamine content in rat brain estimated using HPLC with electrochemical detection. The ED 50 was found to be 0.04 mg/kg. This effect represents e marked inhibition of dapamine release in viva. According to N.E. Anden et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 521~ i00 (1982) it can be attributed to s stimulation of presynaptic dopamine receptors. The inhibition of the dopamine release caused by 5ND 919 Y can be antagonized by h%Ioperidol but not by the selective 01 antagonist SCH 23]90 suggesting a presynaptic agonistic activity of SHD 919 Y at D2 dopamine receptors. From rat brain striatal slices in vitro SND 919 Y inhibits do~e-dependently the electrically evoked ]H doramine release. Thus, the results of the in vitro release studies correspond well to those obtained in viva. We conclude from the r e s u l t s presented that at l e a s t the ~n viva e f f e c t of SND 919 Y is mediated via stimul a t i o n of presynaptic dopamine receptors resulting in a reduction of dopamJne release. This leads to a reduced a v a i l a b i l i t y of the neurotransmitter in the synoptic cleft. Hence, the compound may be a useful tool in the treatment of schizophrenia.

PHASE-I STUDIES WITH AMPEROZIDE, A NOVEL ANTIPSYCHIC DRUG L. ~blander With the aim of developing compounds alleviating both positive and negative symptoms of schizophrenia, without producing extrapyramidal symptoms, a series of diphenylbutyl-piperazine derivatives was synthesized. From this program amperozide was selected. Amperozide represents a novel class of antipsychotic drugs by having a unique type of combined activity on the dopaminergie system, selectively in limbic brain areas and on the serotoninergic system. Anloerozide has been given to normal adult subjects with the aim to study tolerance and acceptability and the phar~acokinetics of amperozide after single oral and intravenous as well as after multiple oral administration. Besides, the pharmacokinetics of one of the metabolites of amperozide has been studied (after single and multiple oral administration of amperozide). The effects of amperozide on the cardiovascular system during rest and physical exercise have been studied. Long-term ECG recordings (Halter monitoring) have been performed during ani0erozide steady state conditions. In none of the studies there were clinically significant changes in vital signs, blood .~nd urine analysis. In all studies where ECG was recorded there occured dose-dependent reversible prolongation of the QT interval and T-wave amplitude changes. No arrhythmias were recorded. Subjective complaints were mainly related to the CNS system, ate-vestibular system and to a lesser degree the gastrointestinal system.

Boehringer Ingelheim KG, Department of Biochemistry, D-6507 Ingelheim, FR. Germany

D e p a r ~ n t of Clinical Pharmacology Phar~acia LEO Therapeutics P.o. Box 839 MALMO Sweden

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EFFECTS OF SAV0XEPINE ON IN VZVO [3-H]-SPIPERONE BINDING TO PITUITARY DOFAMINE (DA) RECEPTORS AND ON PROLACTIN (PRL) SECRETION A. H~usler, S. Eischoff and L. Schenkel Savoxepine (CGP 19486A) is a novel DA antagonist with a preferential affinity for DA receptors in the hippocampus (IDb0 for inhibition of [3-H]-spiperone binding: 0.04 mg/kg, ip) vs. striatum ( I D b 0 : 0 . 7 mg/kg, ip) in male rats. Further it antagonizes apomorphine-lnduced climbing in mice (IDb0:0.06 mg/kg, ip). In rat s, a dose of 1 mg/kg (ip) inhibits pituitary [3-H]-spiperone binding in vivo by more than 50% for at least 24 h. Since blockade of pituitary DA receptors is known to stimulate PKL secretion, the effect of savoxepine on PRL secretion was studied in rats in comparison with the classical DA antagonist haloperidol. In vitro, the compounds were incubated with cultured pituitary cells for 4 h in the presence or absence of the DA agonist ergocornine. In vivo, the DA antagonists were injected sc and blood was collected either 2, 4 or 24 h after injection. PRL was measured by radioimmunoassay. In vitro, both savoxepine and haloperidol antagonized the inhibitory effect of ergocornine on PRL release in a dosedependent manner. In vivo, doses of 0.3-1 mg/kg savoxepine and 0.i-i mg/kg haloperidol significantly elevated plasma PRL at 2 h after injection. A dose of 1 mg/kg savoxepine maintained this elevation for at least 24 h. The ~same dose of haloperidol increased plasma PRL up to 4 h, but not for as long as 24 h. In conclusion, savoxepine is slightly less potent than haloperidol in stimulating PKL secretion, but its duration of action is much longer. This corresponds well with its prolonged pituitary DA receptor occupation. However, these effects of savoxepine are exerted at doses which are higher than the IDb0s for blockade of hippoeampal DA receptors and antagonism of apomorphineinduced climbing, tests which are thought to be good indicators of antipsychotic efficacy in man. Res. Dept., Pharm. Div., CIBA-GEIGY Ltd., CH-4002 BASEL

SAVOXEPINE, A NOVEL ANTIPSYCHOTIC AGENT.: INTERACTIONS WITH NEUROTR~SMITTER RECEPTORS IN VIVO AND IN VITRO. S. Bischoff, H. Bittiger, J. Krauss, K. StCcklin, K. Hauser, M. Sills and H. Blattner. Savoxepine (CGP 19486 A), a novel antipsychotic, has high affinity for brain dopamine (DA) receptors. In vitro, it was slightly more potent than haloperidol (HAL) on Hspiperone binding in rat striatum (IC5~ 0.5 and I nM resp.). In vivo, savoxepine inhibited H-spiperone binding in rat hippocampus at very low doses (ID50 0.04 mg/kg i.p.), being 17 times more potent than in striatum (ID50 0.7 mg/kg i.p.). In this test, HAL was also very active, but it was only 1.6 times more potent in hippocampus than in striatum (ID50 0.075 and 0.12 mg/kg i.p.). Kinetics of DA receptor occupation by savoxepine were measured by in vivo H-spiperone binding at 0.I, 0.3, 1 and 3 mg/kg i.p. of drug. Again large differences were obtained between hippocampus ar.d striatum. At 3 mg/kg, binding was still significantly ir~ibited in hippocampus 72 h after injection (-309), whereas in striatum the effect disappeared between 24 and 48 h. Savoxepine inhibited in vivo 3H-spiperone binding to 5HT2 receptors in frontal cortex (ID50 0.3 mg/kg i.p.). In vitro, it displayed the following affinities for ot~er receptors (liqand, IC50 in nM). a 89 ( Hprazosi~,o 2) alpha-2-adrenergi ~ ( H-cIonidine, 280), 5rHTI (H-5-HT, 2607, 5-HT~A ( B-8-0H-DPAT, 92), 5-HTIB (• 1700), 5-HT2 (~H-~etanserin, I0), histamine HI (-H-doxepine, 34) andiH2 ( H-tiotid~ne, 710), and cholinergic muscarinic (-H-QNB, 3500, E-Dioxolan, 2800). In conclusion, savoxepine is a potent and long acting DA receptor blocking agent. Its strong preference for hippocampal vs striatal DA receptors is indicative of good antipsychotic potential in the clinic with low incidence of EPS as suggested by our new concept (Bischoff et al., Prog.Neuro-Psychopharmacol. & Biol. Psychiat. (1988) 12, in press). Res. Dept. Pharmaceuticals Div. CIBA-GEIGY Ltd., 4002 Basel, Switzerland and Drug Discovery Dept. CIBA-GEIGY Corporation, Summit, USA.

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EFFE~'~fS OF SAVOXEPINE ON DOP~Mih~ (DA) METABOLISM AND ON DA AND ACETYLCHOLINE (ACh) RELEASE IN RAT STRIATUM P.A. Baumann, S.F. Bischoff and P.C. Waldmeier Savoxepine (CGP 19486A) increased the levels of the DA metabolites, homovanillic (HVA} and 3,4- dihydroxyphenylacetic acid (DOPAC) 2 h after oral administration with EDb0 value of 0.05 and 0.12 mgPKg, resp.; 2.5 h after i.p. administration, the corresponding values were 0.085 and 0.22 mg/kg resp. After 1 mg/kg p.o., the effect was maximal at 6 h; both DA metabolites were still increased after 24 h, but not after 48 h. This time course is comparable to that observed with an equivalent dose of haloperidol. In the dose-range in which D A m e t a b o l i s m was increased, no evidence for an alteration of the concentrations of DA. serotonin, 5-hydroxyindoleacetic acid and tryptophan, or of the accumulation of 5-hydroxye_~yptophan after central decarboxylase inhibition (a measure of serotonin synthesis) was observed. The effect of savoxepine on rat striatal HVA and DOPAC was greatly potentiated by amfonelic acid, s i m i l a r l ~ t o what is seen with haloperidol, but not with atypical neuroleptics such as clozapine or sulpiride. The effect~ of s a v o x e ~ n e on the electrically induced release of (-H)DA and (- C)ACh were assessed in vitro in preloaded, superfused rat striatal slices in the presence of the D A uptake inhibitor, nomifensine. The stimulated release of both transmitters ~ s enhanced in a eoncentration-d~pendent manner from i0 -M upwards, but the effect ~ 4 . . on ( C)ACh was much more marked; slmllar results were obtained w ~ haloperidol. Clozapine, in contrast, did not increase J C)ACh relase to a much more marked extent than that of ( H)DA. These results su-gest that savoxepine, like haloperidol, has more potent effects on post- than on presynaptic D2 dopamine receptors Thus, although its side effect profile in schizophrenic patients (particularly ex~ trapyramidal effects) differ markedly from those of halohaloperidol, savoxepine proved to have similar effects on DA metabolism. Therefore, the reason(s) for this difference are unlikely to be related to differences in effect on presynaptic dopaminergic mechanisms. Research Dep. Pharm. Div. C I B A - ~ I G Y Ltd. CH-4002 Basel

PSYCHOPHARMACOLOGY OF SAVOXEPINE L. Maitre, A. Vassout, A. Delini-Stula, R. Ortmann, E. Radeke, M. Schaub, H. Blattner and S. Bischoff The pharmacological properties of savoxepine (CGP 19486A) a novel tetracyclic antipsychotic agent, have been assessed in various tests predictive for neuroleptic-like activities. Thus, it antagonized amphetamine- and apomorphine-induced stereotypies in rats (ED50 0.07 and 0.17 mg/kg i.p.) and apomorphine-induced climbing behavior in mice (ED50 0.06 mg/kg i.p.). In dogs, savoxepine diminished apomorphine-induced emesis (ED50 0.06 mg/kg s.c.). In all of these tests, savoxepine exhibited a potency similar to that of haloperidol (HAL), indicating potent antidopaminergic properties. In contrast, savoxepine was much less cataleptogenic: only 20 % at I0 mg/kg i,p., whereas HAL reached an ED50 at 0.6 mg/kg i.p. 2 h after drug injection. The excellent resorption of savoxepine from the gastrointestinal tract is indicated by the almost similar ED50 in the antagonism of amphetamine-induced stereotypies by savoxepine given i.p., s.c. or p.o. Savoxepine exhibited also un unusual long duration of action. Apomorphine climbing was still antagonized by more than 50% 24 h after 1 mg/kg i.p. savoxepine. At a dose of 2 mg/kg s.c., it produced still 30 % antagonism of apomorphine-induced stereotypies 72 h after injection. Finally, in dogs, the anti-emetic effect of a single injection of 0.i mg/kg s.c. savoxepine lasted for 7-10 days. Savo~epine also antagonized the L-5-HTP-behavioral syndrome (ED50 1.8 mg/kg i.p.) reflecting blockade of central 5-HT2, and possiby 5-HTI receptor subtypes. In conclusion, savoxepine is a strong, and long acting antidopam/nergic agent with a clear-cut dissociation between the potency in antagonizing DA-agonist-induced behaviors and in inducing adverse cataleptic effects. These pharmacological properties are fully in line with the affinities of savoxepine for DA and other neurotransmitter receptors, and its effects on DA turnover. (Bischoff et al., and Baumann et al., this issue). Res. Dept. Pharm. Div. CIBA-GEIGY Ltd. CH 4002 Basel.

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FG5803: A NEW P O T E N T I A L A N T I P S Y C H O T I C C O M P O U N D E. Christensson, A. Bj@rk, B. Gustafsson, G. Pettersson, J. S v a r t e n g r e n and G. A n d e r s s o n The n e u r o p h a r m a c o l o g y of FG5803, a b u t y r o phenone-l-piperazinecarboxamide derivative, has been i n v e s t i g a t e d and c o m p a r e d to h a l o p e r i dol and clozapine using both b e h a v i o u r a l and biochemical test models. FG5803 reduced a m p h e t a m i n e - i n d u c e d hypermotility and e x p l o r a t o r y behaviour. It also showed antiaggressive p r o p e r t i e s and reduced 5-HTPinduced head-twitches. FG5803 did not induce catalepsy and was w e a k in a n t a g o n i z i n g amphetamine-induced stereotypies. Bioehemically, FG5803 was found to have high affinity for 5-HT 2 r e c e p t o r s and w e a k affinity for D 2 and el receptors. F u r t h e r m o r e , the compound increased the d o p a m i n e s y n t h e s i s rate and the ~opamine m e t a b o l i s m in rat limbic forebrain and striatum. FG5803 also i n c r e a s e d the plasma level of e o r t i c o s t e r o n e in the rat, but did not s t i m u l a t e a p r o l o n g e d s e c r e t i o n of prolactin. In conclusion, FG5803 is a p s y c h o t r o p i c drug, which like clozapine and m e l p e r o n e exhibits a spec~flc atypical n e u r o l e p t i c profile. This property of FG5803 t o g e t h e r w i t h its favourable e n d o c r i n o l o g i c a l effects m a k e s it warrantied for clinical studies in schizophrenic patients.

COMPARISON OF ZOTEPINE AND PERAZINE IN SCHIZOPHRENIA

AB Ferrosan, P.O.Box 839,

D e p a r t m e n t of C N S - R e s e a r c h , S-201 80 MALMO, Sweden

Zotepine is a new benzothiepine which blocks DA, NE and 5-HT receptors, resembles chlorpromazine more than haloperidol or pimozide (Puech et a l . , 1987). The unique pharmacological action of zotepine is I. a biphasic effect, 2. effectiveness in both, acute and chronic schizophrenic patients and 3. low incidence on extrapyramidal symptoms (EPS) compared with other neuroleptics (Yamawaki, 1987). The low incidence of EPS is postulated to the strong a n t i serotonergic property of zotepine (Lai et a l . , 1980). Sedation, influence on positive and negative symptoms as well as low incidence on EPS could be confirmed in an open c l i n i c a l study (Dieterle et a l . , 1987). In a double-blind study, zotepine and perazine were compared for c l i n i c a l efficacy, dose-dependent influence or, negative symptoms, influence on EPS and t o l e r a b i l i t y . Methods: Drug administration was o r a l l y for 28 days, with an-~n{tTal dose (150 mg Zotepine or 225 mg perazine) and further on in a f l e x i b l e schedule according to the c l i n i cal requirement. Psychopathometric assessment such as BPRS AMDP, SANS, WEBSTER and SIMPSON were done on days 0 , 3 , 5 , 7 , 14,21 and 28. Results: 39 h o s p i t a l i z e d schizophrenics (group I=zotepine: 20-patients; group II=perazine:19 p a t i e n t s ) diagnosed according ICD=No.9 and DSM I l l were included; in group I , 4 droppe4 out in case of worsening, 3 f u r t h e r in case of marked improvement and discharge. In group I I 6 dropped out in case of worsening and 2 patients q u i t t e d the hospit a l . Diagnosis, mean age and manifestation of i l l n e s s were comparable f o r both groups. In group I I s i g n i f i c a n t more sedative medication was required; a d m i n i s t r a t i o n of b i periden was s i m i l a r in both groups. The r e s u l t s of the psychopathometric scales showed no differences between the groups, however an e a r l i e r improvement in the group I. Psychiatrische K l i n i k der U n i v e r s i t ~ t MUnchen, NuBbaumstrasse 7, D-8000 MUnchen 2

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RILUZOLE IMPROVES NEGATIVE SYMRT~IS IN SCHIZOPHRENIA F. M a i l l a r d * , J.P. Macher**, B. Musch*, J.P. Olie ~ ' * and J.C. Scotto**** Riluzole (2-amino-6trifluoromethoxybenzothiazole, PK 26124 or 54 274 RP) was found to interfere in glutamatergic neurotransmission and to increase slow-wave and REM sleep in rats and cats (cf. poster Stutzmann et al.). F i f t y - t w o patients under neuroleptic treatment and s u f f e r i n g from schizophrenia (DSM I I I c r i t e r i a ) with predominantly negative symptoms p a r t i c i p a t e d in an open p i l o t study. Oral neuroleptics were withdrawn and the p a t i e n t s were submitted to a single drug protocol with r i l u z o l e (50 to 150 m8 per day) during 4 weeks. Patients were assessed by means of the B r i e f P s y c h i a t r i c Rating Scale (BPRS), the Scale for Assessment of Negative Symptoms (SANS), the Hamilton Anxiety Rating Scale (HARS) and the Nurse's Observation Scale f o r I n - p a t i e n t Evaluat i o n (NOSIE) on days D.O - D.8 - D.15 - D.22 - D.29. A c h e c k - l i s t f o r somatic complaints was used on the same days. A f t e r two week treatment with r i l u z o l e a marked improvement of ~he negative symptoms was found e s p e c i a l l y in those with blunted a f f e c t , apathy, h o s t i l i t y and poverty of speech. Extrapyramidal symptoms or other side e f f e c t s were ~ot observed. Durin8 the whole study the l a b o r a t o r y f i n d i n g s remained in the normal range in a l l of the p a t i e n t s . I t is tempting to r e l a t e these c l i n i c a l data to the sleep modulatory e f f e c t observed in animals. The improvement of negative symptoms in schizophrenia with a drug which is not a dopamine antagonist may be considered as a t o t a l l y new approach to the treatment of psychotic disorders. * Rh~ne-Poulenc Sant6, 20, avenue Raymond Aron 92165 Antony Cedex, France ~-~ Centre H o s p i t a l i e r Sp@cialis~, 68250 Rouffach, France H6pital Sainte-Anne, 1 rue Cabanis, 75674 Paris Cedex 14, France ~-~-~*H6pital Sainte-Mar~uerite~ 13277 ~arsei]le France

OPEN RISING DOSE STUDY OF SAVOXEPINE (CGP 19486 A) IN ACUTE SCHIZOPHRENIA: THE PROFILE OF THERAPEUTIC ACTION

340

D. Milovanovic and A. Delini-Stula 1 Savoxepine is a drug of novel tetracyclic structure exerting potent and long-lasting antipsychotic-Like properties in a variety of animal models (Maitre et al. this Congress). The most prominent feature of the drug is, however, its ability to selectively block the D2 receptors in the hippocampus. It was therefore of interest to explore the therapeutic profile of action of this drug in patients suffering from an acute episode of schizophrenia. Ten acutely psychotic patients (5 males, 5 females) aged between 21 and 33 years fulfilling the ICD.9 criteria of schizophrenic disorder were included in the study. After 3 days wash-out period the treatment with 0.1mg/day savoxepine commenced. The dose was gradually increased in the following weeks. The mean daily dose at the end of 4 weeks treatment period was 0.94 mg/day. In all patients an antipsychotic effect was evident after 3-4 days. At the end of the treatment 6 patients were very much or much improved, 3 patients moderately or slightl~ improved, 1 patient did not improve. The initial median total BPRS score of 45 (36-61) decreased by the end of the treatment period to 13 (5-34). The analysis of the ~PRS factors indicated that the regression of thought distOrbances was the most prominent effect. An antianergic effect with amelioration of vital functions was also noteworthy. Few side-effects were observed: sedation (n=2), hypotension (n=2) and general weakness (n=2). Most remarkablyr however, very few EPS were observed: 4 patients showed slight to moderate tremor and 5 slight to moderate rigor. Only 3 patients received antiparkinSon medication. The results of this study indicate rather specific antipsychotic action of savoxepine a_.nd possibly its low EPS potential. Psychiatric Clinic, Faculty of Medicine, 11000 BelgradeiYU 1Clinical Research and Development, CIBA-GEIGY Ltd. Basel/OH.

33.01.44 CLINICAL AND BIOLOGICAL EFFECTS OF SAVOXEPINE (CGP 19486 A), A NEW TETRACYCLIC ANTIPSYCHOTIC DRUG. N. Bohacek, M. Jakovljevic, V. Plavsic, M. Korsic, T. Brataljenovic, A. Delini-Stula I) Savoxepine is a new tetracyclic drug which selectively blocks D2 receptors in the hippocampus and shows potent neuroleptic-like effects in animal experiments. Open clinical studies in acute schizophrenic patients indicated antipsychotic activity of this drug. Apart from this, little is known about other possible biological effects of the drug. Clinical neuroendocrinological, polysomnographic and biochemical investigations could provide some insight into the overall profile of action of the drug. We were therefore interested to study the effects of savoxepine on various hormones, sleep and plstelet 5-HT in schizophrenic patients. Ten acute schizophrenic pattients were included in the study.Plasma TS,T4,TSH,GH,PRE, LH,FSH,cortisol, testosterone, oestradiol, as well as the response to dexamethasone (DST) and the response of PRL, TSH,GH, FSH,LH and TRH-GnRH stimulation were determined before and after the 4 weeks therapy with savoxepine. In addition, platelet 5-HT was measured. An all night polysomnogram was recorded in 5 patients. Therapeutic efficacy of the drug was assessed by BPRS and GCI. The SimpsonAngus Scale was used for assessment of EPS. The mean daily dose of savoxepine was 0.31-0.60 mg. After 4 weeks of treatment 9 patients were considerably improved and I patient was a non-responder. Of 4 previously unresponsive patients to a variety of neuro!eptics, 3 responded favourably to savoxepine. No neuroendocrine or sleep abnormalities specific for schizophrenia were identified. Some appeared to be state-dependent markers and indicators of therapeutic response to savoxepine (DST, TRH-GnRH). In all patients savoxepine showed beneficial effects on sleep disturbances, even though it was given once daily in the morning. ~ p a r t m e n t ofvPsychiatry.School of medicine, University of Zagreb, KispaYi~evs 12, YU-4100 1)Clinical Research & Developm.,CIBA-GEIGY Ltd., CH-Basle

33.01.46 PROPHYLACTIC EFFECTS OF NEUROLEPTICS IN SYMPTOM-FREE SCHI~ OPHRENICS: A COMPARATIVE DOSE-RESPONSE STUDY OF TIMIPERONE AND SULPIRIDE T. Nishikawa r M. T~naka, A: Tsudat I. Koga and Y. Uchid~ Remitted schizophrenic outpatients were treated in order to prevent relapse with three doses of timiperone or sulpiride for 1 year in a double-blind controlled study employing a randomized design. The drug's ability to prevent relapse was evaluated by counting the number of subjects with different outcomes (remission, relapse, Overdose) during the trial and/or the number of symptom-free days for each patient before any sign of relapse or overdose appeared. Patients were randomly assigned to the following drugs orally administered once per day at night: placebo; timiperone 1 mg, 3 mg, 6 mg; sulpiride i00 mg, 300 mg, 600 mg. Se.~um prolactin levels in each patient were estimated by radioimmunoassay. The data from a previous study using haloperido! and propericiazine were utilized as a retrospective placebo group and to compare the characteristics of four drugs for the maintenance treatment of remitted schizophrenic outpatients. Timiperone 3 and 6 mg or sulpiride i00, 300, and 600 mg reduced significantly the number of patients who relapsed compared to the placebo group. Timiperone produced an increased number of signs of overdose relative to sulpiride. Analysis of variance of the number of symptom-free days revealed no significant drug treatment effect. Only sulpiride 600 mg sighificantly prolonged the number of symptom-free days compared to placebo. Prolactin levels were elevated by both timiperone and sulpiride dose-dependently, however a flattening of the prolactin response was found with sulpiride. By comparing the dose-response curve of four drugs tested in the same fashion, haloperidol and sulpiride were superior to propericiazine and timiperone for maintenance treat~.ent of remitted schizophrenic outpatients, from the point of view of having a wider "therapeutic window". Department of Pharmacology, Kurume University School of Medicine, Kurume 830, *Seiwakai Nishikawa Hospital, Hamada 697, Japan

33.01.45 A SINGLE BLIND STUDY OF CLOCAPRAMINE AND S U L P I R I D E IN C H R O N I C S C H I Z O P H R E N I A . S. Y A M A G A M I r N. K I R I I K E A N D K. K A W A G U C H I Therapeutic efficacy and target symptoms with clocapramine dihydrochloride were compared with those of sulpiride by the single blind method in a t o t a l o f 52 c h r o n i c s c h i z o p h r e n i c patients by a d m i n i s t r a t i o n for 8 w e e k s . The final global improvement rating showed no significant difference between the two drugs, but the patients administrered clocapramine appeared to have a more pronounced effect than sulpiride. According to t h e i m p r o v e m e n t r a t i n g s in types of schizophrenia, clocapramine tended to be superior to s u l p i r i d e in disorganized, catatonic and undifferentiated types. In p s y c h o t i c symptoms, clocapramine was superior to sulpir i d e in m o t o r r e t a r d a t i o n , delusion, hallucination and disturbance of self-consciousness, contact (attitude towards other persons), and w o r k or r e c r e a t i o n . While improvement ratio of sulpiride was higher than that with clocapram i n e in m o t o r e x c i t m e n t , t a l k a t i v e , a n x i e t y a n d elation. In addition, frequency of sideeffects was lower with sulpiride than with clocapramine. Drowsiness and constipation occurred more frequently with clocapramine than with sulpiride. Neither side-effect nor abnormal laboratory test results were severe enough to terminate the trials. Clocapramine is t h o u g h t to b e e q u i v a l e n t to s u l p i r i d e in terms of antipsychotic effect in chronic schizophrenia. Department of Neuropsychiatry, Osaka City U n i v e r s i t y M e d i c a l S c h o o l , O s a k a 545, J a p a n

33.01.47 EFFICACY AND TOLERABtLITY OF FLUPHENAZtNE DECANOATE IN ELDERLYSCHIZOPHRENICS MC.Mauri, T.Girardi. B Panetta. A.C.Altamura Neuroleptic treatment in elderly schizophrenic patients dictates caution in ChOOSinga psychopharmacologic agent. The choice is often based on the side-effect profiles of the various agents. 20 elderly schizophrenic in- patients, age ranging from 60 to 73 years, diagnosed as Chronic Schizophrenia according to DSM III were treated with fluphenazine decanoate (FD), 125 mg i.m with repeated administrations (every 21 days) for six months Psychopathological features were assessed by means of BPRS at time 0 and then weekly. At O, 6, 12., 24, 36, 48, 72 hours and 7, 14 and 21 days after each administration, extrapiramidal side-effects were evaluated by means of the EPSE FD was f.ound to be effective in the survey population. The most severe extrabyramidal side-effects occurred within t~he first two days of administration of FD, with a peak,around 36 hrs, possibly related to plasma peak concentrations. The severity of these effects was reduced after the fourth injection indicating a tolerance mechanism during chronic administration. institute of Clinical Psychiatry, University of Milan, Policlinico, Via F.Sforza 35, 20122 Milan, Italy.

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33.01.48

33.01.49

LONG-TE~ ~k~trROLEDAPIC ~ _ OF CHI~NIC SCHIZOPHRENIC PATIL'NTS: CLINICAL AND B I b l I C A L EFFECTS OF WITHDRAWAL K.Kamijim~a, Y.Tsutstmli, S.Murata and T.Mitsuhashi Five p a t i e n t s d e v e l o p e d w i t h d r a w a l symptoms when l o n g - t e r m n e u r o l e p t i c t r e a t m e n t was stopped for seven days in 13 c h r o n i c s c h i z o p h r e nics. G a s t r o i n t e s t i n a l symptoms such as nausea, vomiting, and a n o r e x i a w e r e the p r o m i n e n t w i t h drawal symptoms. Large amount of n e u r o l e p t i c s and a n t i p a r k i n s o nian drugs w e r e r e s p o n s i b l e for the o c c u r r e n ce of w i t h d r a w a l s y m p t o m s . P l a s m a level of prolactin d e c r e a s e d s i g n i f i c a n t l y after 7 days of w i t h d r a w a l and a s i g n i f i c a n t p o s i t i v e c o r r e l a tion was found b e t w e e n basal p r o l a c t i n level and ~ p r o l a c t i n level among the p a t i e n t s w h o m a n i f e s t e d w i t h d r a w a l symptoms. On the contrary, 3 - m e t h o x y - 4 - h y d r o x y p h e n y l g l y c o l ( M H P G ) in plasma, h o m o v a n i l l i c acid(Hl~A) and v a n i l l y l mandelic acid(v~) in urine e l e v a t e d after 7 d a y s . o f w i t h d r a w a l . These data s u g g e s t e d that i n c r e a s e d t u r n o v e r of d o p a m i n e o c c u r r e d after withdrawal. Changes of p l a s m a ?~PG, p r o l a c t i n and other m o n o a m i n e r g i c v a r i a b l e s broke the e q u i l i b r i u m of a u t o n o m i c n e r v o u s system and r e s u l t e d in w i t h d r a w a l symptoms. In our c l i n i c a l practice, we shoud avoid the a b r u p t c e s s a t i o n of n e u r o l e p t i c s and to m i n i mize sy-m~ptoms, a n t i p s y c h o t i c drugs should be tapered gradually, and patients on an a n t i p a r k i n s o n i a n m e d i c a t i o n should c o n t i n u e if for at least a week after the a n t i p s y c h o t i c drug is stopped. Dep.of Reuropsychiatry,KyorinUniv.School of ~dicine 6-20-2 S~hirLka~Mitaka-shiTo~_kyo!8l JAPAN

BRDP OFTHE RATE OF HOSPITALIZATIONS AND RELAPSES IN PSYCHOTIC OUTPAT]ENTS WITH HALOPERIDOL DECANOATE. M. Su~rez Richa~ds; N~ M. Zelaschi About a 50% of psychotic patients f a i l to f o l l o w t h e i r treatment which lead at the reappearance of psychotic condition. The importance of depot neuroleptics on the prevention of relapses and in the reduction the lenght o f the h o s p i t a l i z a t i o n period is also a fact well established. In addition the therapeutic e f f i c i e n c y of haloperidol decanoate (HD) has been proved in several studies, a l t h o u g h % s t i l l scanty know the social aspects related with the i n s e r t i o n of the patient i n t o the community. We have compared the c l i n i c a l evolution of one group the psychotic outpatients with oral treatment (OT) with other one of the same sex and age which was treated wi,th HD, (OT:n=15;M:9,~ age 30.9 - 3.6 - F=6,x age 26.2_ 3,6. HD: n=15;M:7, E age 35,3Z 4.5 - F=8,f age 33.5Z 2.5. sex: x~ = 0.30 NS; age: Mand F together t : 1.5 NS). Both of them were also similars in graveness of the pathology at the s t a r t of the study (BPRS score at week O: OT = 58.9, SD 0.29; HD=54,9, SD 3.2; t : 1,6 NS); the complete ,follow-up period was of 3 years. The OT group showed a higher number of admissions (n=19) than the HD treated patients (n=l). Mann-Whitney t e s t : r = 4.13 ; p< 0.0001. The hi~her rate of h o s p i t a l i z a t i o n s in the OT group woul be imputed a the l a r g e r frecuency of relapses (6 times higher with OT) Mann-Whitney t e s t (adjusted frecuency): ~= 2.73 p< 0.01. 100% of the patients with OT relapsed at l e a s t one time during the study , showing a clearcut difference with the HD group where never appeard signs of relapse in the 73.33% of the cases. Departament of Psychiatry, School of Medicine; La Plata U n i v e r s i t y , Argentine. 17 n~ (1900) La Plata. Argentine.

33.01.50

33.01.51

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~FULTIPLE K~E~SION SYSTEM OF PSYCHOTROPIC DRUGS IN THE TREATmeNT OF SCHIZOPHRENIA l.Das and B.K.Gupta

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In the past few years, some literature reports on the acute psychotic and related illness following sudden withdrawal of long-term treatment of schlzophrenia.Cases of rebound cholinergic supersensitivity as neuroleptic withdrawal behaviour after long-term treatment of schizophrenia have also been reported. As such, in the present study, the multiple emulsion system has been selected as a novel drug delivery system to formulate a suitable dosage form of Trifluoperazine, wherein the rate & amount of drug delivered at the site of action can be sustained or more accurately controlled compared to the conventional dosage forms. In this case, release is designed to follow zero order kinetics to achieve control of therapeutic plasma concentration for prolonged time periods. Thus,. extreme fluctuation in Triflnoperazine plasma levels is avoided, the dose of the drug required to obtain a desired effect is reduced and as a result, the multiple emulsion system finds importance in the longterm tr.eatment and the management of several symptoms of schizophrenia. Since Clozapine is reportedly less prone to precipitate extrapyramidal side-effects and has the abilityto relieve symptoms of tardive dyskinesia,this drug ~as also been formulated in a multiple emulsion system yielding promising results. We have followed the two-step procedure in the formulation of the multiple emulsion(w/o/w & o/w/o). In the w/o/w emulsion, the first step is the preparation of an w/o emulsion and the second stage involves the transformation of this to a w/o/w emulsion by mixing the w/o system with an aqueous continuous phase. In our investigations, we have used sorbitan fatty acid esters as the lipophilic emulsifier in conjunction with a non-ionic surfactant. This drug delivery system holds a great promise in the field of psychopharmacological investigations and treatment. Dept.of Pharmaey,Jadavpur University,Calcutta-32, India

33.01.52

33.01.53

CIPAZO~API~TE - ~TFAP_vP-.ANIDAL S I D E ~ ? E C T S Al~a M i h a ! j e v i ~ , M . J a k o v ! j e v i 6 ~nd M a j a ~ e ! j a Dep ....m~n~ of P s y c h i a t r y , S c h o o l of me ...... . . . .~., . U n i v e r s i t y of Zagreb C I P A Z O X A P I I ~ is a n o v e l ne-;roleptic v h ! : h is claimed ~o have good a n t i p s y c h o t i c . ~ r o } e r t i e s and low e x t r a p y r ~ m i d a l p o t e n t i a l . A n t i ; s y c h o t i c effects are connect@d p r i m a r i l y to t h e i r ability to b l o c k i o p a m i n e r g i c hj-per~ctivity in the hippoc~_mpus ~ d the a s s u m p t i o n that s e l e c t i v i t y of this action p r e d i c t s the absence of extre2yr=~mid&l side effects. ~ r s~ady i n v e s t i g a t e d e x t r a p y r a m i d a l sire effects in two g r o u p s of s h i z o p h r e n i o s treated with c i p a z o ~ a p i n e s~d p h ! u ~ h e n ~ z ~ n e . "'e tried to com~_~e p r e s e n t a t i o n of ~ x t r a p y r a m i d s l side effects in these two g r o u p s . ~ e u s e d two = e t h o d s for r e g i s t r a t i o n side effects:~l. > y the r a t i n g scale for e x t r a p ~ a m ~ d a l side e f f e c t s and 2. b y the e l e c t r o n i c i n s t ~ i m e m t . M e a ~ o r i n g i n s t ~ m e n t s m e a s u r e and ~nalyze side e f f e c t s o b j e c t i v e ! y and ratihg scales are d e p e n d e n t on ~h~ . . . . r a ~~= _ r ' s ~abjeetive judgement.$1e &Iso t r i e ~ to compete the u~'~e~s= .~". . .~ e s e me~.~ods~ ~0~~ the r e g i s t r a t i o n of~ e x t r a p y r a m i d a l side e f f e c t s in clinic?! p r a = ct%ee. Our results i n d i c a t e d that c i p a z o x a p i n e ' s extrap y r a m i d a l p o t e n t i a l had some specific c h ~ a c t e r i stirs comparing to p h l u p h e n a z i n e . Tremor r e g i s t r a t i o n b y e l e c t r o n i c i n s t ~ m e n t s could be ve-~y 6cod for o b s e r v a t i o n of side effects in clinical practice.

33.01.54

S.C. TIWARI, B.B. SETH1, V.P. MAHLA 30 adult chronic schizophrenics, diagnosed according to RDC, were administered Injection HMopericlol decanoate at monthly intervals for a period o~" six months in an open clinical trial. The e-fficacy and side e f f e c t s of the drug were assessed with t h e help of Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression Scale (CGI), Dosage and T r e a t m e n t Emergent Symptoms Scale ( D O T E S ) and Abnormal Involuntary Movement Scale (AIMS). Laboratory investigations were also done in each patient before and a f l e r the trial.The dosage ranged from 50mg-3.q0mg/ month of I/m injection; the majority (70,%) of patient bein'g maintained at week 2# with relatively lo'H dosage of Haloperidol decanoate (l-2ml). There was statistically significant clinical improvement measured on Severity of Illness CG! sub-scale, at week 2/4 in comparison with that at week 0(p/_ 0.01). The s a m e was true for BPRS and its three sub-scale - The Depression Sub-Scale, Thinking Disorder Sub-scale and Anergia Sub-Scale. Significantly less side effects, at week 20 .k 2/4 in comparison to those at week 2, were observed. TD was observed in m;~d form in 3 patients and 19 pat,ents showed other abnormal involuntary movements, albeit in mild to moderate form~. The findings are discussed and it is concluded that haloperidol decanoate iS effective and safe in maintenance therapy of chronic schizophrenics.

33.01.55

SIDE'EFFECTS IN S C H I Z O P H R E N I C PATIENTS U N D E R T R E A T M E N T WITH DEPOT N E U R O L E P T I C UP OF*FOUR YEARS.

HALOPERIDOL DECANOATE IN MAINTENANCE THER.AI'Y OI = CHP.ONIC bCHIZOPI-II~.ENICS

DRUGS:A FOLLOW-

A.Ch~nchj[la;M.Vega;P.Sanchez;F.Lana;L.Jorda;M.Camarero H o s p i t a ~ Ram6n y Cajal. S e r v i c i o de Psiquiatria. MADRID.SPAIN.

25 s c h i z o p h r e n i c patients w h o have undergone treatment w i t h Depot N e u r o l e p t i c s over a period of 4 years were followed.The main side effects and their e v o Z u t i o n ; i n f l u e n c e on the patients' work and social adjustment and n o n c o m p l i a n c e are studied. The most s i g n i f i c a n t results are:e~,trapyramidal d i s t u r b a n c e s are most evident in the first year, d i m i n i s h i n g p r o p o r t i o n a l l y and b e c o m i n g almost i m p e r c e p t i b l e in the last y e a r [ a c u t e dystonic reactions in 32% and tremor in 40%,both during the ffrst y e a r , a n d f i n the fourth year tremor only in the 4%;no cases of T a r ~ i v e ~ D y s k i n e s i a were found~ amenorrhea i n c r e a s i n g a c c o r d i n g to the evolution time up to 2 8 % ; p e r m a n e n t w e i g h t gain in 20 to 24~ dysthymics b e t w e e n 16 and 20%;loss of m o t i v a t i o n m a i n l y in the first year {64%) d e c r e a s i n g in t i me a n d , m a i n t a i n e d subjetive cognitive deficits in 20 to 30%.These were the most common side effects found. N o n c o m p l i a n c e rate was b e t w e e n 4 to 8%. The results are clinically c o r r e l a t e d with the syndromic form, s y m p t o m s , p e r s o n a l and family history of p s y c h i a t r i c disorders and with the type of Depot N e u r o l e p t i e used.

RELATI(iN~IP B ~ l q KXTRAPYRAMIDAL SYMFIDMS AND SERUM ANTICHOLINERGIC LEVELS IN C}IRONIC SCHIZOPI~R~qICS. SOM D. SONI, J. S. BAMRAH, JANET KRSKA. Psychiatric Research Department, Hope and Prestwich Hospitals, Salford, M6 8HD. The neuroleptic induced extrapyramidal symptoms can be relieved by anticholinergic agents, such as procyclidine. In clinical practice, the effect of such agents is monitored with gradual, sequential increases in the dosage until the desired therapeutic response is obtained. Based on an iK~A assay method, we have earlier reported an inverse correlation between serum AnCh and the presence or absence of EPS in treated chronic schizophrenics (B~mrah et al 1986). We have now systeratically investigated various relationships that might affect serua AnCh and neuroleptic induced EPS. Sixty Nine chronic schizophrenics %~o had been stabilised on a single neuroleptic at a fixed dose for over 6 monYhs and a single anticholinergic, prescribed for EPS, for a minimt~, of 4 weeks participated in the study. Serum neuroleptic and anticholinergic levels were measured by the P~I method. The patients were also rated on the Extrapyramidal symptom. Serum anticholinergic levels showed a significant inverse correlation with ~ S but did not appear to be dose related in any of the three anticholinergic drug groups. Percentage binding to proteins was significantly less with benztropine than either benzhexol or procyclidine. Serum free antichoiinergic levels correlated significantly with total serum levels in the benzhexol and procyclidine groups but not in the benztropine group. At senlm levels above 4.5 pmoles/ml atropine equivalents, EPS was significantly less than at levels Oelow that. We discuss the implications of this finding and suggest clinical applications of measurement of serum anticholinergic levels.

343

33.01.56

33.01.57

PLASMA DETERMINATION OF REDUCED HALOPERIDOL AND ITS RELEVANCE TO CL!NICAL OUTCOME IN SCHIZOPHRENIA A.C.Altamura, M C Mauri, R.Cavaltaro, S.Bareggi Although haloperidol (HL) is probably the most widely used neuroleptic, few studies have attempted to quantitate its active metaboh~e, reduced haloperidol (RHL), evaluating its clinical signihcance HL, RHL plasma levels and RHL/HL ratio were studied in 36 schizophrenic ~rl-~atients diagnosed according to DSM Ill and treated with HL (5-21 mg daily; mean 12.34 + 0.70) for six weeks. Clinical outcome, extrapyramidal and antichotinergic sideeffects were evaiuated by BPRS, EPSE and ACS at time 0 (basal values), i (3rd week) and 2 (6th week). Plasma determination of HL and RHL were made at time 2 by both liqLlid-chromatographic and mass-spectrometry electron impact a~_says. After three weeks of treatment there was no correlation between'HL, RHL oiasma level or RHL/HL ratio and clinical outcome (evalua~.eO as % of amelioration at BPRS). But there was a negative correlation between RHL plasma !evel$ or RHL/HL and clinical improvement after s~x weeks of treatment. No correlation was found between HL, RHL plasma levels and side-effects The results of ,ms study are consistent w i t h the hyDothesis that RHL makes a significant contribution to chnlcat outcome in sch~z0pnremc DaQents could have a Dred]ctlve value on the c;m~cal response to HL t r e a t m e n t institute of Ci~n',cai Psychiatry, University of Milan, D0l]climC0, Via F Sfcrza 35, 20!22 Milan, I t a l y

NESSUREMENT OF HALOPERIDOL PLASNA-LEVELS: A TOOLE TO OPTINIZE NEUROLEPTIC TREATNENT K. Meszaros, G. SchOnbeck, W. S i e q h a r t , H. Aschauer, A. Bu#neq

33.01.58

33.01.59

EFFECTS OF MIANSERIN ON NEGATIVE SYMPTOMSIN SCHIZOPHRENIA Y. Mizuki, N. Kajimura, M. Yamada, ~. Tanaka and K. Inanaga The efficacy of mianserin as a supolement in t r e a t i n g chronic schizophrenics was tested by monitoring the Brief Psychiatric Rating Scale (BPRS) and the monoamine metabol i t e s in plasma (HVA, MHPGand 5-HIAA). Twenty inpatients with schizophrenia were administered fixed doses of neuroleptics during the study. A control BPRS scoring and blood drawing from the venosus mediana were done before mianserin administration. The fixed doses of 60 mg/day of mianserin for 2 weeks and the f l e x i b l e doses for 4 weeks were given o r a l l y in an open t r i a l f o r 6 consecutive weeks, and no treatment followed for I week. BPRS scoring was carried out once weekly, and blood samples were obtained a f t e r mianserin treatment. The concentration of HVA, MHPGand 5-HIAA was measured by high-performance l i q u i d chromatography (HPLC). The t o t a l BPRS scores decreased by mianserin administration as compared with the control values. In each item, scores for anxiety, emotional withdrawal and motor r e t a r dation decreased as compared with control values, respect i v e l y . In c l i n i c a l l y , mianserin treatment ameliorated clearly the negative symptoms in 11 patients out of 20 schizophrenics. The HVA and 5-HIAA concentrations a f t e r mianserim treatment in the patients who showed improvement pf t h e i r c l i n i c a l symptoms increased as compared with the control values, however, the MHPGcontents in this group indicated no s i g n i f i c a n t differences as compared to control values. Laboratory findings did not reveal any abnormalities. These results suggest that the negative symptoms of schizophrenia are o a r t l y improved by mianserin treatment, and that the DAnergic and 5-HTnergic neuronal a c t i v i t i e s might play a role in the amelioration of some negative symptoms. Dept. of Neuropsychiatry, Yamaguchi University School of Medicine, 1144 Kogushi, Ube 755, Japan

344

I t has been shown t h a t t r e a t m e n t w i t h h a l o p e r i d o l can be o p t i m i z e d by t a k i n g i n t o cons i d e r a t i o n h a l o p e r i d o l p l a s m a - l e v e l s (HPL) i n a d d i t i o n t o dose. E s p e c i a l l y i n p a t i e n t s w i t h poor t r e a t m e n t response a n d / o r i n t o l e r a b l e s i d e e f f e c t s , HPL-messurement r e v e a l e d e i t h e r a t o h i g h o r a t o low l e v e l a c c o r d i n g t o t h e h y p o t h e s i s o f a " t h e r a p e u t i c window" ( 1 ) . To t e s t t h i s h y p o t h e s i s i n d a i l y r o u t i n e o f psychiatric i n p a t i e n t c a r e , a s t u d y has been performed with a possibility to adjust daily haloperidol dose a c c o r d i n g t o p l a s m a - l e v e l s i n poor r e s p o n d e r s . Recovery has been d e f i n e d as a 30 % a m e l i o r a t i o n i n BPR8, RIA-Assay has been used f o r HPL messurement. Diagnostics according to D S M ~ I I I have been p e r f o r m e d . The h y p o t h e s i s o f a " t h e r a p e u t i c window"could be c o n f i r m e d i n 146 p a t i e n t s , i.e. signific a n t l y more p a t i e n t s r e c o v e r e d when HPL have been i n t h e range o f t h e p o s t u l a t e d 16-27 ng/ml

after

adjustment

of dose.

Literature: 1) Plasma c o n c e n t r a t i o n o f h a l o p e r i d o t and prolactin in acutely psychotic patients. Aschauer H . , et al ( P h a r m a c o p s y c h i a t r y , in p r e s s ) . Psychiatrische UniversiC~tsklinik Wien, W6hringer GOrtel 18-20. A-1090 Wien

CLUZAPINE iN THE THEATMENT OF NEGATIVL bYMPTOM~ IN SCHIZOPHRENAA V. R. Paunovic t M. M. 3a~ovic-Ga~ic~

M. R~ Bo~danovic and S. 0. Totir There is some evidence that clozapine, a dibsnzodiazepine, is superior to standard neuroleptics for the treatment of nearly all categories of schizophrenic symptoms. The results of numerous studies~ concerning this matterj demonstrata this superiority~ particularly in diminishing emotional withdrawal and blunted affect, that are considered as negative schizophrenic symptoms (A. J. Gelenberg, 3. C. poller, 3. Clin. Psychiatry 40, 23B-240, Ig?g). However, studies of E. Guirguis e t a l . (Curt. Therapeutic Has. 21, 707-719, lg7?) reported that clozapine and chlorpromazine had similar efficacy in treating negative symptoms. This study deals with the effects of clozapine and haloperidol for the treatment of schizophrenic syndrome with prevailing negative symptoms. Two statistically homogenous groups of male schizophrenic in-patients, defined by the RDC, with prevailing negative symptoms, were randomly assigned to clozapine ~at median doses 200-250 mg per dayJ or haloperiOol (at median doses 20-40 mg per dayJ for a 6-week p~riod. Clinical assesment was done on the 1st day of addmission and at the end of the 3 and 6 weeks of treat. men,, with the Brief Psychiatric Bating ~cale ~BPRS) and the Positive and Negative Symptom Scale (PANSS). Reduction in th~ negative schizophrenic symptoms was noted in both groups, particularly in diminishing emotional withdrawal, blunted affect and motor retardation, but clozapine was superior to haloperidol by its efficacy and by the patients subjective report of the improvement. The results are discussed in the light of specific action of clozapine on the mesolimbic dopaminergic system and its interaction with the serotonergic and alphl-adrenergic neurotransmission. Department of Psychiatry, ~chool of Medicine, Clinical Center, University of Belgrade, Pas~erova 2, ii000 Beograd Yugoslavia

33.01.60 CL!~ICAL ~-~ALUATION OF CLOZAP!~TE T~ET[',~T IN MEN T ~ DISORDERS A. KIEJNA Clozapine is a neuroleptic differing from the hitherto known ones b y chemical structure, mechanism of action and absence of typical side effects. !t ez~ibits a strong antipsychotic effect, however fraught with a risk of undesired effects, esq?eoial!y of haematolegie ones, which requires further observations of the drug. In our study a ouestionnaire m e t h o d ~.ras used to collect an~mnestie and clinical data from 111 clozapine treated patients. The examined group consisted of 76 women and 35 men, mostly with the diagnosis of long l a s t i n g h i s t o r y of schizophrenia. In 65% of them clozaoine was used with lacking improvement and after other n e u r o l e p t i c ~ Oral and parenteral routes were adopted with divided doses, some patients received a single night dose. ~ e mean initial, as well as maintaining doses w a s 190 mg daily, the maximal doses amounted to 350 mg daily (from 25 to 800 mg) was aonlied on average for 27 days. ~-k~ll remission w a s obtained in 22.5% patients, a satisfactory improvement in 34.2%, slight improvement in 22.5%, no improvement in I~% and deterioration in 2.~%. A m o n ~ the most frequent side e f f e c t s and complications there were: hypersalivation in 3T%, hypersomnia in 5 ~o, ~ , hypotonia in 10. 8,o, hyperthermia in ~.3%,~ exogenous syndromes in 3.6,o~ and gastric symptomes in 2.7% of the patients. Two patients with mania mhowed an inversion into depressive phase; leukopenia occured in 10.0% of patients. The results obtained were evaluated statistically Department of Psychiatry, Medical Academy, 50-229 ~roclaw, Kraszewskiego 25, Poland

33.01.62 R E S U L T S OF THE LONG-T.~R~ TREATI~ENT WITH CLOZAPINE. CLINICAL A]~ E L E C T R O ~ C E P H A L O G P ~ & P H I C STL~Y H.Hanu~, M . Z a o l e t ~ l e k , V . K u S e r a and ~ . K u b a C l o z a p i n e is an efficient n e u r o l e p t i c d r u g , that has a marked a n t i p s y c h o t i c effect and only a scarce incidence of side effects. The purpose of our study is the clinical and EEG assessment of a group of patients on the l o n g - t e r m clozapine treatment. At our clinic there have been 30 patients on a long-term therapy. I n some of them the treatment had been finished for a full adjustment of their state, in some others it had to be broken off for other reasons than a relapse or a side effect; in others the therapy was substituted by other m e d i c a t i o n after a relapse. We a s s e s s e d also a group of 12 schizophrenic patients, who were t r e a t e d v~th clozaoine for l0 years in average (range l~14 y e a r s , ' m e d i a n lO years). I n the course of the treatment with clozapine there were maintained good remissions of the psychosis. There were no serious side e f f e c t s . I n one p a t i e n t we have seen a transitory leu_kopenia. D u r i n g the l o n g i t u d i n a l EEG r e c o r d i n g only one patient had completely normal EEG. All the other patients h a d g e n e r a l i z e d mild changes or dysr~ytmic changes of the recordings. Nine patients had their visual evoked p o t e n t i a l s examined. It was s u r p r i s i n g to find shorter lat e n c y of the evoked response in c o m p a r i s o n to n o r m a l recordings. There was no sign of the l a t e n c y p r o l o n g a t i o n as described a f t e r other n e u r o l e p t i c drugs. Psychiatric C l i n i c , 5 0 0 36 Hradec K r ~ l o v 4 , ~ S S R

33.01.61 CLOZAPINE PLASMA LEI~LS D E T E R M I N E D BY HPLC AN~ UV-DETECTION Ch.Humpel, C h . H a r i n ~ B.Auer. A.Saria, Ch.Barnas? W . F ] e i s c h h a e k e r T H . H i n t e r h u h e r For highest selectivity of measurement of c]ozapine (S-chloro-ll-(4"-methy])-piperazino-5 dibenzo(b,e)(1,4)-diazepine) ~n p l a s m a a t h r e e step extraction procedure was developed. This Drocedure invo]ved a pre-extraction of the acidified plasma to eliminate acidic and uncharged organic contaminations. C]ozapine was extracted by two treatments of the alkaline plasma with n-hexane. The average recovery rate of c]ozapine from plasma was 61.7 + 6.~r To compensate for irreproducible losses during the complicated extraction-procedure fluphenazine was used as interna] standard. Recovery of f]uphenazine was found to be similar to that of clozapine. (56.1 + 14.5~). These results could be confirmed by ~xtraction with radioactive f]uphenazine. Reversed Phase (octy] silica; 5 ~ m , p o r e s i z e 10 rim) h i g h p e r f o r m a n c e liquid chromategraphy was carried out with a singlepiston-pump. The chosen e]uent (10~ water, 90g acetonitrile, 0 . 2 5 mM a m m o n i u m a c e t a t e ) and the f]ow rate o f 0 . 5 m] p e r m f n u t e p r o v i d e d optimml separation from plasma. For absorbance ~easurements a [W-detector (f~lter 2 5 4 nm) w a s used. Ouantification was performed by integration of peak area and peak height measurement. Although the capacity of the detector was not fully exhausted, the lower detection limit was 5 ng/m], d e m o n s t r a t i n g the high sensitivity of this method. U n i v e r s J t i t s k ] i n i k fiir Psychiatrie, Neurechemisches Labor. AnichstraBe 35, A-6020 Innsbruck. Austria.

33.01.63 UNSUSPECTED INTRACEREBRAL PATHOLOGY IN OLDER SCHIZOPHRENICS W~_~-_Hoff~an~ M. Burry, and D. E. Casey Evaluation of patients for extrapyramidal syndromes (EPS), such as tardive dyskinesia (TD) and drug-induced parkinsonism (DIP), can be complicated by the presence of other conditions which cause or exacerbate EPS. Twenty-six schizophrenic patients over age 55 underwent non-contrast computed tomographic (CT) evaluation as part of an examination of EPS in older schizophrenics. Patients with a previous diagnosis of stroke were excluded. TD and DIP were rated on the Abnormal Involuntary Movement Scale and the Sct. Hans Rating Scale for Extrapyramidal Syndromes, respectively. The CT scans were read by a neuroradiologist who was blind to patient identity and clinical data. Presence of stroke was rated on a 0 to 3 scale (none, questionable, probable, and definite). Eleven patients (42%) were rated as none, 7 (274) as questionable, 4 (154) as probable, and 4 (154) as definite. In addition, one patient was found to have'idiopathic basal ganglia calcification. There was no significant difference in either AIMS or Sot. Hans scores between the patients with strokes (probable or definite) and those without (none or questionable). A patient with a large, left hemisphere lesion involving the lenzicular nucleus also had severe right sided hemi-parkinsonism. The patient with basal ganglia calcification had moderately severe orofacial dyskinesia which persisted despite discontinuation of neuroleptics. These older schizophrenics had a high prevalence of unsuspected intracerebral pathology. In two cases, ~his pathology contributed to the severity of EPS. Implications of %hose findings for research and clinical practice will be discussed.

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FRONTAL DYSFUNCTION AND SCHIZOPHRENIA T. K o j i m a * , H. A n d o * , E. M a t s u s h i m a * ~ K. A n d o * ~ R. T a k a h a s h i * a n d Y. S h i m a z o n o . * * Our e a r l i e r s t u d i e s w i t h the e y e c a m e r a m e t h o d indicated that chronic schizophrenic patients with negative symptoms have dysfunction of the visual perception process. Furthermore, our previous study on schizophrenics and patients with frontal lobe lesions using an eye camera and maze tasks s u g g e s t e d t h a t s c h i z o p h r e n i a is n o t p r o d u c e d by a frontal lobe lesion alone, but by a frontal lobe lesion in a setting of more extensive cerebral dysfunction such as limbic system, thalamic nuclei and association areas. From how schizophrenics l o o k e d at the last b l i n d a l l e y in m a z e , they were classified into two groups, the p e r p l e x t y p e a n d the h a p h a z a r d t y p e . The- f o r m e r w a s a p a t i e n t g r o u p t h a t v i e w e d the last blind alley several times and took longer times before starting drawing. This type was seemed to b e c o n f u s e d and poor to u t i l i z e ' a cue. The latter was a patient group that started drawing without caution and viewed the last blind alley for the f i r s t t i m e while drawing near the b l i n d a l l e y . This type indicated an impairment in p l a n n i n g and p r o g r a m m i n g and a p o v e r t y o f the a b i l i t y to l o o k f o w a r d . The correlation b e t w e e n o u r two t y p e s a n d CT findings, maze performances, psychological tests, IQ score, drug dosis and clinical features w i l l b e d i s c u s s e d on 37 schizophrenic s u b j e c t s d i a g n o s e d a c c o r d i n g to D S M - I I I . *Dept. of Neuropsychiatry, Tokyo Medical and Dental Univ. 1-5-45, Yushima, Bunkyo-ku Tokyo 113, JAPAN, * * N a t i o n a l C e n t e r o f N e u r o l o g y and Psychiatry, 4-1-1, Ogawahigashicyo, Kodaira-shi, T o k y o 187, J A P A N

FRONTAL AND TEMPORO-HIPPOCAMPAL I M P A I R M E N T IN SCHIZOPHRENIA: NEUROPSYCHOLOGICAL CORRELATES A. Mucci, S. G a l d e r i s i , M. R. S o l l a , A. G i a c c o and M. Maj. Several neuropsychological investigations have shown an impairment of performance in schizophrenic patients in tests involving frontal and temporo-limbic functions. It is s t i l l c o n t r o v e r s i a l , h o w e v e r , if t h i s f i n d i n g is r e l a t e d to a left h e m i s p h e r e or to a bilateral dysfunction. The p r e s e n t s t u d y w a s d e s i g n e d to clarify this issue by using a neuropsychological test battery in a sample of 13 male DSM IIl s c h i z o p h r e n i c s a n d 14 matched healthy controls. The fronto-hippocampal functioning was evaluated by means of the S p a t i a l C o n d i t i o n a l Associative Learning task (SCAL), the Non Spatial Conditional Associative Learning task (NSCAL), and the Self-Ordering Pointing Task (SOP) for h i g h imagery words and for a b s t r a c t drawings. The temporoThippocampal functioning was tested by u s i n g the H e b b ' s Recurring Digit task (HRD) and the Corsi's Block Tapping task (CBT). The performance of schizophrenics was significantly impaired with respect to n o r m a l c o n t~-ols for both SCAL and NSCAL. On SOP, patients performed significantly worse than n o r m a l s for the " h i g h i m a g e r y w o r d s " . As to the tests for the temporo-hippocampal functioning, the CBT did not detect Oifferences between patients and controls. On HRD, the performance of schizophrenics was significantly poorer than that of normals. These results suggest a bilateral frontal lobe dysfunction and a left temporo-hippocampal impairment. Department of Medical Psychology and Psychiatry, First Medical School, University of Naples, Italy.

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ERPABNORMALITIES IN S C H I Z O P H R E N I A : RELATIONSHIP TO P O S I T I V E A N D N E G A T I V E S Y M P T O M S . S. Galderisi, M. R. Di G r e g o r i o , N. De M a r c h i , G. I o n t a and M. Maj. A reduction of the L a t e P o s i t i v e C o m p l e x (LPC) has been reported by some authors in s c h i z o p h r e n i a and r e I a t e d to a d y s f u n c t i o n of the l i m b i c s y s t e m . T h e p r e s e n t s t u d y w a s c a r r i e d out in 14 m a l e d r u g - f r e e D S M Ill s c h i z o p h r e n i c s and in 19 matched healthy controls. Event-Related Potentials (ERPs) and reaction t i m e (RT) w e r e r e c o r d e d b y u s i n g a v i s u a l t a r g e t d e t e c t i o n p a r a d i g m in w h i c h c o n s o n a n t p a i r s w e r e p r e s e n t e d c e n t r a l i y a n d to t h e r i g h t (RVF) or to the left (LVF) visual field. In the c e n t r a l condition, the L P C p e a k a m p l i t u d e w a s l o w e r in schizophrenics t h a n in c o n t r o l s and i n v e r s e l y correlated with the global score on Andreasen's s c a l e for negative symptoms. For the lateral c o n d i t i o Q , the L P C p e a k a m p l i t u d e w a s h i g h e r f o r R V F t h a n for L V F s t i m u l i in n o r m a l s , w h e r e a s in s c h i z o p h r e n i c s no v i s u a l f i e l d e f f e c t was found for t h i s component. In contrast, S W and P 3 2 0 amplitudes were higher for L V F than for R V F s t i m u l i in s c h i z o p h r e n i c s and d i d not show any visual field effect in normals. M o r e o v e r , in schizophrenics, SW and P320 scores for LVF stimuli were positively correlated with global score on CPRS positive symptoms. As to behavioural data, faster responses were observed in c o n t r o l s for R V F stimuli, while no v i s u a l f i e l d e f f e c t w a s d e t e c t e d in s c h i z o p h r e n i c s . These data support the existence of LPC abnormalities in schizophrenia whose patterns, however, seem~ to b e d i f f e r e n t d e p e n d i n g o n the p r e d o m i n a n c e o f p o s i t i v e and n e g a t i v e s y m p t o m s .

INCREASED SACCADIC DISTRACTIBILITY IN TARDIVE DYSKINESIA (TD): A PUTATIVE GABAERGIC MECHANISM G.K. Thaker~ J.A. Nguyen~ B. Buchanan and C.A. Tammin6a An abnormality of basal ganglia GABAergie effents has been hypothesized to play a role in pathophysiology of TD. Dysruption of these nigrotectal neurons produces increased saccadic distractibility in monkey. We studied the control of saccades in schizophrenics with and without TD. Results from our first study show a two-fold increase in saccadic distractibility in TD compared to non-TD schizophrenics thus suggesting a decrease in nigrotectal GABAergic transmission in TD. A second set of studies were carried out in our laboratory to further evaluate the saccadic control in schizophrenic patients with and without TD and its relationship with the smooth pursuit eye movement (SPEM) performance. Method: Thirty-two schizophrenic patients (20 with TDI participated in different eye movements: saccade (look at the target jump), anti-saccade (look away from the target jump), fixation (fixate the gaze in presence and absence of fixation light) and SPEM (follow,a target with a sinusoidal motion, 0.5 hz). Infra-red technique was used. Results replicated our initial finding of a two-fold increase in saccadic distractibility in TD patients competed to the non-TO patients. Multiple regression analysis revealed that saccadic distractibility was the only oculomotor measure significantly associated with TD (partial r:0.59); other measures including SPEM score showed negligible correlations with TD score. SPEM score, however, was significantly associated with other non-localizing neurological deficits. In conclusion, we observed a distinct oculomotor abnormality (i.e. increased saccadic distractibility) associated with TD in schizophrenic patients. We hypothesize that this abnormality is secondary to the previous chronic neuroleptic treatment and consequent changes in basal ganglia GABA function. Maryland Psychiatric Research Center, P0B 21247, BaLtimore, ~ 2]228, USA

Department of Medical Psychology and Psychiatry, First Medical School, University of Naples, Italy.

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EN~NTIOMERS OF 3-PPP SUPPRESS NEUROLEPTIC-INDUCED PERSISTENT ABNORMAL MOVEmeNTS IN CEBUS APELLA MONKEYS D. Clark*, P. LeWitt and B. Kovacic Following withdrawal from long-term administration of neuroleptic agents, Cebus Apella monkeys can display various persistent abnormal movements (PAM). These movements, which resemble human dyskinesias, are temporarily alleviated by neuroleptic agents but this is accompanied by Parkinsonian-like symptoms. We have recently investigated the effect of the enantiomers of the dopamine (DA) agonist 3-PPP (0.5-8.0 mg/kg) in three Cebus Apella monkeys with PAM induced by withdrawal from longterm administration of fluphenazine. (-)-3-PPP temporarily abolished the PAM in two monkeys without producing any Parkinsonian-like symptoms. One of these monkeys was also tested with (+)-3-PPP; a dose-dependent alleviation of PAM was observed. A biphasic reaction was apparent during the time that PAM were abolished by the highest drug dose. The animal initially showed amphetamine~like stimulation, followed by a period free of PAM and motor stimulatory effects. Neither enantiomer of 3-PPP reduced PAM in the third monkey. (+)-3-PPP produced hyperkinesia and tongue protrusions when the monkey was in a restraining chair, but not when tested in the home cage. These findings confirm the earlier work of Baggatrom and colleagues that the 3-PPP enantiomers can reduce neuroleptic-induced PAM in monkeys, an effect which is likely related (at least in part) to their ability to reduce DA function by stimulating DA autoreceptors. The amphetamine-like symptoms produced by (+)-3-PPP are probably mediated by stimulation of postynaptic DA receptors. The present work supports the contention that (-)-3-PPP and drugs with a similar pharmacological profile might be effective as symptomatic treatments for tardive dyskinesia, with little chance of inducing acute extrapyramidal dysfunction. Dept. Neurology, Lafayette Clinic, Wayne State University School of Medicine, Detroit, U.S.A., and *Neuropsychopharmacology Lab., Dept. Psychology, University of Reading, U.K.

MORTALITY RATE IN SCHIZOPHRENICS WITH TARDIVE DYSKINESIA M.Takamlya, G.Yagi, M.Kamisada, S.Kanba, A.Tanoue, K.KamizLma, T.Suzuki, S.Kaizawa, F.Saito We exsb~,.1.~,~mortality rate in between schizophrenics with (n=63) end wzthout(n=75;age and sex matched controls) tardive dyskinesia(TD), during the average of I 0 years. Relationshlp was also examined between the mortality rate and the clinical variables. The TD grsup had a significantly higher mortality rate (41%), as compared with the control group(20%, p<.05). The average of s'~u~vival years from the beginning of the investigation in the deceased patients of the TD group(~6 years ) was shor-_er than that in the control group(~7 years). The mortal'_ty rate in the TD group was not related to any of the clinical variables such as severity and clinical course of UD, presence of physical complications, duration and course of pharmacotherapy, etc. In the female TD group , the deceased patients were significantly older than the surviving patients when antipsychotics were first given as well as TD appeard. A prevalence rate of hypertension was alsc higher in the former group. When c~-,,p, ared causes of death, we found that respiratory and cerebrovescular diseases were more predominant in the TD group[the fermer;5vs3, the latter;4vsl ). The.,org~nzc fragirity which may exist in the TD patients, especialiy in ~he females, was discussed.

t~tal

T. Inada. K. 0hnishi, M. Kamisada. S. Nakajisa. S. Kanbe, ~. Takamiya, K. Kamijima. 6. Yagi Recent tardJve dyskinesia studies have moved from c l a s s i c a l orofacial dyskinesia to subtyping of clinical variants such as limb dyskinesia, dystonia, akathisia, and so forth. We examined prevalence of involuntary movements in psychiatric patients between Oct. through Dec. in 1987. The sub,ants comprised 706 inpatients and 49 outpatients, who received psychiatric therapy for at least one year at Sakuragaoka mental hospital in Tokyo. The clinical diagnoses of the patients included schizophrenia (n=~43), mental retardation (n=64), epilepsy r

and so forth.

Ye identified tardive dyskinesia in ]45 patients. Ten variants of tard/ve dyskinesia could be distinguished: classical oro-facial dyskinesia (]4.8~), limb dyskinesia (2.1%), trunk dyskinesia (0.~'. respiratory dyskinesia (0.3~), dystonia (0.9~), akathisia (0.~.Tourette llke syndrome (0.]~), rabbit syndrome (2.0~), ,yen]orms (].7~), choreoathetosis (0.7~). ~e found similar prevalences of tardive dyskinesia variants in Japan and the West, despite cross-cultural differences in psychiatric practice.

Dept. ~europsychiatry, Keio [niv. Med. School. 35 Shinanomachi, Shisjuku-ku, Tokyo, 160, Japan.

33.01.71

33.01.70

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PR_~'_I~E OF TARDIVE DYSKI~SL~ VARIANTS IN JAPAN

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ANALOGICAL TESTS AND PSYCHOTIC DISORDERS. L.Bourrelly, M. Ohayon The authors present the ciinicai stage of a research program about tre mooel]zation of normal and Psychotic analogical processing. The cognitive abilities of psychotic patients are always grossly upset, t~ougn IO .s often subnormal. Thought disturbances are more obvious Ouring r e actwe phases than in remissions. Our hypothesis is that analogical reasoning is the basis of cognition and learrang: on the ground of me likeness of a new object with something a reaoy ,~nown, one will put it mto the same ctass. Finding differential proderties will ~ead to more class links. Language is involved in this process, as it provioes "pointers" :o ctasses, and ready-made object and class links. Therefore, the authors built, a set of "analogical puzzles", designed as fa}~mvs: Ill ",4" becomes "B", what about "C'? Are you pleased with your ansv,,er ~ A/B conversion and A/C likeness may be graphical, semantic, or a biend of both. :-he answer patterns elicit the ability in: 1) finding out implicit AfB convers=on ru,es, 2) applying them to "C'. 3)managing compromises between cons'u'au'Tm, 4) estimating one's work. The rating includes 3 stages: 1) is the C/D conversion analogous In A/B c~,'wers=on according to the imolicit rules?, 2) which kind of transformation was orionsad?, 3) is the auto-valuation accurate? Psychotic patients usually find out a C/D link disregarding A/B and their autovaluation takes no account of the value of the analogy. It seems It-~atthe ma~ dis~rbance is in the lack of reliability of the )udgment about their own proOuctions. The result Is that not only their analogies are Inadequate, but also that t[3ey applle them as a knowledge. The nevrotic or depressive Patients make correct analogies. In depression, the auto-valuation is usually low, obsessionals often choose the graphical ru~es while hysterics stress the seman~c associations. The Dsychotic disturbances are permanent, even dunng remissions. The pseudo Tudng test (test-based diagnosis/clin~.al diagnosis) is s'Jiking~y accurate, and was able to detect genuine psychotic patients in our "normal" sample. Laboratoire de Tra~tement des Connaiss&nces, CHU Sainte-Marguerqe. 270, Bou!evard de ate-Marguerite, 13009-Marseille (FRANCE)

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A S T U D Y OF R A B B I T S Y N D R O M E : F O C U S S I N G ON T H E L I N G U A L C O M P O N E N T A N D S L E E P EEG C R I T E R I A Utpel GoswamI, R. S u n d a r a r a i a n , B.N. G a n ~ a d h a r , P. Satish Chandra S.M. C b a n n a b a s a v a n n a , E. Frecska, M. A r a t o and A ndras P e r e n y i In !972, Villeneuve first coined the term " R a b b i t S y n d r o m e " to describe a tardive, neuroleptic-induced hyperkinetic syndrome c h a r a c t e r i s e d by r h y t h m i c , 5 to 5.5 Hz i n v o l u n t a r y movements of the perioral and m e s t i c a t o r y musculature resembling the c h e w i n g m o v e m e n t s of a r a b b i t . Later 5ovner and DiMaseio (1977), 3us et el. ( 1 9 7 9 ) and Todd et el. (1985) c o n f i r m e d that the syndrome reversed with anticholinergic challenge and/or neuroleptic withdrawal. The Canadian investigators proposed two other features as the integral part of this syndrome - (i) sparing of the tongue and (ii) persistence in sleep - t h r o u g h o u t the stage [ NREM sleep until the onset of stage I] N R E M . During the .past 8 years, w o r k i n g in f o u r c e n t r e s , 11 cases of Rabbit Syndrome were i d e n t i f i e d , of which seven patients consented for the present study. A f t e r 3 days of h a b i t u a t i o n in the sleep EEG lab, spontaneous night sleep E E G was done on . day 4, in a d d i t i o n to polygraphic recordings of labial and lingual m o v e m e n t s . The records were blindly end independently e v a l u a t e d by t w o authors with standard staging procedure by Kales and R e c h t s c h a f f e n . Except for on,e p a t i e n t , the 5.5 Hz movements disappeared with the onset of stage I NREM and not stage [I NREM as was c l a i m e d by the Canadian group. Also 5 of the seven subjects showed definite presence of a lingual c o m p o n e n t synchronus with periorel-masticetory movements. The syndrome subsided with intravenous promethazine c h a l l e n g e , temporarily. It naturally follows that the syndrome is neither tongue-sparing nor does it persist in s l e e p . a s s t a t e d e a r l i e r . J s w s h s r l a ] Institute of P o s t g r a d u a t e M e d i c a l E d u c a t i o n and Research, P o n d i c h e r r y - 6 O S 0 0 6 ; N I M H A N S , Bangalore; C M C , Vellore, I N D I A end N a t i o n a l I n s t i t u t e f o r Nervous and Mental Diseases, 1281 Budapest 27, Pf 1, H U N G A R Y .

33.01.74 RISPERIDONE VERSUS HALOPERIDOL IN SCHIZOPHRENIC PATIENTS : A 12 WEEK CENTER DOUBLE-BLIND PARALLEL STUDY.

CHRONIC MULTI-

Cuvper H_. Malfroid H.. Peuske~s J.. Bo!l~n J. and Eneman M. Risperidone (R 64 766) is a potent combined serotonin-S2 and dopamine-D2 antagonist. In previous studies in chronic psychotic patients it was demonstrated that this substance combined an effective antipsychotic action with a significant improvement of negative symptoms, without inducing acute extrapyramidal symptoms (EPS) , while existing EPS were reduced significantly. TO confirm these results, 40 chronic schizophrenic patients (according to DSM-III-R criteria) were selected for the present study, after informed consent was obtained. They all presented positive, negative and/ or ext r a p y r a m i d a l symptoms although the neuroleptic medication was optimalized repeatedly. This study lasts for 15 weeks. The first 2 weeks, (from day -21 till day -7) the patients are e v a l u a t e d with the existing treatment kept unchanged; then all neuroleptic and antiparkinson medication is stopped, and they have a single-blind placebo wash-out period of 1 week (day -7 till "day 0) . On day 1 the double-blind medication is started, with an initial dose of 1 mg b.i.d., both for risperidone and haloperidol. According to the achieved therapeutic effect or the appearance of side-effects, this dose is adapted whenever necessary, with a maximum dose of 10 mg b.i.d, for the first half of the trial. For the next 6 weeks, i.e. from day 43 on, the dose of the doubLe-blind medication is kept unchanged untill day 84, end-point of the study. Patients are evaluated by means of the SADS-C (on day -21, 0 and 84) and the pANSS, NOSIE-30, CGI, and Chouinard EPS-rating scale on day -21,-14,-7,0,7,14,28,42,56,70 and 84. On the same days, a target symptom and 4 sleep-parameters are scored with visual analogue lines, vital signs are recorded and sideeffects noted. A complete safety-screening is done on day 0, 42 and 84. At the end of the study a comparison is made with the previous therapy, both by the investigator and the patient. The preliminary results are discussed. Univ. P=sychiatr. Centre Sal~ Mater, 3042 Lovenjoel, Laurel, Belgium.

348

COMPARISON OF THE CLINICAL EFFECTS OF LITHIUM CARBONATE AND CARBAMAZEPINE ON EXCITED SCHIZOPHRENICS M.Kamisada,M.Tateyama,Y.Nakano,Y.Kawachi,Y.Fujii ,A.Tanoue,M.Takamiya,S.Nakajima,K.Sakuma, E.Oguchi,G.Yagi A t o t a l of 30 i n p a t i e n t s ( a g e d 21 t0 57) of I C D 9 schizophrenic psychosis were administered lithium carbonate (LT), c a r b a m a z e p i n e (CB) o r placebo (PL).Patients w e r e i n c l u d e d if t h e y w e r e r a t e d as m o d e r a t e o r m o r e in " t e n t i o n " , "mannerisms and posturing" or "excitement" of B P R S . T h e d o s e s of r e a l m e d i c a t i o n s were on the double-blind fixed-flexible method for 8 weeks" ( s t a r t at 4 0 0 m g s / d , u p p e r limit at 1200mgs/d). Other antipsychotics,if administered concomitantly, was fixed throughout the study period. T h e f i n d i n g s w e r e as f o l l o w s ; ~)Backgrounds of p a t i e n t s : m o r e frequently catatonic PL~CB. (p<0.1). 2)General Improvement Rating:PL~LT(p<0.01). PL>CB(p<0.1) 3)Global Usefulness Rating:PL>LT,CB (p<0.05). 4)Overall Safety Rating:CB>LT,(p<0.1). 5)Side effects:two c a s e s o n 6 0 0 m g s / d of C B d e v e l o p e d d i f f u s e s k i n r a s h e s w i t h f e v e r in w e e k s 2 thenfthe medication was ceased. 6)Although no difference appeared among the tree g r o u p s in i m p r o v e m e n t expressed by the decrease of t h e t o t a l B P R S s c o r e o r t h e a c t i v i t a t i o n score,the thrapeutic effects occured more rapidly f o r t h e L T g r o u p . It h a s b e e n s p e c u l a t e d that LT rapidly ameliorates the psychiatric symptoms of e x i t a b l e s c h i z o p h r e n i c s . Inogashira Hospital. 4-14-1 Kamirenjaku Mitakashi 181 T o k y o J a p a n .

33.02.01

POSTER PRESENTATION 33.02

Anorexia Nervosa and Bulimia

THE EFFECT OF LEVOPROTILIN ON THE BASIC SYMPTOMS OF EATING DISORDERS F. Faltus, G. Wendt In the course of therapy of some cases of depressive states with l e v o p r o t i l i n e i t s favourable e f f e c t on a p p e t i t e r e g u l a t i o n , hunger f e e l i n g s and s t a b i l i s a t i o n of body weight was observed. Therefore we decided to apply l e v o p r o t i l i n in p a t i e n t s with d i f f e r e n t types of eating disorders. In p a t i e n t s s u f f e r i n g from anorexia nervosa repeated r a t i n g s were done in basic symptoms: enhancement of a p p e t i t e and f e e l i n g of hunger, improvement of a t t i t u d e to e a t i n g , increase of body weight. In patients s u f f e r i n g from bulimia nervosa we studied the e f f e c t of l e v o p r o t i l i n e on r e g u l a t i o n of f e e l i n g s of hunger, on purging, and s t a b i l i s a t i o n of body weight. In both treatment groups we evaluated the e f f e c t of l e v o p r o t i l i n e on emotional s t a b i l i t y , on occurence of anxious and depressive symptoms and on s e l f esteem. Detailed r e s u l t s w i l l be presented and discussed. Psychiatrische K l i n i k , Medizinische F a k u l t g t d. K a r l s - U n i v e r s i t ~ t , Ke Karlovu 11, CS 12821 Praha 2

33.02.02

33.02.03

CONTROLLED TRIAL OF FLUVOXAMINE AND BEHAVIOR THERAPY IN THE TREATMENT OF DEPRESSED OBESE D.O. Nutzinfler, M. de Zwaan, G. Sch6nbock, A. BuQnar, R. M a c u r a , S. C a y i r o Q 1 u , P. B e r q e r , G. A s c h a u e r - T r o i b e r , A. K i s s , S. M e r y n . There is a close i n t e r r e l a t i o n o f a p p e t i t e and emotions. This fact is of particular importance in the treatment of depressed obese, where

A OOMPARATIVE EVALUATION OF THE BEHAVIOURAL AND ANTIPSYCHOTIC EFFECTS OF CENTBUTINDOLE IN RHESUS MONKEY (MACACA MULATTA) G. Palit, C. Nath, M.B. Gupta, R.C. Srimal, B.N. Dhawan and G.P. Gupta CentbutindoJe (CB), a new antipsychotic drug developed at Central Drug Research lnstitute~ Lucknow, India, was studied ior its effects on behaviouraI patterns and amphetamine induced psychosis in rhesus monkey, and compared with standard antipsychotic drugs (haloperidol and chlorpromazine). Centbutindole (12.5-50 ~ug/kg im) produced a dose-dependent decrease in social behaviour patterns (social groom, approach, body jerk and reactivity). In solitary behaviour, the spontaneous motor activity (SMA) was markedly decreased, auditory response and sell groom, were suppressed. Larger doses of CB (100-200 ~g/kg im) produced a marked cataleptic posture. Haloperidol produced similar extrapyramidal eIIect but in lower doses (#0-80 ~g/kg im). Amphetamine (t~ mg/kg ira) produced checking, stereotypy and suppression of feeding, drinking and grooming behaviour which were blocked by prior treatment with CB (20 ~ug/kg im), haloperidol (40 jug/kg im) or chlorpromazine (1 mg/kg ira). In equipotent antiamphetamine doses, chlorpromazine caused more marked sedation and decrease in SMA than CB and haloperidol. Thus, the profile of behavioural eflects ol CB is similar to that of other antipsychotics with lesser propensity to cause extrapyramidal effect than haloperidol. Neuropharmacology Unit (CDRI), Department ol Pharmacology, K i n g George's Medical College, Lucknow-226003, India

d i e t i n g is often linked with d e t e r i o r a t i o n of depressive symptoms. The use o f traditional t h e r a p e u t i c approaches i s l i m i t e d i n t h i s subgroup as c o n v e n t i o n a l a n t i d e p r e s s a n t s (AD) commonly cause weight gain respectlively dietary management (DM) alone o r in a b e h a v i o r t h e r a p y s e t t i n g t a k e s the r i s k o f a high drop o u t r a t e due t o a g g r a v a t i o n o f depressive symptoms. I n our study we have chosen an i n n o v a t i v e approach t o these problems: Fluvoxamine(F), a new AD w i t h w e i g h t reducing p r o p e r t i e s combined w i t h cognitive behavior t h e r a p y ( B T ) . In a doubleblind, four-cell study design we compared f o u r treatment modalities: F and BT, F and DM, p l a cebo and BT, placebo and DM. S i x t y f o u r obese women aged 19 t o 54 with present or past Depressive D i s o r d e r according t o D S M - I I I - R were randomly assigned t o one o f t h e f o u r t r e a t m e n t conditions. Their b o d y mass index a t baseline rang&d from 29 t o 47 kg/m2 (median 36). The t r e a t m e n t l a s t e d 24 w e e k s w i t h weekly group

therapy s e s s i o n s t h r o u g h 12 w e e k s , f o l l o w e d by 8 weeks o f p l a c e b o controlled drug treatment a l o n e and f u r t h e r 6 weeks o f placebo administration. Subjects were a s s e s s e d at regular intervals throughout treatment. Blood samples for measurement o f F w o r e t a k e n p r o - , m i d - and posttreatment. Follow-up a s s e s s m e n t s are p l a n n e d 8 and 12 month a f t e r treatment phase. Results will be p r e s e n t e d . Psychiatrische UniversitAtsklinik Wien, W&hringer G~rtel 18-20, A - 1 0 9 0 Wien

349

33.03.01 THE PSYCHOPHARMACOLOGY OF RITANSE~IN: DIFFERENTIATION WITH

CHLORDIAZEPOXIDE T.F. Meert, F. Awouters and P.A.J. Janssen Ritanserln, a central 8erotonln 5-HT 2 antagonist with complete LSD-antagonist properties, was compared with the

POSTER PRESENTATION 33.03

benzodlazepine ehlordiazepoxide (CDZ) in different animal models of anxiety. In conflict procedures using electric shock as an inhibitory stimulus, a dose related dlsinhibition was observed w i t h CDZ but not with ritanserin. In different other anxiety tests involving more natural aversire stimuli, riteunserin dlsinhlbited exploratory behaviour over a broad dose range while CDZ was marginally active. The differences between ritanserin and CDZ were also clear in drug discrimination test procedures. CDZ but not ritanserln had intrinsic discriminative properties. Furthermore, ritanserin did not generalize with CDZ nor with fentanyl, LSD, cocaine, d-amphetamine and 8-OHDPAT. These results indicate that ritanserin is unlikely to possess abuse potential. Unlike the benzodiazepine, ritanserin did not induce motor incoordination or sedation, was devoid of interaction with alcohol, produced no stmte dependency, w~s not self-administered and did not affect basal corticosterone plasma levels. On sleep, ritanserin is known to increase SWS and CDZ to affect REM sleep. These ~ x p e r i m e n t a l studies indicate that ritanserin possesses anxlety-reducing effects with a mechanism of action different from that of the benzodiazepines. The clinical effects of ritanserin in dysthymic and anxiety disorders are considered to be based on a neurotransmitter interaction that avoids the limitations of classical anxiolytic

Biological and Pharmacological Aspects of Anxiety Disorders

drugs. Department of. Neuropsychopharmacology, Foundation, B-2340 Beerse, Belgium

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33.03.03

33.03.02 PERSONALITY

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RITANSERIN-AN ORIGINAL THYMOSTHENIC-IN THE TREATMENT OF GENERALIZEDANXIETY DISORDERS. A. A. I. Jansen ~nd E. A. Pangalilia-Ratu Langi. In a double-blind t r i a l , 22 patients treated with 5 mg b . i . d , of the selective serotonin-Sz antagonist ritanserin for 4 weeks were compared with 26 patients treated with placebo for generalized anxiety disorder (DSM I i i : 300.02). Symptoms were assessed using the Hamilton Anxiety Rating Scale (HARS) and the Visual Analog Mood Rating Scale (Noris, Bond and Lader). Patients were further evaluated by means of a c l i n i c a l global impression. The present treatment was also compared with the previous treatment for generalized anxiety disorder. At the end of the treatment ritanserin was s i g n i f i c a n t l y superior to placebo in i t s effect on the psychic cluster of the HARS, es#ecially for the items insomnia (already after 1 week of treatment) tension and depressed mood. According to the Mood Rating Scale, the ritanserin-treated patients rated themselves as calme~, more energetic and more relaxed. This significant symptomatic improvement with ritanserin was confirmed by the c l i n i c a l global impression and in the comparison with the previous treatment, both al~o s i g n i f i c a n t l y in favour of the ritanserin-treated patients. As only one side-effect was reported in the ritanserin group versus 5 in the placebo group, i t may be concluded that ritanserin provides a novel and very well tolerated therapy for outpatients suffering from generalized anxiety disorder. Janssen Pharmaceutica B,V.,dept. of Clinical Research, P.O.Bo• 90240, 5000 LT Tilburg, The Netherlands.

33.03.04

33.03.05

MEDETOMIDINE, A POTENT AND HIGHLY SELECTIVE ALPHA-2ADRENOCEPTORAGONIST HAS ANXIOLYTIC PROPERTIES IN RODENTS E. MacDonald, A. Haapalinna, R. Lammintausta & R. Virtanen Medetomidine (MED) is an imidazole derivative, recently introduced for veterinary sedation in cats and dogs etc. I t is a potent a2-adrenoceptor agonist, with no m a j o r binding a f f i n i t y to any other studied CNS receptors. MED caused a dose-dependent i n h i b i t i o n of noradrenaline (NA) turnover as assessed by levels of NA metabolite or i n h i b i tion of a-methyl-p-tyrosine induced depletion of NA levels in brain. MED also i n h i b i t e d the turnover of dopamine and 5-hydroxytryptamine (5-HT). The effects on these other biogenic amines were blocked by p r i o r treatment with the a2-antagonist, atipamezole (ATI, 1.0 mg/kg). The doses of MED used in the above experiment (30-300 ug/ kg) caused sedation, at the higher doses even complete loss of the r i g h t i n g r e f l e x . Lower, non-sedative doses of MED (I-5 ug/kg) had clear a n x i o l y t i c properties in several rodent anxiety t e s t s . In r a t s , a considerable increase in punished dfinking was seen a f t e r MED. In mice, rearing behaviour in the staircase test and an increase in the number of t r a n s i t i o n s from lighted to dark chambers in the two compartment t e s t , t h i s l a t t e r e f f e c t blocked by ATI, were indicative of a n x i o l y t i c a c t i v i t y . Treatment Dose Transitions Activity (~g/kg) (no. per 10 min) (counts per 10 min) Salin~ (5) 19.6• 594• MED (5) 2.5 36.4 • 1.2"* 711 • 29 ATI (5) 50.0 28.6 • 2.6 712 • 12 MED + ATI (5) 2 . 5 + 5 0 . 0 20.1• 558• * * = s t a t i s t i c a l l y d i f f e r e n t from c o n t r o l , P
FUNCTIONAL INTERACTION OF NOVEL ~NXIOLYTICS WITH 5-HT l - AND ADRENERGIC RECEPTORS A * T. GIaser, L.A.A. van Rooiien and J. Traber Recent evidence strongly supports the existence in brain of at least five subt}~es of serotonin (5-HT) receptors named 5-HT - 5-HT 5-HT - 5-HT - and IA ' IK' iC ' 2 5-HT3-receptors. Especlally the o-HTl~-receptor subtype seems to be involved in mechanisms ~6hderlying anxiety (Traber and Glaser, Trends Pharm. Sci. 8, 432-437, 1987). The aim of the present study was to compare on a biochemical level the novel 5-HT.]A-receptor related anxiolytics buspirone, gepirone and-zpsapirone as well as the 5-HTiA-receptor ligand 8-hydroxy-2-(di-n-propylamino)tetralYn (8-OH-DPAT) in respect to their functional interaction with 5-HTIA- and a-adrenergic r eceptors.

Department of Pharmacology & Toxicology, U n i v e r s i t y of Kuopio, PL 6, SF-70211Kuopio, Finlana

The four compounds bound in the rank order 8-OH-DPAT > ipsapiro~e > buspirone > gepirone to hippocampal 5HTiA-recepters. 8-OH-DPAT acted as a full agonist on these receptors as measured by inhibition of forscolinstimulated adenylate cyclase. The intrinsic activity of buspirone, gepirone and ipsapirone was" considerably lower than that of 8-OH-DPAT. At higher concentrations ipsapirone, but only marginally buspirone could antagonize the agonist-induced inhibition of enzyme activity. 'Ipsapirone interacted with a higher affinity than buspirone, gepirone or 8-OH-DPAT with central al-and ~2-adrenergic receptors. Functional in vitro studies revealed ipsapirone to possess antagonistic or agonistic properties on ~i or ~2-adrenergic receptors, respectively. The results indicate differences in the intrinsic activities of 5-HTiA-reeeptor-related anxiolytics which might be relevant Tor their pharmacological profile. Neurobiology Department, Troponwerke, Neurather Ring i, D-5000 K61n 80, F.R.G.

33.03.06

33.03.07

&NTI-ANXIETY EFFECTS OF THE 5-HT~ RECEPTOR ANTAGONIST ~ 205-930 AND D!AZEPAM IN THE PLACE AVERSION OTNDITIONING IN RATS. K. PanD. Evidence from experimental and clinical studies has ~ointed to the rmle of central 5-HT, and 5-HT= receptors as target sites for new non-benzodiazepine compounds with putative anti-anxiety properties. In the present paper the anti-anxiety effects of ICS 205-390, an antagonist of 5-ET3 receptors and diazepam (DIA), were studied in a place aversion conditioning test. The obtained results show that when one of two distinctive and previously preferred compartment was associated with an inescapable fsmtshock (eightl-mA shocks, applied throughout a 20-min session for 3 consecutive days), a conditioned aversion developed and control animals did not enter that compartment in the post-condltioning test. DIA (I.0 - 4.0 ~ / k ~ i.p.), given 60 mln before the post-conditioning test, increased in a dmse-dependent manner the amount nf time spent by animals in the conditioned compartment (F(3,20)=9.896; p
EFFECT OF BUSPIRONE AND ITS METABOLITE IPYRIMIDINYLPIPEP_&ZINE (I-PP) ON STRIATAL DOPAC IN VIV0 F. Crespi Buspirone is a novel antianxiety agent devoid of anticonvulsant, sedative and muscle relaxant activities which are associated with the benzodiazepines. Pharmacological and biochemical studies indicate that buspirone modulates the activity of dopamine (DA) and serotonin (5HT) neurones. While buspirone directly affects the serotonergic system by interacting with the 5HT I . subtype of the high affinity 5HT. receptor (J. ~raser & T. Giaser, TIPS 8, ~32, I~87), some studies suggest a m i n u t e of agonist and antagonist effect on DA synapses (L. Eiblit et al, J.Clin.Psychiatry ~3, 11, 1982). This complicated pharmacology on the DA system may be partially attributable to the metabolism of buspirone to I-PP which rapidly accumulates in brain tissue after buspirone administration (S. Caccia et al, Xenobiotica I_~, 147, 1983) and, like buspirone, shows activity %n certain animal conflict tests (D. Taylor, Drug Dev. Res. 4, 95, 198~). To define the role of I-PP in the biochemical effects of buspirone on DA neurones we compared the effects of the two compounds together with hal operido! and apomorphine on the striatal DOPAC levels in vivo. Anaesthetised rats were prepared for voltammetric recording in the striatum (F. Crespi, Neurosei.Letts. 66, I, 1986). The injection of buspirone (10 mg/kg i.p., n=5) doubled extracellular DOPAC within 40 min and lasted for 1.5 hr. In contrast, I-PP (10 mg/kg i.p., n=5) did not change Peak 2 (DOPAC). Haloperidol (I mg/kg i.p., n=5) tripled extraeellular DOPAC while apomorphine (5 mg/kg, s.c., n=5) halved the DOPAC oxidation peak. These results indicate that the effect of buspirone on the DA system in the striatum is not dependent on the metabolism of buspirone to I-PP. However, the change in DOPAC is consistent with inhibition of nigrostriatal pre-synaptic DA receptors. Department of Physiology and Pharmacology, Queen's Medical Centre, Nottingham NG7 2UH, U.K.

351

33.03.08

33.03.09

NEW EXPERIMENTAL ANXIETY MODEL: EFFECT OF BUSPIRONE ON GASTRIC LESION INDUCED BY THE COM~UNICATIO~ BOX METHOD IN MICE C. Hara and N. Ogawa The communication box (CB) method was introduced by Ogawa and Kuwahara (1966) to induce the experimental anxiety using the intraspecies emotional communication. The animals (responder,"R") receiving the e/ro~ional cues (EC) from the animals (sender,"S") exposed to electric shock (ES) preceded by conditioned stimuli (CS) were leaded to the anxiety state. "R" was reported to have gastric lesions (GL) in mice. However, o n l y CS also elicited GL. Therefore, the present study exa~ined whether only EC from "S" without CS could elicit GL to "R", and did the possibility for the tool evaluating anxiolytics using buspirone (BSP). Male ICR mice were used. The CB with the grld floor to deliver ES, consists of 36 small compartments divided by transparent plastic walls. Eight "R" were individually placed in the compartments shielded from ES. Sixteen "S" were arranged in the compartments surrounding the "R" compartments. Influences of single and repeaned exposures to EC on incidence of GL in "R" were examined. "R" were fasted for 24 hr before the final experimental day. "S" were daily renewed to intact animals in the repeated exposure. The experiment was s t a r t d at 7:00 PM. After completing the ES period, the stomachs of "R" were inspected GL visually. BSP was tested in the repeated exposure to EC. 0.2, 1.0 and 5.0 mg/kg of BSP were administered i.p. to "R" once a day 15 min before the experiment. "R" exposed to the 3 Day exposure to 3 hr EC exerted 100% incidence of GL. BSP 0.2 and 1.0 mg, but not 5.0 mg, significantly prevented GL. The results suggest that the CB method wlthout CS is a valuable model to study psycho-social factor implicated in peptic ulcer and to induce anxiety psycholog=cally. Ehime University School of Medicine, Dep~rtment of Pharmacology, Shigenobu-cho, Onsen-gun, Ehire 791-02, JAPAN.

A COMPARISON OF THE 5-HT RECEPTOR P~ELATED ANXIOLYTICS BUSPIRONE, GEPIRONE, IPS~IRONE, SM-3997, THEIR COMMON METABOLITE I-PP AND DIAZEPAM IN ANIMAL MODELS OF ANXIETY J. Traber T. Sehuurman and U. Benz Four second generation anxiolytics, buspirone (B), gepirone (G), ipsapirone (I) and SM-3997 (S), which exert at least part of their anxiolytie effects via interaction with the 5-HT subclass of central 5-HT receptors, their A common m e t a b ~ i t e I-PP and the reference benzodiazepine anxiolytic diazepam (D) were compared in different animal models of anxiety and in motor function tests. These conflict and anxiety tests were the shock-suppressed drinking (SSD), Geller-Seifter conflict, conditioned emotional response (CER). social interaction (SI) and ultrasonic vocalisation (USV) test, all with rats. The data show that D, B, G, I and S disinhibit punished behaviour in the SSD and Geller-Seifter test. Rank order of potency was D > G ~ I > B > S. In the CER test rats were trained to press on a lever for food reward (FR I0). One day before drug testing, delivery of each food pellet was combined with footshock. This shock session was signalled by a tone and a light. On the next day, tone and light were presented again, resulting in a reducion of lever pressing. D and the serotonergie anxiolyties disir~ibited lever pressing. In the USV test ultrasonic vocalisation of rats was elicited by footshocks. All test substances decreased the amount of 22 l~Hz vocalisation. Furthermore, D, B, G and I increased the duration of social interactions between rats paired in a brightly illuminated test arena, whereas S and I-PP were inactive. Interestingly, prosocial effects of I but not of D, B or G were also observed under less stressful test conditions (low illumination of test arena). I-PP was active in a few of the ar~xiety models, potency being lower than that of the parent compounds. Finally, it was demonstrated that D affected motor function of mice more strongly than B, G, I and S. Neurobiology Department, Troponwerke, Neurather Ring I, 5000 K61n 80, FRG

33.03.10 THERAPEL~IC EFFICACY OF NEW ANTI-ANXIETY DRUG, BUSPIRONE ON NEL~OSIS. M. Ni~hizono as a representative of 30 institutes. The anxiolytic properties of a new nonbenzodiazepine anxiolytic "buspirone" with a unique Pharmacologic profile were assessed at 30 institutes in the Western Japan area. The study population consisted of 136 adult neurotic patients (Male:68, Female:68) with an age range of 16-66 years. The drug was administered orally with 5 mg tablets to a maximum dose of 25 mg t.i.d. The administration period was ]-70 days with 22 days the mean period. Patients were evaluated at 0,1,2,3 and 4 weeks, according to the Psychoneurosis Rating Scale for Symptom (PNRS-S), the Symptom Rating Scale for Neurosis (SRSN), Japan and the Hamilton Rating Scale for Anxiety (HAM-A). The Amiiioration Rate on Final Global Improvement Ratings (AR) for the 136 patients is 73.5%. By type of neurosis, the AR for anxiety neurosis (N=54) is 74%, for depressive neurosis (N=20) 65%, for phobic neurosis (N=19) 65%, for obsessive-c6mpulsive neurosis (N=I0) 80%, for other neurosis 76%. By previous severity, the AR for slight severity is 62%, for moderate severity 73%, for severe severity 81%, By previous treatment, the AR for fresh cases is 84%, and for cases'previously treated with benzodiazepine or others is 66%. By dosage of final administration corse, the AR with a 5 mg t.i.d.(N=79) is 73%, and for a i0 mg t.i.d. (N=32),is 72%. On the alteration in H.~M-A and SRSN scores~ the reducation of total scores in fresh cases was significantly improved than cases previously medicated with benzodiazepines. Adverse reactions appeared in 3S% of the patients and included drowsiness (Ii%), iight-headedness (8%), nausea (8%) and other minor reactions. Abnormality (GOT:23~45, GPT:53+71) of clinical laboratory findings with relativity to the drug was shown in one of the patients. Our clinical open trials in patients with neurosis have shown that buspirone may have equivalent efficacy to benzodiazepines without causing euphoria, functional impairment and alcohol interaction. Department of Psychiatry, Fukuoka University School of }~ed~clne. No.7-45-] Nanakuma Jonanku, Fukuoka City, Japan.

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33.03.11 CLINICAL PHASE II OPEN TRIALS OF BUSPIRONE IN HOKKAIDO AREA, JAPAN I. Onodera, F. Okada~ K. Itoh, Y. Asano and I. Oka Clinical phase II open trials of a new nonbenzodiazepine anxiolytic buspirone with a unique chemical structure were performed at 20 institutes in the Hokkaido area. The study population consisted of i01 adult neurotic patients (male: 36, female: 65) with an age range of 15-75 years. The drug was administered orally with 5 mg tablets to a maximum dose of i0 mg t.i.d. The administration period was 2-55 days with 23 days the mean period. Patients were assessed at 0, I, 2, 3 and 4 weeks, according to the Psychoneurosis Rating Scale for Symptom (PNRS), Japan and the Hamilton Rating Scale for Anxiety (HAM). The amelioration rate on final global improvement ratings (AR) for the i01 patients is 65 %. By type of neurosis, the AR for anxiety neurosis (N=50) is 67 %, for depressive neurosis (N=I3) 84 %, hypoehondriasis (N=I8) 66 %, for other neurases 43-100 %. By previous severity, the AR for moderate severity (N=55) 67 %, for severe severity (N=41) 66 %. By previous medication, the AR for fresh cases is 88 %, and for cases previously treated with henzodiazepine is 26 %..This phenomenon may be concerned in withdrawal s ~ p t o m s from benzodiazepines. ~ne AR increases gradually by administration period as follows: 50 % (-i week), 30 % (2 weeks), 50 % (3 weeks), 82 % (4 weeks) and 92 % (over 4 weeks). On the change in Ii4_M scores, the reduction of total scores in fresh cases was significantly better than cases previously treated with 5enzodiazepines. Adverse reactions appeared in 2 1 % of the patients and included drowsiness (7 %), dizziness (8 ~), nausea (5 %) and other minor reactions. Abnormality of clinical laboratory findings with probable relativity to the drug was not shown. Our phase II open trials suggest that huspirone will have higher effectiveness for cases ~ith more than 4 weeks of administration period, with a lower incidence of adverse reactions, and for fresh cases ~ithout prior benzodiazepine treatment. Sapporo Okamoto Hospital, Japan, 060

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Ipsapirone in the treatment of generalized anxiety disorders. Results of a phase II US-multicenter trial. B. Kuemmel, M. Beneke, G. Krol*, G. Schoellnhammer, H. Spechtmeyer Ipsapirone a specific 5-HT IA receptor agonist is a substance in a new class of anxiolytics/antidepressants representing a possible new therapeutic principle for anxiety and depression. In a randomized, placebo-controlled, parallel-group study the efficacy and safety of Ipsapirone was investigated in a total number of 267 patients with moderate to severe generalized anxiety (DSM I I I : 30o.o2) in dose ranges of 2,5 mg; 5,0 mg and 7,5 mg Ipsapirone t.i.d. over 28 days. The primary efficacy variables in these studies were the Hamilton Anxiety Scale (HAM-A) and the Zun~ Anxiety Scale, the safety aspects were detected through laboratory routine and listing of adverse reactions. The improvement in HAM-A scores was significantly greater in the 5.o mg Ipsapirone group than in the placebo group at all visits. The mean HAM-A score wa% 24.2 at baseline. Improvements in scores of 5.8, 8.2, 9.8 and 1o.9 were seen following each consecutive week of treatment. In the 14-item Zung scale a greater improvement relative to placebo was observed over the treatment course with 5.0 mg Ipsapirone with a significance at week 3. The laboratory data were within normal ranges and did not significantly differ from tho~e of the preexamination test. The most frequently reported adverse experiences (% of patients) are: headache (Ipsapirone 2o.3 %; Placebo 28 %); Nausea (Ipsapirone 16 %; Placebo io %); Dizziness (Ipsapirone 45 %; Placebo 17 %); and Sedation (Ipsapirone 15 %; Placebo 6 %). with regard to the primary efficacy variables Ipsapirone proved to be an effectiv treatment of anxiety disorders. Medical Department, Troponwerke, Neurather Ring I, D-5ooo K61n 80, FRG *Biochemical Department, 4o0 Morgan Lane, West-Haven, CT 06516, USA

T r e a t m e n t of A n x i e t y N e u r o s i s w i t h I p s a p i r o n e . M . B e n e k e , B.Kfimmel, I . S . R o e d , H . S p e c h t m e y e r Ipsapirone, a pyrimidinylpiperazine derivative, exhibits strong anxiolytic properties (Brain Res. Bull. 1 2 , 7 4 1 - 4 4 ) in a n i m a l m o d e l s w i t h o u t i n t e r a c t i n g w i t h the G A B A - r e c e p t o r complex, and t h u s r e s u l t i n g in l a c k of s i d e e f f e c t s , i.e. sedation, ataxia and muscle relaxation.Neurobiological findings confirm high affinity binding s i t e s at 5 - H T r e c e p t o r s for i p s a p i r o n e , w h i l e I developing predominantly serotonin agonistic properties (Brain Res. 3 5 8 , 1 2 9 - 1 3 6 ) . In s e v e r a l randomized double-blind clinical trials conducted in the F R G the t h e r a p e u t i c e f f i c a c y of i p s a p i r o n e c o m p a r e d to p l a c e b o in a n x i e t y n e u r o s i s and n e u r o t i c d e p r e s s i o n ( I C D - 9 : 3 0 0 . 0 , 300.4) treatment were assessed.- Patients - recruitment o p t i o n : H A M - A m i n s c o r e = 20 - w e r e t r e a t e d w i t h a fixed dose per centre allowing dose titration d e p e n d i n g on the o c c u r e n c e of s i d e - e f f e c t s and the d e g r e e of t h e r a p e u t i c e f f e c t ( 2 . 5 - 1 0 m g / t i d ) . A n a l y s i s b a s e d on p o o l e d d a t a of 124 m a l e a n d female patients treated with either medication s h o w e d a s i g n i f i c a n t s u p e r i o r i t y of i p s a p i r o n e w i t h r e s p e c t to c l i n i c a l v a r i a b l e s (STAI-Xl/X2, HAM-A,HAM-D) and global ratings (global improvem e n t , s a f e t y , u t i l i t y ) . W h e n c o m p a r e d to p l a c e b o i p ~ a p i r o n e d e v e l o p e d a h i g h e r r a t e of a d v e r s e e f f e c t s w h i c h is in a c c o r d a n c e w i t h p h a s e - I findings, and mainly characterized by dizziness, d a z e d f e e l i n g s , a n d 'soft' or u n s a f e f e e l i n g s in the l e g s . - G l o b a l a n a l y s i s i n d i c a t e s t h a t ips a p i r o n e i m p r o v e s as w e l l s y m p t o m s a s s o c i a t e d w i t h d e p r e s s i v e s t a t e s . It is j u d g e d to h a v e n e a r l y e q u i v a l e n t s a f e t y w h e n c o m p a r e d to p l a c e b o a n d to be an e x t r e m e l y u s e f u l d r u g in the t r e a t m e n t of a n x i e t y . -

Medical Department, Troponwerke, Neurather Ring I, D-5000 K61n 80, FRG

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TOIZRANCEANDPHARMACOKINETICS OF ZOLPIDEM I N , H E HEALTHY V O L U N T E E R S U S I N G ~ - B L I N D M A N N E R Y. Kudo, H. Suzuki, Y. Nakamura and T. Kudo The tolerance and pharmaeokinetics of zolpidem, a new imidazopyridine hypnotic, were investigated in healthy male volunteers. The single and nmltiple dose studies were designed in a double-blind manner. In the single dose study, the subjects were randc~ly allocated to each of two gr~aps; the ist group censisted of 8 subjects(6: receiving zolpide~ 2.5 and 7.Smg, 2: placebo). Zolpidem was well tolerated in all the subjects at all dose levels. A marked hypnotic activity was observed at the dose levels of 5-10r~ and there were some changes in clinical signs, objective expressions and psychological parameters, which were attributed to the pharmacological activities of the compound. The plasma concentrations were dose-dependent and the peak concentration(Cmax) and the area under the plasma concentration curve (AUC) were linearly dose-related. The plasma concentrations declined with mean half-lives (tl/2) of 1.8-2.3 hours. Excretion of unchanged zolpidem in the urine accounted for less than 1% of each given dose. In the multiple dose study, nine subjects were randcmly allocated to receive either 10n~ zolpidem(6 subjects) or placebo(3 subjects) once a day for 7 consecutive days. Zolpidem was well tolerated. A marked hypnotic activity was ~bserved during the dosing period with zolpid6~n. As well as in the single dose study, there were same changes in clinical signs such as equilibrium on standing one leg, facial expressions, and psychological parameters (Flicker, Line-drawing and Fmller-lyer test) . The plasma concentration profiles, Cmax, time to reach the peak concentration(Tmax), AUC and tl/2 on day 1 were similar to those on day 7. less than 1% of the given dose was excreted unchanged in the urine on day i, 4 and 7. These findings indicated that zolpidem is well tolerated and is expected to be useful for patients with i n s c ~ a . Aino Institute of Clinical P h a r m a e o l ~ .

ELECTROPHYSIOLOGIC.~_ AND BEHAVIORAL ASPECTS OF ETHYLESTHER OF BETA-CARBOLINE 3-CARBOXYLIC (OR BETA-CCE) ACID IN RHESUS MONKEYS. A FIRST APPROACH. D. LAGARDE (I), C. MILHAUD (I), J. LAL-RF.ET (2), H.J. AUBIN (1), L. GAYET (1) and D. DELVlLLE (1) Beta CCE is usually considered as having an affinity for benzodiazepine receptors and as an inverse agonist of benzodiazepines. Administered alone it can induce convulsions or anxiety. The first approach made in our laboratory was designed to observe the effects of the administration of three increasing doses of Beta-CCE (0.5-1,0-2mg/kg in IV) on heart rate (HR), EEG signal and power density spectrum, and behavior of four male rhesus monkeys (mean b.w. 10kg). Heart rate was studied by measuring R-R.intervals. The power density spectrum was obtained after automatic EEG (FFT) processing from a left parieto-occipital lead. Behavior was observed off-line, on a video tape, noting the frequency and duration Of behavioral criteria. Administration of increasing doses of Beta-CCE induces EEG, ECG and behavioral hhanges. High doses of Beta-CCE (1 and 2 mg/kg) administered alone triggered a convulsive crisis in one subject. The spectral analysis evidenced increased power on fast frequencies. The very high increase in HR and the development of unusual, even abnormal behaviors seem to reflect a neurovegetative effect, maybe even anxiety. It can therefore be suggested that Beta-CCE is a molecule which ~an induce convulsions and anxiety in Primates. If sudh properties were confirmed, this molecule could be used to create an anxiety model. (l) Centre d'Etudes et de Recherches de M~decine A~rospatiale. Division de Neurophysiologie, 5 his, ave de la Porte de S~vres 75731 PARIS CEDEX 15 F ~ E C E . (2) ROUSSEL UCLAF ROMALNVILLE 93230 F ~ ; C E

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T H E D I S C R I M I N A T I V E S T I M U L U S P R O P E R T I E S OF T H E B - C A R B O L I N E ZK 95 962: A N O N - S E D A T I V E B E N Z O DIAZEPINE-RECEPTOR LIGAND WITH ANXIOLYTIC-LIKE

PHARMACOLOGICAL PROFILE OF ALPIDEM, A NOVEL ANXIOLYTIC DRUG OF IMIDAZOPYRIDINE STRUCTURE G. Perrault, E. Morel, D.J. Sanger, D. Joly, 8. Zivkovic and K.G. Lloyd Alpidem (6-chloro-(4-chloro-phenyl)2N-N di-n-propyl imidazo [ 1,2-a] pyridine acetamid~ binds the w sites of the GABA-A receptor complex as do benzodiazepines (BDZ). In contrast to BDZs alpidem is highly s e l e c t i v e for the m I s i t e and has a very high a f f i n i t y for the peripheral BDZ ( m 3) recognition s i t e . In accordance with this binding p r o f i l e alpidem exerts anticonvulsant and a n x i o l y t i c a c t i v i t i e s but unlike BDZ i t f a i l s to induce sedative and myorelaxant effects. Moreover, a f t e r repeated treatment less tolerance develops to the anticonvulsant effects of alpidem than to those of BDZ. In tests p r e d i c t i v e of a n x i o l y t i c action, a l p i dem shows a potency s i m i l a r to that of chlordiazepoxide. In mice, i t i n h i b i t s burying, a defensive behaviour, (MED = 3. mg/kg ip) and increases food intake in an unfamiliar environment (MED = I0 mg/kg pc). At these dose~, alpidem does not i n t e r e f e r e with the acquisition of conditioned fear, i n d i c a t i n g a lack of memory impairment. However, in rats, the general a n x i o l y t i c p r o f i l e d i f f e r s ' f r o m that of BDZ. Alpidem exerts an a n t i c o n f l i c t action in the punished drinking paradigm (MED = 30 mg/k9 ip) but f a i l s to produce a benzodiazepine-like inte~oceptive stimulus. Moreover, alpidem appears more e f f i c i e n t in tests requiring high degree of motivation. This could explain the large difference between the doses of alpidem inducing a decrease in spontaneous locomotor a c t i v i t y and an impairment in rota-rod performance. These results indicate a good a n x i o l y t i c potent i a l for alpidem with minimal central depressant a c t i vity.

PROPERTIES J. S. Andrews and D. N. Stephens Benzodiazepines (BZ), although effective in the treatment of anxiety possess many unwanted side effects, in particular strong sedative and musc!e-relaxating properties. The 8-carboline ZK 95 962 has been identified as a partial agonist at the BZ receptor. ZK 95 962 generalises to chlordiazepoxide (CDP) in drug-discrimination procedures, has anticonflict and antiepiieptic properties, but is non-sedating. The interoceptive properties of CDP and ZK 95 962 were compared using a drug-discrimination procedure. Rats were trained to discriminate either CDP (5 mg/kg) or ZK 95 962 (i0 mg/kg) from veh&cle in a standard 2-1ever drug-discrimination procedure (Stephens et al., Psychopha_~macology 83, 233, 1984). Following training, differences between the two cues were investigated using a series of BZ receptor agonists and antagonists. CDP and ZK 95 962 genera!ised to one another with similar potencies. In general full BZ agonists behaved simi!arily in each of the cues; one exception was the B-carboline ZK 93 423 which generalised to CDP but neither generalised nor antagonised ZK 95 962. However, BZ antagonists and partial agonists behaved differently, e.g. RO 15-1788 and ZK 93 426 antagonised the CDP cue but generalised to the ZK 95 962 cue. Phenobarbital generalised to CDP, but not to ZK 95 962. The results suggest that the removal of sedative effects of BZ ligands alters the discriminative-stimulus properties. Department of Neuropsychopharmacology, Schering AG, D-!000 Berlin 65, F.R.G.

Laboratoires d'Etudes et de Recherches Synth@labo (L.E.R.S.), 23-25 ave Morane Saulnier, 92360 Meudon-laFor~t, France

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FTuNDLING HABITUATION MODIFIES ~ EFFECTS OF BENZODLg-~z ~-PINES ON SHUTTLE AVOIDANCE ACQUISITION BUT NOT ON ~.~??.?ICOSTERONE RESPONSE.* A. Fernandez, R.M. Escorihuela, F. Boix and A. Tobeff=. The acquisition of two-way shuttle avoidance (40 trials) was used to test the anxiolytic action of diazepam (2 and 4 mg/kg) and alprazelem (1.25 mg/kg) vs. vehicle in rats which had previously received one of three different treatments: acute, acute with previous handling habituation for 15 days and chronic combined with handling habituation for 15 days. Both the preand post-test corticosterone levels were also measured. The acute treatment showed a comparable anxiolytic effect of diazepam and alprazclam, reflected through an improvement in avoidance acquisition. After handling habituation, no effect on shuttlebox was obtained in the rats treated acutely. When handling habituation was combined with chronic treatment, the drug's anxioly~ic action persisted. The two acute treatments provoqued an enhancement of the ccrzicosterone basal levels, but a decrease was observed after the chronic treatment, both in the basal'and after the shuttlebox session. Those behavioral results are discussed in relation to the emotional changes induced by the, procedure of handling, and they are tem;atively linked with possible changes in the functionality of GABA neurotransmission at the level of the GABA-BZ receptor complex, which has been associated with handling habituation in some studies. These results also showed a lack of relationship between the anxiolytic action of the benzodiazepine treatment and the plasmatic levels of corticcszerone. *Work supported by a CAICYT gr~nt n.1839/82 and Up~,o~ SA. Dept. of Pharmacology and Psychiatry. Medical Psychslc~ Unit. School of Medicine. Universitat Aut6noma de Barcelona. 08193 Be!laterra. Spain.

EFFECTIVITY OF CAVAIN IN TRANQUILIZER INDICATION A. Klimke, E. Klieser, E~_Lehmann r W.H. Strauss There is a problem in treating patients who suffer from anxiety and psycho-reactive disorders with drugs like Benzodiazepines because of addiction and other undesired effects. Therefore Cavain, a drug derived from natural substances, which did not produce such undesired side-effects, seems to be indicated in these patients. At the university psychiatric hospital in DUsseldorf a double blind placebo-controlled study was conducted in order to record the influence of Cavain on anxiety states and psycho-reactive disorders. The therapeutic effectiveness was rated by the global appraisal of the doctor, the Hamilton-Anxiety-Scale (HAMA) and the Adjective Check List (EWL) on days 0, 14 and 28 of treatment. Side-effects were also checked in a global rating on days 14 and 28. We found a statistically significant difference in favour of Cavain in reducing ~he neurotic symptoms. On the basis of MMPI and life history questionnaire (LAZARUS) before treatment, responders and nonresponders are described in more details. Department of Psychiatry, University of D~sseldoff, Bergische Landstr. 2, D-4000 DUsseldorf 12 (F.R.G.)

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EVALUATION OF ANXIOLYTIC EFFECTS OF KETAZOLAM U S I N G E E G FREQDT/qCY A N A L Y S I S C. A l m e n a r , E. E s t i v i l l , C. P i n e t , M. C a s a s , C. U d i n a , J. C o n i l l , E. A l v a r e z .

SEDATIVE ACTION OF ALPROZOLAM AND DIAZEPAM AS MEASURED BY EWL AND TWO DIFFERENT FLICKER FUSION METHODS

Computerized e lec t r o e n c e p h a l o g r a p h y (CEEG) has been used mainly in pre-clinical studies in order to d e t e r m i n e t h e c e n t r a l b r a i n p r o p e r t i e s of new compounds s u c h as the beginning and duration of their effects and their effective doses. All psychotropics produce systematic and significant changes in bioelectric brain activity, which are detected by a CEEG; being directly related to the pharmacological family and dose, and also being similar in other substances with a different chemical composition but with the same clinical effect (therapeutic e q u i v a l e n t ). We h a v e " s t u d i e d i0 p a t i e n t s with generalized anxiety disorder who were treated, as out patients, w i t h k e t a z o l a m and, i n g e n e r a l t e r m s , we aim to evaluate the following: - T h e n~inimum e f f e c t i v e d o s e . - Begiruning a n d d u r a t i o n o f C N S a c t i o n . - CEEG evaluation of hypnotic and aruxiolytic ef~[ects. We " also tried to determine the possible p r e d i c t o r r o l e in c l i n i c a l e f f e c t i v e n e s s a f t e r a s i n g l e o r a l d o s e of t h e d r u g . The authors describe the methodology used in the present study a n d s u g g e s t its u s e i n clinical psychopharmacology as a convenient and noninvasive technique. Servicio de Psiquiatria, Laboratorio de Cronobiologia y Unidad de Toxicomanias. Programa S a n t Pau-CITILAN. Univ. Aut6noma de Barcelona. Hospital de ia Santa Creu i Sant Pau. Avda. Sant A n t o n i M. C l a r e t , 167. 0 8 0 2 5 . B a r c e l o n a . S p a i n .

A. Frei, W. Mollenkopf~ H.J. Gaertner In a double-blind pharmacopsychological experiment approved by the Tuebingen Ethics Commission, 20 healthy volunteers each (total, I00) received diazepam (10 mg or 5 mg), alprazolam (I mg or 0.5 mg), or placebo. Flicker fusion was determined at 30-minute intervals with two different devices (ZAK automatic flicker fusion tester, Metabo visual stimulator). At measurement, blood samples were taken for determination of plasma alprazolam and diazepam levels, and the EWL-N was completed (JANKE and DEBUS 1978). Measurements were made before drug administration and 9 times thereafter. Only female volunteers between the ages of 18 and 35 were entered in the trial. Whereas the ZAK device measures critical flicker fusion (CCF) (i.e, flicker frequency is increased until flicker is no longe~ percieved), the Metabo device measures perception threshold (i.e.,constant light is added to a certain selectable flicker frequency until flicker is no longer perceived [de Lange curve]). We expected the Metabo device to be more sensitive for registeration of fatigue. Our findings show that dose-dependent sedation is demonstrable by EWL; significant differences, however, were established for the tested drugs. Findings obtained by flicker fusion methods corresponded well with those obtained by EWL. The two methods, therefore, did not differ as expected with respect to the information they provided, since measurements with the Metabo device appears to be more sensitive, but their scatter is broader. These devices for measuring the sedative action of benzodiazepine do not depict dose differences any better than than the rating scales. Department of Psychiatry (Director: Prof. Dr. H. Heimann), University of TObingen, Osianderstr. 22, 74 TSbingen

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EFFECTS OF ISAZOTANE (CGP 361 A) IN MONKEY GROUPS, GROUPS OF HEALTHY VOLUNTEERS, AND IN PATIENTS WITH CHRONIC ANXIETY SYNDROME J. Jaekel, R. Kohnen, H. P. KrUger, A. D e l i n i - S t u l a , K. D. S t o l l Isazotane, a phenoxypropanolamine d e r i v a t i v e shows a n t i neophobic, a n x i o l y t i c as well as antiaggressive propert i e s in classical animal models in r e l a t i v e l y low dosages. In much higher dosages isazotane exerts ~-blocking effects. a) In rhesus monkey groups both alpha- and omega-animals were integrated into group i n t e r a c t i o n s (i.e.grooming) with isazotane more than u s u a l l y , under placebo conditions, or with other psychotropic drugs. b) A series of psychopharmacological group experiments with healthy students was able to detect p o s i t i v e influences on social stress reactions, social i n t e r actions and speech processes. Results of those studies with new experimental models are, as f a r as comparable, in good p a r a l l e l with the findings of the monkey studies. c) The f i r s t m u l t i c e n t r i c c l i n i c a l t r i a l s , a placebo cont,r o l l e d dos e f i n d i n g study favouring a d a i l y dose of 4 mg and a comparison of 2 and 4 mg/day with diazepam (5 mg t . i . d . ) , were able to demonstrate the a n x i o l y t i c effects of the drug by using repeated ffatings with HAMA and SDS. Results of animal studies, experiments with healthy volunteers, and c l i n i c a l studies w i l l be presented and discussed with focus on p a r a l l e l i s m s , possible social implications of a n x i e t y , and consequences drawn f o r a now running placebo-controlled c l i n i c a l t r i a l in chronic anxiety syndrome: degree of social problems ( f a m i l y , f r i e n d s , job) f o r s t r a t i f i c a t i o n s as well as repeated ratings of social components of anxiety are used in addition to usual characterizations of patients resp. to classical anxiety scales (HAMA, SDS). CIBA-GEIGY AG, Neurobiochemie, CH 4002 Basel

EXPERIMENTAL INVESTIGATION OF ANXIOLYTIC EFFECT AND SPEECH BEHAu IN HEALTHY VOLUNTEERS ON BETA BLOCKER

CGP 361A OR PLACEBO I. BOscher and H.J. Gaertner The drug CGP 361A, a water-soluable hydrochloride, has a phenoxypropanolamine structure typical os beta blockers. Behavioral-pharmacologic experiments, e.g., on rhesus monkeys, have shown that CGP 361A dosages, lower than that required for peripheral beta blocking action, change general and social behavior. This finding suggests a centrally mediated anxiolytic effect for CGP 361A. In his "Monkey Observation Test," JAEKEL (1986) observed an induction or intensification of positive social contacts at lower dosages. _ In a field study with healthy volunteers, KOHNEN and KROGBR (1986) found that speech behavior of subjects who had classified themselves as "socially handicapped" differed markedly under CGP 361A as compared to placebo. 90 heslth~ male volunteers participated in a placebocontrolled double-blind study to test the effect os CGP 361A on anxiety and social behavior. Speech behavior on the Thematic Apperception Test was used to operationalize social Behavior. The tests were videotaped and later analyzed. Anxiety, mood, and personality characteristics were rated by additional scale& The pulse rate served as physiologic correlate. The data were evaluated by an analysis of variance. Department of Psychiatry (Directo~ Prof. Dr. H. Heimann), University of TObingen, Osiander~tr. 22, 74 TObingen

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33.03.24 PREVENTION OF "LEARNED HELPLESSNESS" IN THE RAT BY HYDROXYZINE

33.03,25 NEuRoPSYCHOLOGICAL DISORDER F.N. Neziroglu,

C.E. Giurgea1, P. Martin2. A. Lend,re 3. S. Froma~e3 and R.D. P0rsolt3 The effects of hydroxyzine (8, 16 and 32 mg/kg i.p.), administered either 30 minutes before exposing rats to a series of inescapable shocks ("stress") or during the subsequent aeqnlsidon of a shuttle box avoidance response, were investigated. In these conditions untreated rats, previously exposed to stress, show a marked increase in escape failures in the shuttle box when compared with non-shocked control animals (qearned helplessness'). Control experiments examined the effe.cls of hydroxyzine on memory (p~ssive avoidance test) and on electric shock sensitivity. Diazepam (2 mg/kg i.p.) was used as a reference compound. Hydroxyzine, when administered before "stress', dearly decreased at 32 mg/kg the number of escape failures observed but was without effect when administered after "stress" during the subsequent shuttle box avoidance learning. Similar results were observed with dlazepam. Unlike diazepam, hydroxyzine at 32 mg/kg induced no amnesia in the passive avoidance test whereas dear amnesia was observed with diazepam. Neither compound altered the rats' sensitivityto shock. These results suggest that hydroxyzine decreases the effects of "stress" and that these effects cannot be attributed either to impaired memory for the aversive stimulatiofi or to diminished shock sensitivity.

1 : Dept. Psychopharm, Univ. Cathol. Louvain, 1348 Louvainla Neuve - Belgium 2 : Fad. Med. Pifi~-Salprtri~re, 91 Bd de l'H6pital, 75013 Paris - France 3 : I.T.E.M.-Labo, 93 Avenue de Fontainebleau, 94270 Kremlin-BicEtre - France

STUDIES IN OBSESSIVE-COMPULSIVE

F.I. Penzel, J. Vasguez and

J.A. Yar~ura-Tobias The present study was made of 17 patients diagnosed as having obsessive-compulsive disorder (DSM-III-R), using the Halstead-Reitan Neuropsychological Test Battery and encephalography (EEG). Nine of the 17 were on psychotropic medications at the time of testing. Routine blood chemistries, liver and thyroid profiles were normal. Complete physical examinations were within normal limits. Of 1 5 a v a i l a b l e EEG's, two evidenced non-specific abnormal. ities, and two seizure disorders. Analysis of group data indicated more than half were at or below the borderline range for consistency of organic impairment on the Halstead Impairment Index. Twelve of the patients showed impaired performance on one aspect of the Tactual Performance Test (TPT), eight on another, and 15 on a third, which is s u g g e s t i v e o f tactual-spatial impairment. Eight patients performed within the brain-damaged range on the Category Test, possibly indicative of logicalanalytical reasoning deficits. Deficits were also detected on the Finger Oscillation Test in 12 patients, which might be indicative of motor impairment. Additionally, longer than expected performance times were seen in ii patients on the Tactile Form Recognition Test, suggestive of tactile sensory deficits. A comparison of impaired versus non-impaired scores showed no significant relationship to either the presence or absence of medications. As a group, these scores point to a concentration of deficits in the anterior regions of the brain - the frontal and parietal lobes, and the inferior motor strip between them. Further, these findings would seem to replicate the results of two previous studies, which reported frontal lobe dysfunction in one case, and spatial perception deficits as measured by the TPT in another. Bio Behavioral Psychiatry 935 Northern Boulevard Great Neck, New York 11021

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BLOOD ;f.iE~ PROFILE IN OBSESSIVE C ~ U L S I V E DISORDER J.A. Yaryura-Tobias, W. Essrein, F. Neziroglu and B. Lindeel. Based cn the serotonergic theory of Obsessive Co~oulsive Disorder (OCD) a blood amine profile, Serotonin, (5-HT), 5-Hydroxyindolacetic acid (5-HIAA), Dopamine (DA) , Epine/nrine (E~I), and Norepinephrine (NE) ,was studied in 102 ounpatients. Patients were classified according to the D~r III-R, as OCD (N=-56), Generalized Anxiety Disorder (GAD), (N=I9), and [~jor Affective Disorder (:&AD) ('.~=27). All patients were drug free for at least 2 weeks. A control group (N=48) without mental illness was used for cc~parison. Multiple t-tests, and a BEHRE{-FISI~ZR test with Welch degrees of freedom were computed. Overall results indicated lower neurotransmitter levels in OCD. The OCD as compared to the GAD group_ had significantly lower 5H-T levels (pf0.05). Sis differences in inter and intracorrelations were primarily observed in the OCD group. Also 16% of 0CD patie_nts had 5-HT levels that fell b e l ~ t/~e 95% inter~Ll of the control group, 11% in the [~AD, and 5% in the GAD. This study indicates that 5-HT may not be the only biological marker for OCD, but one indicator for a subset. Finally the presence of strong intercorrelations arsDng its neurotransmitters suggests a more cc~plex biochemical disorder to exq31ain OCD physi +opatholoqy.

DRUG RESPONSEAND BIOLOGICAL VARIABLES IN OBSESSIVE COMPULSIVE NEUROSIS J. Ananth, A. Djendredjian, R. Polland, A. Kaur, J. Garb~r and R. Gamal 45 patients diagnosed as having OCD on DSM I I I c r i t e r i a for over two years were treated with Clomipramine in a dosage of I00 to 300 mg d a i l y . The patients who had schizoid p e r s o n a l i t y , head i n j u r y , drug h i s t o r y and seizures, were excluded from the study. The patients were assessed p e r i o d i c a l l y by a structured c l i n i c a l i n t e r v i e w on the basis of which family h i s t o r y , Yale Brown Scale for OCD and C l i n i c a l Global Impression Scale were completed. I n i t i a l l y , Neuropsychological Test Battery, MMPI, and Brain E l e c t r i c a l Area Mapping (BEAM) were conducted once, while laboratory t e s t s , electrocardiogram and biochemical tests were conducted p e r i o d i c a l l y for one year a f t e r the i n i t i a t i o n of the study. Response to Clomipramine was assessed by Group vs period ANOVA technique. Neuropsychological Test Battery results did not differentiate the drug treated group from the unmedicated group. I n i t i a l severity score correlated with the'final response. Patients Self Ratings correlated with the Yale Brown Scale Scores. There were two groups of patients with and without family history of OCD. Responseto Clomipramine was significantly correlated with T-I values for right frontal white matter. Prolactin increase also correlated with positive response. As a group, OCD patients BEAMrevealed higher alpha index in the frontal lobe. Side effects did not predict response except that those who i n i t i a l l y had severe agitation could not be continued on the study. Detailed analysis of these various biological variables and their significance in the prediction of Clomipramine response in the treatment of obsessive disorders will be discussed. Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, California 90509 USA.

Bio Behavioral Psychiatry 935 Northern Boulevard Great f$eck, New York 11021

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CLINICAL EXPERIENCE AND EXPERIMENTAL RESULTS WITH LORMETAZEPAM IN A NEW SUBLINGUAL WAFER FORff,ULATION Bischoff,R.C., O t t , H., Rohloff, A. Research Laboratories of Schering AG Berlin/Bergkamen, FRG

CCIrPARIS0~ OF THEP_~PEUTICAL EFFECT OF TOFLAZE-PATE CGNT~ARY TO BROEAZEPAM V e n z o v s k y E.,S o u k u p o v a E. Authors present the results of treatment of 60 patients with loflazepate.The patients were di vided into two groupe of 30 subjects,one group was treated with lof!azepate and the othergroup with bromazepam. The therapeutic results we re evaluated by Hamilton scale of depression. From the diagnostic point of view the patients were diagnosed as neurotic and anxious states, fcbic disorders, masked depressions and sexual insufficiencies. The therapeutic results were with both groups very good. But with the group of patients, %rested by loflazepate was therapeutic effect better / 84 % of improved sub~Jects / than with the group ,treated by bro mezepam / 77 % of improved sub~ects /. The the raoeutic effect of loflazepate was particularl y excellent with masked depressions and from t h i s point of view loflazepate represents a v~iu~ble a d d i t i e n s ~ o r their t h e r a p y for its clear antidepressive / non psychotic / feat-~res.-Loflazepate is produced under the name V i c t a n / Clin - ~{idy, Paris / and bromszepam as L e x o t a n i 1 / Hoffmann Le Roche, Basel /. Psychiatric University C!inic,Sverdlovska 80, 323 18 Pilsen, Czechoslovakia.

Lormetazepam is a benzodiazepine derivative with an e f f e c t ive duration of approximately 6-8 hours and a terminal h a l f - l i f e of I0 hours. In the t a b l e t fonT. i t has been on the market f o r 6 years. The lormetazepam wafer is a new formulation which consists of a small cellulose "stamp" into which the benzodiazepine has been e=~edded. Lormetazepam, which is absolutely tasteless, is released when the wafer is placed in the cheek or under the tongue. The main advantage of t h i s form of application is that the wafer leads to a f a s t e r r~se in plasma levels compared to the t a b l e t administration .Secondly this application route is advantageous f o r the many people who have d i f f i c u l t y swallowing p i l l s . Thirdly the g a s t r o i n t e s t i n a l t r a c t is not involved, an advantage in various medical conditions including the use of benzodiazepines as p r ~ e d i c a t i o n s before surgery or f o r diagnostic procedures. Various experimental and c l i n i c a l studies w i l l be described, qhe results of experimental studies involving EEG and a psychometric test battery showed that the sublingual route of application is preferable to the buccal route from t h e pharmacodynamic point of view. The use of the wafer in sleep disturbance (n=60) as a sedative f o r diagnostic procedures (n=49) and as a premedication before surgery (n=40) have a l l indicated a very high rate of acceptance by the patient (75-80% of patients preferred the wafer to t r a d i t i o n a l t a b l e t s ) . IT~uber U., et a l . , Plasma levels of lor~etazepam a f t e r sublingual and oral administration of I mg zo humans. Drug Development and I n d u s t r i a l Pharmacy 10 (10) 1587-1596 (1984).

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1S IT POSSIBLE YO~A~JR~.&NTICIPATORY AXIETY IN ANI~ALS? F. Borsini, A. Lecci and A. Meli During exnerL~ents aimed at determining the effect of drugs on rectal temperature in mice, it was casually obser red that, among animals of the same cage, those removed later had a higher tenmerature as compared to those removed earlier. It was noted that this ~henomenon a) could be observed by reversin~ the order of removal of the animals from., the cage; b) persisted, at least, over 5 days; c) was present regardless the number of the animals in each cage and d) was independent td~ether the animal which has been taken was transferred to a different cage or again allocated in the same cage. These findings, together ~dth the observation that the mice remoVed earlier~.hec~me h}~erthermic~ ~ k e n a~ain immetliat~ ly after the removal of the last one, could be interpreted as indicati~,e of a state of anticipatory, anxiety. This could be also substantiated by the fact that this rise in rectal temnerature was prevented by d i a z e ~ administered either orally (2.5 and 5 mg/kg, 30 min) or intracerebroventricufarly (O.IO and O.17 mg/kg, IO min), but not by imipramine (15 and 30 mg/kg, po, 60 min) or haloperidol (0.5 and 1 mg/kg, po, 60 min). Presunfably, this rise in rectal temoerature is not attributable to the physical exercise due to an attempt to escape, since a) there is no correlation between motor activity (open-field) and rise in rectal temnerature and b) rise in rectal temnerature was also observed in mice sedated by haloperidol. This model could renresent a new tool for studying the neurobiolo~" of anticinatory anxiety. '~. Menarini" s.a.s. Pharmaceuticals, Research Division, Via Sette Santi 3, 50131 Firenze, Italy.

LEVOPROTILINE - TREATMENT OF ANXIETY STATES G.-E. KUhne, U. Binz, G. Wendt Levoprotiline is the R-(-)-enantiomer of the racemate o x a p r o t i l i n e , the hydroxylated d e r i v a t i v e of the a n t i depressant maprotiline. The pharmacological p r o f i l e s of the three drugs are comparable, but in contrast to maprotiline and oxaprotil i n e , l e v o p r o t i l i n e is completely devoid of NE-reuptake inhibition. A series of double-blind c l i n i c a l studies vs. standard antidepressants revealed both antidepressant and a n x i o l y t i c efficacy as well as superior t o l e r a b i l i t y of levoprotiline. A new study was aimed at the a n x i o l y t i c effects of l e v o p r o t i l i n e in patients with anxiety states ( i . e . generalized anxiety syndrome, social phobia sensu DSM I I I ) . A broad spectrum of scales was used to find out the possible a n x i o l y t i c p r o f i l e of the drug: s e l f ratings with Erlanger Anxiety Scale (EAS-S), an Interaction-Anxiety-Test (IAF), and the KUSTA, and the physician's rating scales HAMA, HN4D, ASI and CGI. A d d i t i o n a l l y , sleep q u a l i t y was repeatedly rated with a newly developed short scale. F i r s t analyses of the data gave clear evidence of sleep improving properties and a n x i o l y t i c effects in both somatic and psychic symptoms as well as in social aspects. Detailed results w i l l be presented and discussed. Klinik fSr Psychiatrie und Neurologie "Hans Berger" Bereich Medizin, F r i e d r i c h - S c h i l l e r - U n i v e r s i t ~ t Jena Philosophenweg 3, DDR 6900 Jena

357

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EFFECTS OF A NEW BENZODIAZEPINE DERIVATIVE, ETHYL LOFLAZEPATE (CM6912), ON THE AROUSAL LEVEL OF NORMAL HUMANS: ASSESSMENTBY THE AVERAGED PHOTOPALPEBRAL REFLEX H. Isozaki*, M. Tanaka*: Y. Mizuki*** and K. Inanaga**** The averaged photopalpebral r e f l e x (PPR) is a reocord of the mean of summated r e f l e x i v e contractions of o r b i c u l a r i s oculi muscle in response to p e r i o d i c a l l y applied photic s t i m u l i . The peak latencies of PPR have been reported to be s e n s i t i v e l y shortened and prolonged according to elevation and lowering of the arousal level of the subjects, respectively (M. Tanaka et a l . , Folia Psychiat. Neurol. Jpn., 3__77,67, 1983). In the present study, we investigated the effects of a new benzodiazepine d e r i v a t i v e , ethyl l o f l a z e p a t e (CM6912), on the arousal level of normal male humans by use of PPR f o r assessing the arousal level of the subjects and predicted the p o s s i b i l i t y of the drug as a hypnotic and/or a n x i o l y t i c . The ten u n i v e r s i t y student volunteers, ages from 20 to 24 years were subjected to the study. Four doses of ethyl l o f l a z e p a t e , i . e . , 2 mg, 4 mg, 6 mg and 8 mg, and a plcebo were administered to each subject 30 min a f t e r lunch according to a double-blind, crossover design. Ethyl l o f l a z e p a t e s i g n i f i c a n t l y prolonged both latencies of PPR with a dose-dependent manner. The dose-response curve f o r both l a t e n c i e s , derived from the maximum prolongation, showed a d e f i n i t e and l i n e a r dose-response r e l a t i o n s h i p . The drug action occurred w i t h i n I hour, peakdd at 2.5-3 hour and continued s l i g h t l y even 4 hour a f t e r medication. In the subjective assessments, vagueness of thought, sleepiness, and weakness were only s l i g h t l y observed. These results suggest t h a t ethyl loflazepate could be a potent hypnotic and/or a n x i o l y t i c which possesses a r e l a t i v e l y rapid onset of action with moderate duration and has no severe side e f f e c t s . * C l i n i c a l Laboratory, ** Department of Pharmacology and ****Department of Neuropsychiatry, Kurume University School of Medicine, and ***Department of Neuropsychiatry, Yamaguchi University School of Medicine, Ube 755, Japan.

MIDAZOLAM, TRIAZOLAM AND TEMAZEPAM RESIDUAL EFFECTS U P O N VISUAL SEARCH BEHAVIOR AT INTERSECTIONS DURING AN U R B A N DRIVING T E S T Ih Quasten, w.J. Riedel, C. Hausen and J.F. O'Hanlon Benzodiazepine hypnotics can have residual sedative effects on driving performance that last throughout the day following nocturnal ingestion. Studies until now have concentrated upon the occurrence of such effects in one particular driving environment; i.e. during prolonged, uninterrupted high-speed operation on highways. The question remains whether driving would be equally impaired during low-speed operation in busy urban traffic. The present study was designed to answer this question. Sixteen shiftworkers were treated subchronically (5 days) ~dth hypnotic drugs and placebo according to a 4way, double-blind design. The doses were midazolam 15 mE, trlazolam 0.5 m g and temazepam 20 mE, d.d., p.o. After the Ist and 5th successive doses the subjects slept during the day within sleep-lab facilities and were awakened for testing which began six hours after tablet ingestion. The driving test consisted of operating a specially instrumented vehicle under an experimenter's supervision around a 9.3 k m urban circuit. Subjects' eye movements and fixations were measured using a NAC-4 eye mark camera and video recording system. The a n a l y s i s of t h e s e d a t a w a s c o n f i n e d to l o c a t i o n s a l o n g t h e r o u t e w h e r e t r a f f i c c o n f l i c t s w e r e l i k e l y to o c c u r ; i.e. a t i n t e r s e c t i o n s . F a i l u r e s to s e e k v i s u a l i n f o r m a t i o n i n d i c a t i n g t h e p o t e n t i a l p r e s e n c e of a p p r o a c h i n g v e h i c l e s w e r e t h e p r i m e p e r f o r m a n c e m e a s u r e s . In a d d i t i o n , t h e s a f e t y of t h e s u b j e c t ' d r i v i n g p e r f o r m a n c e w a s r a t e d b y an expert u s i n g a s t a n d a r d c h e c k - l i s t . R e s u l t s ~dll be p r e s e n t e d a t t h e c o n f e r e n c e . I n s t i t u t e f o r D r u g s , S a f e t y a n d B e h a v i o r , U n i v e r s i t y of L i m b u r g , P.O. Box 616, 6200 MD M a a s t r i c h t , The Netherlands

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ASSESSMENT OF THE ANTIAGGRESSIVE E F F E C T S OF A PUTATIVE ANXIOLYTIC, CGP 361A, VERSUS THOSE OF DIAZEPAM AND PLACEBO IN HUMANS USING A NOVEL EXPERIMENTAL APPROACH C. v a n L e e u w e n , W. Riedel, H. Hamers a n d J.F.O'Hanlon A r e c e n t l y d e v e l o p e d p r o p r a n o l o l d e r i v a t i v e , CGP 361A, was f o u n d to h a v e b o t h c o n v e n t i o n a l a n t i a n x i e t y e f f e c t s and unusual antiaggressive effects in studies employing animal models of emotional behavior. It seemed i m p o r t a n t to c o n f i r m t h e l a t t e r in h u m a n s b u t m e t h o d s f or r e l i a b l y e l i c i t i n g a g g r e s s i v e f e e l i n g s a n d o b j e c t i v e l y m e a s u r i n g t h e same a p p e a r e d to be l a c k i n g . The f i r s t p u r p o s e of t h i s p i l o t s t u d y w a s to d e v e l o p a method a n d t h e n a p p l y i t in a c o m p a r a t i v e s t u d y of CGP 361A's, d i a z e p a m ' s a n d p l a c e b o ' s e f f e c t s u p o n c o n t r o l l e d a g g r e s s i o n . P a r a l l e l g r o u p s c o m p r i s e d of 12 or 13 y o u n g males who e x p r e s s e d positive interest in v i o l e n t contact sports were studied during separate 1-hour p r e s e n t a t i o n s of a c o n t r o l v i d e o film a n d o n e s h o w i n g a p a r t i c u l a r l y v i o l e n t b o x i n g match. R e s p e c t i v e g r o u p s w e r e t r e a t e d w i t h o r a l d o s e s of CGP 361A 2 rag, d i a z e p a m 10 mg a n d p l a c e b o 1 h o u r b e f o r e t h e l a t t e r presentation. Various physiological, subjective and psychomotor parameters were measured before, during and after both presentations. Most revealing were catecholamine excretion rates determined for urine sam!~les c o l l e c t e d o v e r p r e s e n t a t i o n p e r i o d s . Diazepam b l o c k e d b o t h t h e p r o n o u n c e d subjective e f f e c t s of w a t c h i n g t h e v i o l e n t p r e s e n t a t i o n a n d t h e 300% + (p<.001) r i s e in a d r e n a h n e e x c r e t i o n w h i c h o c c u r r e d c o m p a r a b l y i n t h e two o t h e r g r o u p s . Simple sedation could not have been r e s p o n s i b l e for the d i a z e p a m e f f e c t s i n c e t h e d r u g h a d l i t t l e i n f l u e n c e on p s y c h o m o t o r p e r f o r m a n c e . The t e s t s e e m s s e n s i t i v e to t h e e f f e c t s of a n x i o l y t i c s on i n d u c e d e m o t i o n a l s t a t e s i n man. Institute for Drugs, Safety and Behavior, University of Limburg, P.O. Box 616, 6200 M D Maastricht, The Netherlands

LONG TERM COMPATIBILITY OF LOW DOSE TREATMENT WITH FLUSPIRILEN (FLU) IN OUTPATIENTS - PRELIMINARY RESULTS

358

M . O s t e r h e i d e r and G . R e i f s c h n e i d e r There is a change in the drug m a n a g e m e n t of patients with p s y c h o s o m a t i c and phobic disorders among general p r a c t i t i o n e r s and psychiatrists. Drug dependency under B e n z o d i a z e p i n e (B) treatment has become a severe problem. Alternative p r e s c r i p t i o n of low dose n e u r o l e p t i c s (NL) becomes more favored. Main topics are focused on side effects of N L - e s p e c i a l l y on e x t r a p y r a m i d a l symptom (EPS); specific abnormal involuntary movement (AIM). There is a lack of i n f o r m a t i o n about severity and frequency of n e u r o l o g i c a l impairment in this group of patients. Outpatients with minimum three years under continous or interval t r e a t m e n t with FLU onl~ are compared with patients under B without any NL treatment in their history. Diagnostic criteria include DSM III 300, 307, 309, 316 and ICD 300, 306, 309 categories. S t a n d a r d i z e d diagnostic i~ formed by using rating scales of SIMPSON (EPS), AIMS (NIMH), Akathisie schedule (TEGELER) UKU and WEBSTER-scale. Psychopathometric evaluation includes FPI, CGI, HAMA, STAI and SDS. The rate'of AIM and EPS under FLU shows only a mild tendency to rise compared with spontaneus oc-

curence, The d i a g n o s t i c t o o l s a correct evaluation

have t o be i m p r o v e d f o r of these side effects.

Psychiatrische Universit~tsklinik WOrzburg F O c h s l e i n s t r a 6 e 15, D-8700 WOrzburg

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In the course of open medication trials with social phobics, we observed two types of socially anxious patients. The first had discrete fears of one to several situations, such as speaking, writing, or eating in public. These patients usually had normal interpersonal relationships. In contrast, a second group had pervasive avoidance of or severe anxiety during most or all activities involving social interaction. These generalized social phobics led severely restricted or nonexistant romantic and social i ives. Patients with DSM III social phobia entering a double blind controlled trial of phenelzine, atenolol and placebo were prospectively classified as having the generalized or discrete subtype. To d~te 56 patients have completed the acute 8 week treatment trial. At week 8 five of the 20 (25%) patients on placebo, 5 of 18 (28%) on atenolol, and 13 of 18 (72%) on phenelzine were considered responders; these rates of response differ significantly (p =.02). Phenelzine was significantly more effective than placebo (p = .Ol) and atenolo! (p = .02), which did not differ. Response rates among the 41 generalized social phobics were 79% (11/14) for phenelzine, 15% (2/15) for atenolol, and 21% (3/14) for placebo (p < .001). Phenelzine was significantly more effective than both atenolol (p = .001) and placebo (p = .003), which did not differ. Among the 15 discrete social phobics, 1 out of 4 (25%) of patients on phenelzine, 3 out of 5 (60%) on atenolol, and 2 out of 6 (33%) on placebo were judged responders (N.S.). Phenelzine is showing a trend toward being more effective (p = .08) in generalized than discrete, and atenolol more effective (p = .i0) in discrete than generalized, social phobia.

HYPNOTIC AND ANTIANXIETY EFFECTS OF ZOPICLONE VS NITRAZEPAM V. Manna, N. Martucci and A. Agnoli The effects of zopicIone (7,5 mg per os at bedtime), a new non-benzodiazepine drug, on anxiety levels, time of sleep induction, hours of sleep, number of nocturnal arousals, quality of sleep and quality of daytime arousal were evaluated by using psychometric ratings. A random double-blind cross-over study versus nitrazepam (5,0 mg per os at bedtime) was performed on 20 patients (8 M and 12 F, mean age 38,2 +.2,1 yrs) affected by insomnia and Generalized Anxiety Disorders (DSM I I I ) . The treatments lasting 2 weeks were intervalled with a week of placebo administration. The effects were evaluated by using HRSA, a time-signed semiquantitative scale for anxiety and the Tolouse-Pieron Attention Test. Time of sleep induction (p/-,O,OOl), quality of daytime arousal (p~O,Ol), HRSAscores (p~,.O,OS), daytime anxiety levels (p~O,OOl) and Tolouse-Pieron Attention Test results significantly improved after zopiclone than after nitrazepam administration. The results of the t r i a l confirm the effectiveness of zopiclone in the treatment of insomnia with effects similar to nitrazepam on quality and duration of sleep and number of nocturnal arousals, but superior in all the other parameters. I.N.I. - 00046 Grottaferrata - Roma - I t a l y

ABS880001

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POSTER PRESENTATION 33.04

Pain and Psychopharmacology

RANDOMIZED PLACEBO-CONTROLLED DOUBLE-BLIND 5PERIOD CROSSOVER STUDY ON ANALGESIC PROPERTIES OF THREE ACUTE O R A L DOSES OF CM 40907 AND ASA EMPLOYING CO2-LASER FOR NOCISTIMULATION W. Klausnitzer*, K. Schaffler* A randomized, double-blind crossover study was run with three acute oral dosages (600, 900 and 1200 mg) of CM 40907 - a newly d e v e l o p e d a n t i c o n v u l s a n t d r u g , w h i c h c h e m i c a l l y is a 6( 2 ' c h l o r o p h e n y l ) - 3 - ( 4 ' h y d r o x y p i p e r i d i n o ) - p y r i d a z i n e - vs ASA (1000 rag) and placebo in 12 male healthy volunteers to compare analgesic potencies. CO2-1aser radiant heat emission, which - with high selectivity stimulates nociceptive A-delta and C-fibers, was employed for nocistimulation. Objective algesimetry was done by means of CO slaser somatosensory evoked potentials (LSEP). Effects on vigilance were screened by auditory evoked potentials (AEP). There was a simultaneous control of vigilance alterations with regard to both types of evoked potentials by means of an adaptive pursuit tracking task (APTT). Subjective pain intensities were measured by postLSEP pain ratings. Subjective sedation, excitation and anxiety were screened- by visual analog scales. Blood pressure, heart rate (supine and upright) and tolerance ratings were recorded in addition. All dosages of CM 40907 showed an analgesic effect in the laser model, with. significant reductions of P2-LSEP-amplitudes. With regard to this component the effect of 1200 mg CM 40907 was more marked than that of ASA, which was also effective in the N I component. Like ASA CM 40907 reduced pain as measured by subjective rhtings. Subjective sedation was decreased, however A E P findings cued a decrease of vigilance after CM 40907. Excitation and anxiety were not significantly altered after CM 40907. Blood pressure and heart rate were not significantly raised after CM 40907, which was in general well tolerated. The onset of action was somewhat slower after CM 40907, when compared with ASA. There were cues that CM 40907 (1200 rag) is active till hour 6 after dosing with a peak effect within hour 1 and 2. With regard to the majority of measures CM 40907 showed a linear dose-efficacy. * Institute for Pharmacodynamic Research, Chamm~nsterstr. 4a, D 8000 Munich 82, FRG

359

33 04 02

33.04.03

WHAT IS CHRONICADMINISTRATION OF ANTIDEPRESSANTS IN ANIMALS ? ILLUSTRATEDBY THE STUDYOF THE ANALGESIC EFFECT OF CLOMIP~MINE IN MICE. A. Eschalier, J. Fialip, 0. Varoquaux, M.C.Makambila, H. Marty, P. Bastide. The pattern of repeated administration of antidepressants in animals varies from one study to another making comparison of results d i f f i c u l t . The aim of the present work is to propose standardized pattern of administration based on animal pharmacokinetic parameters, to be close to clinical use. Therefore, chronic administration should correspond to injections repeated every plasma elimination h a l f - l i f e i . e . 130 min for clomipramine (CMI) in the Swiss CD] mice used, though daily administration, so often used in-rodents, is merely repeated acute administration.The antinociceptive action of CMI(10 or 20 mg/kg,i.p.) varied according to the pattern of administration used : the effect obtained after an acute injection was increased twofold after 5 chronic injections ; closely-repeated injections (every 40 min) gave a more marked effect than chHonic administration, and daily administration (for 3-8 or 16 days) was ineffective. The antinociceptive a c t i v i t y was correlated with blood and brain levels of CMI and of its demethylatedmetabolite, independant of any modification of motor activity (especially after 5 chronic injections), and was suppressed by naloxone. These results emphasize the importance of the pattern of administration and' of pharmacokinetic data, often overlooked, for pharmacodynamic studies in animals which therefore w i l l better predict effects in humans.

ANTINOCICEPTIVE EFFECT O F THE TRIAZOLOBENZODIAZEPINE ALPRAZOLAM O N EXPERIMENTAL PAIN. A N T A G O N I S M BY R0-15.1788 BUT NOT BY NALOXONE. J.A.Mico, M.C.G6mezTCama , J.Casas, I.Leonsegui, R.Maldonado, R. Fernandez and J.Glbert-Rahola. The benzediazepines (BZP) in general have shown mixed results w i t h respect to their ability To increase nociceptive thresholds. A l t h o u g h some studies report no effect,others have reported m i l d antinociceptive effects in man and in animals. Moreover, the m e c h a n i s m of this effect is not clear. The aim of this study was to investigate the influence of alprazolam (ALPZ) on experimental pain and to attempt elucidation of the m e c h a n i s m s of action. The experiments w e r e carried out on OF1 m i c e lhot plate test and acetic acid test) and W i s t a r rats (tail flick test). The doses of ALPZ used were: in the acetic acid test, 0.007/ 0.015/ 0.031/ 0.062/ 0.125/ 0.25/ 0.5 and ] m g / k g i.p. In the hot plate test and tail flick test, 0.5/ 1/ 2 y 4 mg/kg i.p.In another experience the effect of chronic ALPZ (0.5 mg/kg, tree days} on the acute effect of m o r p h i n e (0.25 m g / k g s.c) was investigated. Finally, t]se mediation of opioid and BZD-receptors was evaluated. The results were analyzed w i t h the KxllskallWallis tes~ (H} and M a n n - W h i t n e y U test. ALPZ alone in the doses used did not affect significantly The nociceptive responses of mice in the hot plate test (H=3.322) and rats in the taJ] f) ick test at any time(30 rain. H=6.063t 60rain. H=1,8501 90 rain. H=5.334; 120 min. H=3.605l. These two tests are freqQently used to dete6t potent narcotic analgesics. Similarly, in the hot plate test, chronic ALPZ treatment did not affected significantly the effect of m o r p h i n e given acutely (H=4.500). However, in the acetic acid test, ALPZ elicited ~ntinociceptive p r o p e r t i e s at v e r y small doses (0.031 mg/kg, U=41.5 p~=.05) w i t h a good dose-effect correlation {y=3.58+4.99b, r=0.665 p~=.O5}. The specific BZD-antagonist Ro-15.1788 inhibited in a dose-dependent m a n n e r the antinociceptive effect of ALPZ (20 mg/kg U=28.5 n.s; 40 mg/kg U=9.5 p ~ = . 0 1 l . T h e opiate antagonist naloxone (0.5 and I mg/kg} was completely i,effective. In conclussion, this study has revealed that ALPZ like other clasic BZD induces antinociceptive test-dependent properties and that this effect could be mediated by BZD-recept ors.

Laboratoire de PharmacologieM~dicale, INSERM U195, Facult~ de M~decine, 63001Clermont-Ferrand C6dex.France.

Department of Neuroscience. Faculty of Medicine. Plaza de Falla, 11003, Cadiz (SPAIN}.

33 04 04 EFFECT OF MU OPIOIDS ON SYNAPTIC MEMBRANE (Na§ ACTIVITY FROM RAT CEREBRAL CORTEX IN THE PRESENCE OF SEVERAL DIVALENT CATIONS. T. Nishikawa, T. Teramoto and S__~.Shimizu It has been reported that opioids inhibit the enhanced release of several neurotransmitters in the central nervous system. However, the biochemical mechanism of their inhibitory action has not been elucidated so far. In the present experiments, effects of opioids were studied on the synaptic membrane (Na++K+)-ATPase activity f r o m r a t c e r e b r a l c o r t e x in t h e p r e s e n c e of biolo~ically impoltant divalent metal ions such L + Z + Z + ~ + as Ca , Fe , Cu = and Zn . Mu opioid agonist~, morphine (I0-=-I0 -u M) and dynorphin A 3-8 (10 -~, 10M) but not k~ppa ags dynorphin-(1-8)octapeptide (10 -=, 10 -~ M), s t i m u l a t e d the suppressed sy~aptic membrane (Na~+K+)-ATPa~e activity by ~e (10- -10- M) or Fe plus Zn (10 -~, 10 -v M _) i n t h e i D c u b a t i o n ~edium containing I0-b-2.2 x 10 - ! M f r e e Ca z+. M U opioids, however, failed to s t i m u l a t e the (Na++K+)-ATPase activity in the absence of Fez and s c % r c e l y ~ f f e c ~ e d the s u p p r e s s e d enzyme activity by Cu z+, Zn z+ and Fe2+ plus Cu 2+. The stimulatory effect of mu opioids was antaggnize ~ by specific opioid antagonist naloxone (10-=-I0 T M M). 'The concentrations of the synaptic ~embrane bound Fe, C~ and Zn were 3.2 + 0.4 ~ 10 -~, 3.9 + 0 . 4 x 1 0 - " a n d 7 . 0 ~ 0 . 6 x I 0 - " m o l eq. /g membrane protein, respectively. These results indicate that mu opioid agonists may stimulate the suppressed ~(Na++K+) ATPase activity by interacting with Fe z+ at its opioid receptor sites and inhibit the cell depolarization through their stimulatory action on this enzyme in the brain. Department of Pharmacology, Kagoshima University, Dental School, Kagoshima 890, Japan

360

33.04.05 D E V E L O P M E N T OF C O N T R O L L E D

RELEASE DRUG

DELIVERY SYSTEMS CONTAINING DIAZEPAM

S.C.Chaicta~aj, S.K.Da~, S.K.Gho6~ and B.K.Gupiza The most prominent CNS effects of diazepam are sedation, hypnosi% anxiolytic, muscle relaxation and anticonvulsant activity. The distributive (alpha) half-life of diazepam is about 2.5 hours which requires frequent administration of the drug in anxiety neurosi% psychosomatic disorders, muscu]o-skeletal spasm in order to maintain the effective therapeutic concentration of the drug in blood. The aim of this study was to develop drug delivery systems capable of maintaining the plasma level of diazepam for a prolonged period thus increasing the therapeutic potential of the drug with much lesser side effects. Drug delivery systems were fabricated adopting the principles of microencapsu|ation, pelletization and gastric retention systems. Physicochemical characterisation of the dosage forys were carried out to have reproduceable delivery syst-ems. In ~/tro drug release profile was studied using the USP methods. In vivo bioavailability of the drug delivery systems were assessed in experimental animals. Satisfactory drug level was maintained in the blood for 24 hours with single administration. Prolongation of sedation time was also observed. Such drug delivery systems for diazepam would be highly efficacious in maintaining the optimum CNS activity. The dosage forms also serves the requirements of patients corn pliance. Division of Pharmaceutics, Department of 3adavpur University, Calcutta - 700 052. India

Pharmacy,

33.04.06 THE ANALGESIC PROPERTIES OF SOME SUBSTITUTED AMPHETAMINES L M. Beaton. F. Beningon and R. D. Morin. We have previously shown that two amphetamine analogues, the alpha-methyl and alpha-ethyl derivatives of methylenedioxymethamphetamine, have potent analgesic properties. We believe that the analgesic action of these agents is due in part to their substituents in the para position. Therefore, a series of amphemmlne analogues, substituted in the para position were synthesized and tested for their ability to induce analgesia in mice. The compounds tested were amphetamine, 2,5-dimethoxy-4-methyl-amphetamine (DOM), 4hydroxy-amphetamine (4-HO-AMP), 4-HO-N-methyl-AMP, 4methoxy-amphemmlne (4-MeO-AMP), 4-MeO-N-methyl-AMP, 4HO-2,6-dimethyl-amphetamine, 4-MeO-2,6-dimethyl-amphetamine and the N-methyl derivatives of these last two compounds. Analgesia was measured using a tail-flick apparatus manufactured by the Columbus Instruments Corp. Dose response curves were obtained using groups of five mice for each dose. The doses ranged from 0.75 to 24 gmol/kg. The animals were tested at 10 min intervals, beginning 30 min after intraperitoneal administration of the compounds in a volume of 0.1 ml/10g. Testing continued until each animal's response time had returned to preinjection control levels. With some of the higher doses, testing was terminated 180 rain post-injection, although some analgesia was still present. All compounds showed some degree of analgesia. In general, the N-methylated compounds were more potent than the nonmethylated equivalent compounds. It is hypothesized that the mode of action of the analgesia is via an interaction at the mu opiate receptor and that these compounds bind to this receptor in a manner similar to that of enkephalin, as suggested by Horn and Rogers (Nature 260, 795, t976). (Supported in part by the Alabama Consumer Fund). Neuropsychiatry Research Program and Department of Psychiatry, University Station, Birmingham, Alabama 35294, U.S.A.

33.05.01

POSTER PRESENTATION 33.05

Miscellaneous

A U D I T O R Y B R A I N S T E M EVOKED R E S P O N S E LATENCIES AND M E T N Y L P H E N I D A T E PLASMA C O N C E N T R A T I O N S J.A. C a m p - B r u n o and B . G . W i n s b e r 9 We have reported prolonged auditory brainstem evoked response (ABER) latencies in Attention Deficit Disorder Hyperactivity (ADDH) children and latency normalization with methylphenidate (MP). Using 0.25, 0.5, and 1.0 mg/kg MP, we then reported that for right ear stimulation, Wave Ill was shorter at 1.0 than 0.5 mg/kg and Wave VI shorter at 1.0 than 0.5 mg/kg and placebo. We now present data relating A B E R latencies and MP plasma levels in 13 A D D H boys tested under placebo, 0.25, 0.5, and 1.0 mg/kg, A B E R s to left and right ear clicks were recorded between vertex and ipsilateral mastoid with contralateral mastoid as ground; plasma MP was assayed by gas chromatography, Wave I l l latency change re placebo for l e f t ear stimuli correlated with plasma MP at all three doses, whereas for right ear stimuli significance obtained only with 0.25 mg/kg. However, since not all children showed a linear latency decrease with dose, we reanalyzed Wave I I I using the dose condition which demonstrate~ maximum latency decrease. This approach yielded a highly significant correlation between right ear maximum latency change in Wave I l l and plasma MP. Based on our prior finding that the major effect of MP was a latency decrease under 1.0 relative to 0.5 rag/ks, difference scores using the 0.5 and 1.0 mg/kg dose data were computed for Waves I I I and VI and for MP concentrations. Wave V: dose-difference scores for right ear stimuli significantly correlated with plasma MP dose-difference scored: correlation for Wave I l l was significant only for the subgroup showing shorter latencies at i.0 than at 0.5 mg/kg. Like our earlier finding that MP decreased only right ear ABER latencies, no significant correlations emerged between dosedifference scores for left ear latency change and plasma MP. These relations between plasma levels and ABER latency change suggest that MP may exert its therapeutic effect in children by modulating CNS information transmission, perhaps by either a direct effect on monoaminergic activity os afferent generators of ABER components and/or indirectly via pharmacologic alteration of efferent feedback from higher CNS structures, Division of Child Psychiatry, Nathan S, Kline I n s t i t u t e f o r Psychiatric Research, Orangeburg, Ny 10962, USA.

361

33.05.02

33.05.03

PSYCHOPHARMACOLOGICAL TREATMENT DISORDERS IN A D O L E S C E N T S G.-E.

Trott,

T. Elliger,

H.-J.

OF E A T I N G

Friese

The p h a r m a c o l o g i c a l t r e a t m e n t of e a t i n g - d i s o r d e r s is not v e r y common, and there have b e e n v e r y few i n v e s t i g a t i o n s as to their e f f i c i a n c y . R e c e n t b i o l o g i c a l s t u d i e s have i l l u c i d a t e d on the m e c h a n i s m s of the p e r i p h e r a l and central m e d i a t o r s of s a t i e t y and a p p e t e n c e . It seems to be the logical c o n s e q u e n c e to try to i n f l u e n c e these m e d i a t o r s p h a r m a c o l o g i c a l l y - e s p e c i a l l 7 the n e u r o t r a n s m i t t e r s s e r o t o n i n e and n o r e p i n e phrine. In the t r e a t m e n t of a n o r e x i a n e r v o s a m i n o r tranquilizers, antidepressants, lithium , Metoclopramid, N a l o x o n e , C l o n i d i n e and C y p r o h e p t a dine have b e e n used. R e l a t i v e l y good e x p e r i e n c e has b e e n m a d e w i t h n o r a d r e n e r g e a n t i d e p r e s s a n t s and C y p r o h e p t a d i n e , b u t their effet was not convincing. In the t r e a t m e n t of b u l i m i a a n t i d e p r e s s a n t s , C a r b a m a z e p i n e and F e n f l u r a m i n e have b e e n used. P o s i t i v e e f f e c t s h a v e b e e n seen W i t h F e n f l u r a m i n e and D e s i p r a m i n e . T h e r e is also e v i d e n c e for ~ good r e s p o n s e by F l u v o x a m i n e , but these effects s h o u l d still be f u r t h e r e v a l u a t e d . A m u l t i m o d a l t r e a t m e n t c o n c e p t should be designed for b u l i m i c and a n o r e c t i c patients. A p h a r m a c o l o g i c a l c o - t h e r a p y c o u l d be of great i m p o r t a n c e in this context. Universit~tsklinik und-Poliklinik K i n d e r - und J u g e n d p s y c h i a t r i e Direktor. Prof. Dr. G. N i s s e n F u c h s l e i n s t r . 15 D-8700 W ~ r z b u r g

A c u t e 6mg doses of b r o m a z e p a m , g i v e n b o t h as a l i q u i d and in 2 d i f f e r e n t t a b l e t f o r m u l a t i o n s , w e r e c o m p a r e d in a d o u b l e - b l i n d , p l a c e b o and v e r u m ( l o r a z e p a m 2mg) c o n t r o l l e d study, i0 female s u b j e c t s r e c e i v e d all t r e a t m e n t s in a c r o s s o v e r d e s i g n ~rith e a c h s u b j e c t a c t i n g as h e r own control. Morning drug administration was a s s e s s e d at i, 2, 4 and 6 h o u r s p o s t dose. C r i t i c a l f l i c k e r f u s i o n f a i l e d to d i s t i n g u i s h active t r e a t m e n t s f r o m p l a c e b o . R e a c t i o n time, t r a c k i n g and w o r d r e c o g n i t i o n t a s k s w e r e s i g n i f i c a n t l y i m p a i r e d b y the verum. The time c o u r s e and d e g r e e of i m p a i r m e n t s e p a r a t e d d i f f e r e n t f o r m u l a t i o n s of b r o m a z e p a m . The l i q u i d p r e p a r a t i o n c o u l d not be d i s t i n g u i s h e d f r o m p l a c e b o on any m e a s u r e s . E a c h of the t a b l e t f o r m u l a t i o n s was s e p a r a t e d b y d i f f e r e n t l e v e l s of i m p a i r m e n t on p s y c h o motor performance. These r e s u l t s e m p h a s i s e the r o l e of g a l e n i c s in the p r e p a r a t i o n of a n x i o l y t i c c o m p o u n d s , w h e r e t h e i ; e f f e c t on the s k i l l e d p e r f o r m a n c e of arabuiant p a t i e n t s is i m p o r t a n t . H u m a n P s y c h o p h a r m a c o l o g y R e s e a r c h Unit, Dept. of P s y c h o l o g y , U n i v e r s i t y of Leeds, L e e d s LS2 9JT, England.

f~r

33.05.04 THE EFFECTS OF ALCOHOL AND BENZODIAZEPINES ON BEHAVIOURAL AGGRESSION AND MOOD A.J. Bond and M.H. Lader A competitive reaction time task designed to measure behavioural aggression has been used to examine the effects of alcohol and benzodiazepines. Self-ratings of mood, anxie~y and aggression were completed pre and post treatment and post task. In the first study, subjects were administered a low dose of alcohol (0.25 mg/kg), a moderate dose of alcohol (0.75 mg/kg) or placebo. It was found that alcohol increased bshavioural aggression in a dose-related way without increasing ratings of anxiety or aggression. In the second study, subjects were administered lorazepam (i or 2 mg), oxazepam (15 or 30 mg) or placebo. The two benzodiazepines had very similar subjective effects but the 2 mg dose of lorazepam increased behavioural aggression more than any other treatment. This may be related to ceiling efficacy. Currently a study of the combined effects of 0.5 g/kg alcohol and 1 mg alprazolam on behavioural aggression and mood is being undertaken. Institute of Psychiatry, De Crespigny Park, London SE5 8AF. U.K.

362

THE E F F E C T S OF D I F F E R E N T P R E P A R A T I O N S OF B R O M A Z E P A M ON L A B O R A T O R Y A N A L O G U E S OF C A R DRIVING C.A. A l f o r d t J.Z. B h a t t i and I. H i n d m a r c h

33.05.05 THE EI~fECTS OF MINAPRIME TAKEN WITH AND WITHOUT ALCOHOL ON INFORMATION PROCESSING, PSYCHOKOTCR PERFORMANCE AND CAR H A N D L I N G ABILIT7

iT.A.Betts, 2p.Morrison and 3Z.Subhan Minaprine hydrochloride is an aminophenylpyridazine derivative currently under development as an antidepressant. It facilitates serotonergic and dopaminergic transmission (by presynaptie and postsynaptic mechanisms) and facilitates cholinergic transmission by a direct action at the muscarinic receptor site. The results of several placebo controlled studies evaluating the psychopharmacological effects of minaprine both alone and in combina'cion with alcohol in healthy volunteers are presented. Objective assessments of pharmacodynamic activity included critical flicker fusion threshold (CFFT), choice reaction time (CRT), memory scanning, and both simulated and actual car driving. Subjective ratings of mood and degree of sedation were also conducted. In summary, results from these studies provided no evidence of deleterious effects of mi/naprine on human cognitive function including actual vehicle handling ability. Further, minaprine does not augment or potentiate the disruptive effects of alcohol on aspects of human performance. These findings are discussed in the context of minaprine's original profile of activity. 1 . 2Unlverslty of Aston, Aston Triangle, Birmingham, U.K. _Guys Drug Research Unit , London, U .K . j Sanofi U.K. Ltd, Wythenshawe, Manchester, U.K.

33.05.06

33.05.07

IS EEG MONITORING OF ELECTROCOI,YOLSIVE THERAPY CLINICALLY USEFUL? R. G. McCreadie, K. Phillips and A. D. T. Robinson EEG monitoring was carried out in I~9 bilateral and 114 unilateral applications of ECT, given to 51 patients in an everyday NHS setting by junior medical staff. In 2.5% of bilateral and 8% of unilateral applications there was disagreement between clinical ~nd EEG assessment as to whether a fit had occurred. When an EEG fit was said to have occurred only if it lasted longer than 25s, then disagreement rose to 7% in bilateral and 28% in unilateral applications; disagreement was higher with unilateral applications as they produced shorter fits than bilateral applications. IZ future work shows seizure duration is clearly associated with clinical efficacy, it is suggested the case for routine EEG monitoring is greatly strengthened. Crichton Royal Hospital, Dumfries, Scotland, DG2 4TG

DIFFERENTIAL EFFECTS OF SINGLE AND REPEATED ELECTROCONVULSIVE SHOCK (ECS) ON FORSKOLIN BINDING IN RAT BRAIN Christoph H. G l e i t e r * , Jurgen Deckert#, David J. Nutt*~ Paul J. Maranqos# Since ECS has been shown to increase as well as decrease f o r s k o l i n - s t i m u l a t e d cAMP accumulation in cerebral cortex I adenylate cyclase was invest i g a t e d using [3H]Forskolin (FOR) binding in r a t cerebral cortex (COR), cerebellum (CER), hippocampus (HIP) and s t r i a t u m (STR). Rats were given e i t h e r a single or repeated ECS (80 mA, 0.5 s) via e a r c l i p s without anaesthesia. They were sac r i f i c e d 30 min or 24 h a f t e r a s i n g l e ECS and 24 h a f t e r 10 once-daily ECS. Binding of FOR to crude membrane preparations of the above brain regions was examined at a concentration of 12 nM. Membranes of each time point were assayed in p a r a l l e l . Results in fmol/mg p r o t e i n : 30 min 24 h ECS x 10 CTRL ECS CTRL ECS CTRL ECS COR 8 1 + 3 7 6 + 3 105+2 124+ 7 105+3 103+ 2 CER 7 7 + 4 89+4* 129+5 119+ 4 114+4 132+ 6 HIP 6 8 u 57u 60u 59u 5 56u 44u 2* STR 88u 146u 186u 181u 178u 135u (mean• n =-8/group; *= p-
33.05.08

33.05.09

OOUBLE-BLIND COMPARISON OF LOPJ~ZEPAMVS. HALOPERIDOL FOR THE TRF.ATMEJ~TOF MANIC AGITATION. R.h. Lenox, W. Creelman, G. Amori, S. Weiner.

THE I ~ 0 R T A N C E OF BRO~0CRIPTINE/PARLODEL/ THERAPY AND DA RECEPTORS IN ALCOHOL ABUSE S. P~lfi~ Z. Kovlcs The authors treated chzooic alcoholic patients with Psrlodel in m six-month period of time using the method of double blind examination~ There was a significant difference in the numbe~ of alcoholic abuses between those taking Pazlodel end the controls. /exact p-statistics by Fischer - two-side p=o,o126 / Applying the dose /daily 7~ mg/ there was no need for the suspension of drug sdministretion because of side effects in any case. Fluctuations in the pro!scrim levels of those in the control group may be ~eleted to more fre@uent and more severe expositions to alcohol, which may elso refe~ %o the involvement of DA metabolism. The change in p~olactin level after the administration TRH is a basic information in the therapeutic effect. Department of Neuzo!og2 and Psychiatry Medicel University SzeEed , Hungary P.OoB.397. H-67oi

Current approachesto the clinical treatmentof manic agitation have generally included the widespreaduse of neuroleptics to managethe patient while awaiting the therapeutic effects Of lithium. We have previously described an open study examiningthe efficacy of lorazepam for the treatment of manic agitation in patients being treated concurrently with lithium (Modell et al 1985, Lenox et al 1986). We are reporting the results of our recently completeddouble-blind study comparingthe efficacy of lorazepamvs. haloperidol in such a patient population. Twenty acutely manic patients f u l f i l l i n g DSM-III criteria for bipolar disorder, manic type, participated in this study on our inpatient service. Upon admission to the protocol patients were administered lithium or carbamazepine,.and orders written for administration of the blinded medications either p.o., i.m., or i . v . every 2 hours as needed to achieve a level of behavior sufficient to allow patient compliancewith milieu and medication. Patients were rated daily at the sametime by an independentrater using the Brief Psychiatric Rating Scale, Mania Rating Scale and Side Effects Scale. I n i t i a l data revealed evidence ~f three different profiles of response: patients respqnding to the lithium or carbamazepinewith l i t t l e additional treatment for agitation; patients responding only with addition of the blinded medications; patients requiring discontinuation of protocol due to side effects or uncontrollable agitation. We will report data regarding the characteristics Of these response profiles and present a rationale consistent with the use of Iorazepam as a recommendedapproachto the treatment of manic agitation within the hospital setting. Neuroscience Research Unit, Dept. of Psychiatry, University of Vermont College of Medicine, Burlington VT, U.S.A.

363

34.01.01

POSTER PRESENTATION 34.01

Various Pharmacological Studies

SIBUTRAMIh~E RCL AND OTHER ANTIDEPRESSANT TREATMENTS DECREASE CORTICAL ~.-BUTI NOT 82-ADRENOCEPTORS. W. R. Buekett and D. J. Heal The specific 9.-antagonist CGP 20712A can be used to ! quantify BI- and ~9-adrenoceptor binding (D. J. Dooley, et al, Eur J. Phar~ae. 130, 137, ]986). In this study CGP 20712A was used to determine rat cortical ~1- and -adrenoeeptors after the administration of S~butramine HCI (BTS 54 524) and other antidepressant treatments. Male CD rats (75-175g) were used. Sibutramine HCI (3 mg/kg), ami~riptyline, desipramine (DMI) or zimeldine (all 10 mg/kg) were given orally once daily for ten days. Controls received distilled water. Five eleetroconv~isive shocks (ECS) wer e given to anaesthetised rats also over 10 days, with controls receiving halothane alone. 24h after the final treatment, saturation binding experiments were performed using [SH]-dihydroalprenolol (0.]4-2.8 riM). Specific b~nding to ~ - and (81 + 9?)-adrenoceptors was defined by I ~M C~P 207]2A'and 200 ~M isoprenaline respectively. ~ -Adrenoceptor binding was calculated by difference. "~ortieal Bmax values were S1=77 • 7; ~2=40 • 6 fmol/mg protein and Kd values ~i = ].1 • 0.4; ~2 = 0.78 • 0.] riM. After 10 days S.- but not -adrenoceptors were reduced by all treatments: S~butramine BCI (47%), amitriptyline (28%), DMI (45%), zimel~ine (26%) and ECS (31%). After 3 days, sibutramine HCI and DMI reduced ~ -adrenoceptors I by 23% and 40% respectively, but amitriptyline and zimeldine had no effect. A single ECS was also ineffective. The data show that monoamine reuptake inhibitors of varying profile, as well as ECS, all reduce S]-adrenoceptors alone. Furthermore sibutramine HCI, w~ich rapidly reduces ~-adrenoeeptors (W. R. Buekett et al, Br. J. Pharmae 90, 94P, 1987) achieves this solely by decreasing the @ ! subtype. Research Department, The Boots Company PLC, Nottingham NG2 3AA, United Kingdom

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EFFECT OF SOKE CALCIU~ CHANNEL ANTAGONISTS AND THE CALCIUX CHANNEL AGONIST BAY K 8644 IN PHARMACOLOGICAL MODELS RELATED TO DOP/L~INERGIC ACTIVITY E. Mo~ilnicka. A. Czvrak. K. Golemblowska and J. Nni The effects of calcium channel antagonists [(the dihydropyridine antagonists, nifedipine (NIF), nimodipine (NIK)~ nitrendipine (NIT) and the non-dihydropyridine ones diltiazem (DIL) and verapamil (VER)] and the calcium channel agonist BAY K 8644 on the apo~orphine (APO)-, and amphetamine (AEPH)-induced steremtypy and on the APO- and LY 171555-induced yawning were investigated in rats. In mice the effect of these substances on the AHPH-induced hypermotility was checked. The level of HVA was measured in the rat striatum by the HPLC after i.p, administration of BAY K 8644. None of the investigated calcium antagonists influenced the APO- or AKPH-induced stereotypy. BAY K 8544 increased the APO-induced stereotypy, this effect being counteracted by NIF and. DIL. NIF (5, I0 mK/kg) significantly increased the APO-induced yawnfng in a dose-dependent manner; NIF, NIK and NIT (I0 mg/kg)~ but n o t o t h e r antagonists si~i~ioa~t~y inoreaced the APC- and LY 171555-induced yawning. BAY K 8644 (0.05! 0. I, 0.gmKlkg i.p,) reduced dose-depently the APO- and LY l?1555-induced yawning. The BAY K 8644 (0.5 m~/kg)-induced reduction was antagonized by NIF (I0 m~/kg). BAY K 8644 (2 mg{kg) significantly increased the HVA level in the raf striatum. None of the calcium antagonists (2.5, 5, i0, mg/k~) affected the spontaneous motility in mice, the only exception being VER which decreased it. Of all the compounds tested only NIM and VER (5 mg/kg) significantly reduced the AMPHinduced hypermotility. BAY K 8644 (0.5, 1 mK/kg) reduced the spontaneous motility and AMPH-induced hypermotility~ these effects being counteracted by NIF (5, 10 m~/kg). The obtained results support the hypothesis that brain Da dopamine receptors may be functionally linked to calcium channels. Institute of Pharmacology, Polish Academy of Sciences, 12 Sm~tna St., 31-~43 Krak6w, Poland

MONOAMINE TURNOVER IN DISCRETE RAT BRAIN NUCLEI AFTER ADMINISTRATION OF MEDETOMIDINE, A NOVEL a.-ADRENOCEPTOR AGONIST U~. Pesonen, S. Koskinen, H. H~mninen, R. V[rtanen and M. Koulu Medetomidine is a new imidazole derivative which selectively activates a2-adrenoceptors. In animals, as weU as in humans, medetomidine has shown sedative, hypotensive and bradyeardic effects. Saline or 3, 30 or 100 ug/kg of medetomidine was injected s.c. to male Sprague-Dawley rats (n=8 in each group), which were decapitated 90 rain later. In a separate experiment, 100 mg/kg of NSD 1015, an inhl"bitor of L-aromatic amino acid decarboxylase, was injected 30 rain before decapitation to rats pretreated with 3, 30 or 100 ug/kg of medetomidine or saline 60 rain earlier. The brain stem nuclei were punched according to the method of Palkovits. HPLC-EC was used for the chemical determinations. MedetomkIine significantly inhibited the accumulation of DOPA in area A1-C1, nucleus tractus solitarii (NTS) and raphe dorsalis (RD), but not in the locus coeruleus (LC). The basal catecholamine levels remained unchanged after medetomidine. Furthermore, medetomidine decreased the concentrations of 5HIAA, the ratio 5HIAAJ5HT and 5HTP accumulation (after NSD 1015) in area A1-C1, NTS, area A5 and LC. In RD the ratio 5HIAA/5HT dccreased, but 5HTP accumulation remained unchanged. Th~ results obtained suggest that medetomidine decreases the turnover of NA in various brain stem nuclei, an effect which is consistent with the known a2-agonistic properties of the drug. An effect of medetomidine on inhibitory a2-receptors located presynaptically on serotonergic neurons or indirect actions of medetomidine via interactions of noradrenergic and serotonergic neurons could explain the observed decrements in 5HT turnover after medetomidine. Department of Pharmacology, University of Turku, Finland

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PHOSPHOLIPASE A s SYSTEM CONTROLS PURINE p ~ 9.&SE A N D cAMP LEVELS IN C U L T U R ~ GLIAL CELLS F. Cacia@ll, R. Ciccarelli~ P- Di Iorio, L. Tacconelli "and P. Ballerlni Purines h a v e been identified as Lmportant cotransmltters in t h e CNS, able to inhibit n e u r o n a l activity a n d 81ial cells r e p r e s e n t a considerable source of t h e s e substances. It is accepted t h a t p r o t e i n K i n a s e C (PK-C) r e g u l a t e s C a R+ , K + a n d CI- f l u x e s a n d promotes transmitter a n d cotransmitter release. Different m e m b r a n e molecular systems h a v e been suggested to e x h e r t opposite effects o n this Key-enzyme. A m o n g these, a possible role c a n b e a s c r i b e d %o p h o s p h o l i p a s e A E - p r o s t a g l a n d i n (PLAE-PG) s y s t e m that, at n e u r o n a l level, s e e m s to directly control PK-C, w i t h o u t r e q u i r i n g t h e activation of phosphollpase ~ To ascertain t h e possible presence of this m e c h a n i s m at glial level a n d its significance, basal a n d electrically-evoKed p u r i n e release a n d c A M P levels w e r e m e a s u r e d in u n t r e a t e d c u l t u r e d glial cells a n d D e x a m e t h a s o n e ([x[o-6 M) or I n d o m e t h a c l n ([xto -4 M) suitibly treated cells, to o b t a l n a complete i n h i b i t i o n of P L A E - P G system. T h i s i n h i b i t i o n greatly e n h a n c e s e v o k e d p u r z n e release a n d c A M P levels. T o e v a l u a t e if P L A E - P G system could be linked to A t r e c e p t o r activity, the effect of H-etrzylmalelmlde (txlo-5 H), a b l O C K e r of G i p r o t e i n l i n k e d to A t r e c e p t o r s for adenosine, w a s assayed b y adding it to treated glial cultures. T h i s d r u g does not modify Dexamethasone or I n d o m e t h a c i n effect o n p u r i n e release, while basal a n d e v o k e d c A M P levels result greatly stimulated. This zncrease is s t r o n g l y counteracted w h e n A s receptors are blocked. O u r results suggest that, in glial cells, P L A s - P G s y s t e m s e e m s to b e linked to A t receptors a n d inhibits p u r i n e release a n d c A M P accumulation, p r o b a b l y e x h e r t i n g a n inhibition o n P K - C activity. Dept. of P h a r m a c o l o g y Medical School. U n i v e r s i t y of Chieti. V i a del Vestini, St - 66Ot3 CHIETI. Italy.

REGZ3L~TION OF IDENTIFIED NIGROSTRIATAL AND MESOACCUMBENS bOP&MINE NEURONS IN THE RAT M. Exner, L.A. Chiodo" and D. Clark Previous work has suggested that midbrain dopamine (DA) neurons projecting to functionally distinct forebrain re~/cns are regulated in a different fashion. In light of the potential importance of these regulatory differences, we are currently using standard extracellular single unit recording and microiontophoretic techniques to study the regulation of antidromically identified nigrostriatal and mesoaccumbens DA neurons in the chloral hydrate anaesthetised rat. The present project focn~ses on the response of these populations of DA neuron to electrical stimulation (i00 x 0.2 msec pulses, 0.SHz0 0.5-3.0mA) of the caudate nucleus or the nucleus accumbens. Neuronal responses were determined by analysis of peristimulus time histograms. Following single pulse stimulation of the caudate nucleus, the majority (83%) of nigrostriatal DA neurons responded with a period of inhibition followed by excitation. In contrast, only 30% of mesoaccumbens DA neurons exhibited this form of response following s t i m u l a t i o n of the nucleus accumbens, while 22% displayed only inhibition of firing. The highest proportion (39%) responded with a brief period of marked excitation followed by inhibition, a response never observed with nigrostriatal DA neurons. These findings suggest that a population of mesoaccumbens DA neurons are regulated by long-loop feedback pathways from the forebrain in a different fashion to nigrostriatal DA neurons. Current studies are focused on delineating the neurochemical identity of the systems involved in m e d i a t i n g these neuronal responses to forebrain stimulation. Neuropsychopharmacology Lab., Dept. Psychology, University of Reading, U.K., and "Lab. Neurophysiology, Center for Cell Biology, Sinai Research Institute, Detroit, U.S.A.

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STRAIR-SPECIFIC SENSITIZATION OF BRAIN STIMULATION REWARD By A9-T~-rt{AHYDROCABNABINOL IN LABORAI~RYRATS E.L. Gardner. W. Paredes. D. Smith, T. See~er. A. Donner, C, Milling, D. Cohen, and D. Morrison Previous studies have shown that most drugs of abuse sensitize brain stimulation reward, presumably deriving their abuse potential from this neuropharmacological action (R.A. Wise & M.A. Bozarth, Prog. Neuro-Psychopharmacol. 5, 467, 1981). However, the action of the cannabinoid drug class on these brain mechanisms has remained unclear. We therefore studied the action of A9-tetrahy drocarmabinol (Ag-THC), the psychoactive constituent of marijuana, on brain stimulation reward obtained from the medial forebrain bundle in four strains of laboratory rats. A titrating threshold paradigm of brain stimulation reward was used (J.M. Nazzaro & E.L. Gardner, Brain Res. 18___99,279, 1980). Ag-THC (1.5 mg/kg i.p.) produced robust and consistent decreased thresholds for brain reward in Lewis rats, but no effect at a wide range of doses (0.37, 0.75, 1.5, 2.0, 4.0 mg/kg) in Long-Evans, Sprague-Dawley, or Fisher rats. We recently reported that Ag-THC has potent dopamine agonist-like effects in brain reward loci (J.M. Ng Cheong Ton et al., Brain Res. in press% 1988), as measured by in vivo brain electrochemistry and intracranial microdialysis - HPLC methods. Given the involvement of dopaminergic mechanisms in brain reward (R.A. Wise & M.A. Bozarth, Brain Res. Bull. 12, 203, 1984), these prior findings, together with the present data, strongly suggest that A9-THC acts on similar brain mechanisms as other drugs of abuse. The ~resent clear strain differences in vulnerability to A=-THC's sensitization of brain reward implicate genetic variability in drug abuse vulnerability to cannabinoids, analagous to that previously suggested for ethanol. Laboratory of Behavioral Pharmacology, Department of Psychiatry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, New York, NY 10461, U.S.A.

LEVELS OF NERVE GROWTH FACTOR ARE ALTERED DURING EXPERIMENTAL DIABETES MELLITUS: A POSSIBLE ROLE FOR NGF IN THE PATHOGENESlS OF DIABETIC NEUROPATHY? R. H e l l w e g and H.D. H a r t u n g Diabetes mellitus (DM) is t h e l e a d i n g cause of n e u r o p a t h y in n o n t r o p i c a l countries. In e x p e r i mental animal models of DM an impairment of retrograde axoplasmic transport of several molecules including nerve growth factor (NGF) has been o b s e r v e d . T h i s c o u l d be o f r e l e v a n c e for the pathogenesis of diabetic neuropathy (DNP) since in DNP t h e N G F - s e n s i t i v e neurons (i.e. sympathetic and n e u r a l crest-derived sensory neurons) are a f f e c t e d in p a r t i c u l a r . Using an improved rapid and h i g h t y sensitive two-site enzyme immunoassay f o r NGF, we have i n v e s t i g a t e d whether NGF l e v e l s a r e a l t e r e d in rats with streptozotocin-induced DM w h i c h a r e known t o develop the e q u i v a l e n t t o DNP. We have f o u n d i n c r e a s e ~ NGF l e v e l s (up t o 300% o f c o n t r o l ) not befo.re 2 t o 3 weeks a f t e r i n d u c t i o n o f DM in target organs of the autonomic nervous system (such as i r i s or vas d e f e r e n s ) . NGF l e v e l s are increased p r o b a b l y due t o a d e v e l o p i n g DNP and lacking r e m o v a l of NGF by i n n e r v a t i n g neurons. Moreover, the observed a]terations o f NGF l e v e l s were r e f l e c t e d in t h e NGF-sensitive perikarya suchi as s u p e r i o r c e r v i c a l g a n g l i o n where NGF levels were s i g n i f i c a n t l y decreased. Since NGF exerts its neurotrophic activity in the perik a r y a of N G F - s e n s i t i v e n e u r o n s , o u r r e s u l t s are consistent w i t h t h e h y p o t h e s i s t h a t NGF p l a y s a role in t h e p a t h o g e n e s i s o f DNP as f a r as NGFsensitive perikarya are affected. This hypothes i s p o s s i b l y opens new s t r a t e g i e s for a therapy o f a u t o n o m i c DNP. Max-Planck-lnstitute for Psychiatry, Kraepelins t r a s s e 2 - 1 0 , 8000 Munich 40, F . R . G .

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EFFECT OF SINGLE AND MULTIPLE DOSE TREATMENT WITH ANTIDEPRESSANTS ON APOMORPHINE-INDUCED YAWNING IN THE RAT: EVIDENCE FOR NORADRENERGIC MODULATION OF PRESYNAPTIC D2-RECEPTORS.

NEUROREGULATION OF MiTRICIDAL SUPPRESSION BY CENTRAL MONC~MINES IN THIAMINE DEFICIENT RATS K. ONODERA Previously, Onodera et al., (1981) reported the characteristics of muricide induced by thiamine deficiency in rats. In this study, I investigated the effects of monoaminergic agents on this muricide to clarify the neuroregulation of muricidal suppression by brain monoamines. On the 30th day of experimental feeding, the incidence of muricide was 70% ~ne intraperitoneal injection of L-5-hydroxytryptophan, Ldihydroxyphenylalnine (L-dopa), L-dihydroxyphenylserine, and L-histidine suppressed this muricide. The ED50 values are 50, 86, 115 and I55 mg/kg, respectively. Muricidal suppression by L-dopa was potentiated by carbidopa, but reduced by pretreatment with ~-mon0fluoromethyldopa or FLA-63. The suppression by L-histidine was reduced by pretreatment with &-fluoromethylhistidine (FMH). In addition, intracerebroventricular injection of serotonin (5-HT) or histamine "(HA) suppressed this muricide. Abe et al., reported that the microinjection of 5-HT or noradrenaline (NA) into the medial part of amygdala can inhibit this muricide, but dopamine can not. These data indicate that the inh2bitory meeanisms could be a reflect of activation of central monoaminergic system, especially 5-HT, NA and HA. Hence, the effects of various depletors of monoamines on thiamine deficient non-killer-rats were investigated. ~-Me~hyl-p-tyrosine, ~-monofluoromethyl-p-tyrosine, FLAG3, FMH and brocresine could not enhance the muricide. Parachlorophenylalnine, a 5-HT synthesis inhibitor can enhance the muricide. Moreover, this muricide was more potently suppressed by antidepressants, which inhibit 5-HT reuptake (clomipramine etc.) rather than NA reuptake (desipramine, maproti!ine, Y-8894). In conclusion, the data obtained here clearly indicate that, among the monoaminergic system, only the serotonergic system is involved in the inhibition of ~uricide induced by thiamine deficiency. Department of Pharmacology, Tohoku University School of Dentistry, Seiryo-machi 4-1, Sendal 980, Japan.

A. Delini-Stula, Ch. Hunn Several lines of evidence suggest that antidepressants may modify the function of presynaptic D2-receptors, although the mechanism of this interaction is not clear. Yawning behaviour induced by low doses of apomorphine is considered to be a functional expression of presynaptic D2-receptor stimulation, but the effect of antidepressants on this behaviour has not been systematically studied. Male albino rats weighing 180-220 gr were treated with single (10 and 20 mg/kg ip) or multiple (10 mg/kg 2xD for 7 days) doses of imipramine, maprotiline, citalopram and (+) and (-) enantiomers of oxaprotiline (OXA). (+) OXA is a highly selective NA-uptake inhibitor. (-) OXA is devoid of any action on the monoamine uptake. APO (0.05 mg/kg sc) was given 30 min. after drugs. Yawning was recorded in 10 min. fintervals for I h. Only 20 mg/kg (+) OXA significantly (p<0.01) inhibited yawning after single doses; CIT increased it (44%). After subchronic administration, IMI apd MAP showed 98% and 52% inhibition respectively, and t~e effect of (+) OXA was enhanced (99% inhibition). Other drugs were inactive. The results of this study indicate that most probably the NA-uptake inhibiting component of action of antidepressants is responsible for the modulation of the presynaptic D2-recepter function. Research Department, CIBA-GEIGY Ltd., CH-4002 Basle

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ACTION MYOCLONUS T R E A T M E N T ~ ] T H HIGH DOSE PIIL%-

LOCUS COERULEUS IN DEPRESSION- MODEL RATS K. Inoue, S. Murase, T. Komori, M. Otani, S. Kawaguchi, M. Koishizawa, M. Harada, L Kitayama, N. Hatotani, and J. Nomura Locus eoeruleus (LC) neurons were investigated in depression-model rats which continuously showed inactive state after long-term forced running stress. The following two groups of rats were also studied : recovery rats which spontaneously recovered after the stress and short-term stressed rats which were exposed to the stress for 2-4 days. Amounts of norepinephrine at LC area slightly increased in short term stressed rats ,and significantly mcreased in depreesion-model rats. Tyrosine hydroxylase activity in LC neurons increased in short-term stressed rats ,but decreased in depression-model rats.Spontaneousfiringrateand foot-shockevokedresponseof LC neurons slightlydecreasedin short-termstressedrats,and significantlydecreasedin the model rats. These changes except chemical data of norepinephrine levels in depression-model rats were not found in recovery rats. Imipramine restored central norepinephrine level in the model rats along with the the restoration of spontaneous running activity. These results suggest that activity of LC neurons was decreased in the depressive illness.

CETAM ~ . Akpmar, M. Yardlm. O. Vural, O. T a n n d a ~ . T. Alver, D. G/indfiz. 4 Female patientS a # n g 14,17,21 and 60 ),ears a n d 2 male patients a # n g 21 and 20 3-ears with action m y o c l o n u s {AcM) were included in the study. In 5 out of 6 patients generalized tonic clonic seizures (GTCS) and bilateral massive epileptic m y o c l o n u s (PMEP) appeared between the ages 10 to 14 years and cerebellar symptonls and AcM were added later. The 60 years old patient had her first GTCS and BMEM at the age of 43. These, later subsided b u t cerebellar s y m p o t m s and AcM developed. In 6 cases, daily activities were challenged b y AcM which changed in d e ~ e e f r o m nmderate to severe and made the patients d e p e n d a n t o n others. It was assymetric, being more severe at one side, showed changes in severity and exagerated the cerebenar s y m p t o m s . . C a s e s were diagnosed as d y s s i n e r # a cerebellaris m y o clonica (DcM). Oaily 6 mg clonazepam (CzP) and 8 0 0 mg sodium valproate (SvP) controlled the seizures b u t n o t AcM in 5 out o f 6 pafients..Compare to placebo piracetam (PrC) 10.4 gr daily in one case alone and in 2 cases in addition to above d r u ~ ameliorated tim AcM 80-90 percent. In one o f the remaining 3 cases in addition to 6 mg CzP,,800 mg SvP and 10.4 gr Prc-daily 3 0 0 nag p h e n o b a r b i t a l and in 2 cases besides these 4 d r u ~ I 0 0 0 nag acetazolaulide had to be added. Then, 70-80 percent amelioration was achived. In 6 cases o f DcM clinical an neurophysiological (EEG, SEP) acute effects o f PrC, mepetidine, codein sulfate, naloxone, theophylline, metoclopramide and chronic effects o f PrC will be discussed. Giilhane Mil. Med. A c a d e m y and Medical Faculty. E t l i k - A N K A R A TURKEY

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LACK OF TOLERANCE TO IBUPROFEN/CODEINE: A PLACEBO CONTROLLED CLINICAL PHARMACOLOGYSTUDY H. Friedman,G. RoTer,H. Oster,C. Seckman and C. Stubbs This m u l t i p l e dose, double-blind placebo c o n t r o l l e d , randomized, normal volunteer study compared formulations of ibuprofen/codeine and aspirin/codeine f o r systemic tolerance. S i x t y male subjects were randomized to one of four treatment groups: I ) ibuprofen/codeine 200/30 mg; 2)ibuprofen/codeine 400/60 mg; 3) aspirin/codeine 650/60 mg; 4) placebo. Medications were administered in a double dummy manner every four hours for seven days. Vital signs, standard hematologic, biochemical and urinary parameters, side e f f e c t s , e s p e c i a l l y of the g a s t r o i n t e s t i n a l t r a c t and central nervous system, as well as mood and mental alertness, were monitored. After 7 days of treatment, s i g n i f i c a n t l y lower pulse and r e s p i r a t o r y rates were seen in the active treatment groups compared to placebo. The magnitude of the differences was greater f o r the r e s p i r a t o r y (2-3 breaths/minute, 11-18%, p=.O02) than the cardiac effects (3-12 beats/minute, 4-14%, p=.03). The uricosuric effect of a s p i r i n was the only consistent medication group-related trend seen in the l a b o r a t o r y t e s t s . The placebo group had less g a s t r o i n t e s t i n a l side effects and higher stool counts than the active treatment groups. Hematemesis was seen in two subjects on aspirin/codeine. There was s t a t i s t i c a l evidence for adverse effects of aspirin/codeine on mood and mental alertness in comparison to ibuprofen/codeine and placebo. Thus, ibuprofen/codeine has a more favorable adverse effect p r o f i l e than aspirin/codeine. Tolerance to the r e s p i r a t o r y and cardiac depressant effects of codeine was not evident in any a c t i v e treatment group a f t e r seven days of frequent therapy. More work needs to be done to elucidate the factors regulating the development of tolerance to the r e s p i r a t o r y and cardiovascular depressant effects of opiates in general, and for codeine in p a r t i c u l a r . The Upjohn Company, Kalamazoo, Michigan 49001,USA

SCHIZOPHRENIA AND MAJOR DEPRESSIVE DISORDER: DIFFERENCES IN SENSORIMOTORPERFORMANCE. W. Classen and G. Laux Basic d e f i c i t s of c o g n i t i v e and motor performance are common to schizophrenic and depressed patients. However, differences considering specific aspects of performance can be demonstrated, i . e . dysfunction of r i g h t nondominant hemisphere r e l a t e d tasks is more frequent in depressed patients, whereas schizophrenics suffer from l e f t hemisphere d e f i c i t s and/or altered interhemispheric processing. A t o t a l of 56 i n p a t i e n t s (29 schizophrenics according DSM I I I c r i t e r i a , mean age 31,2 yrs; 29 patients with major depressive disorders, mean age 48,9 yrs) were treated with h a l o p e r i d o l , remoxipride, m a p r o t i l i n e or moclobemide r e s p e c t i v e l y and assigned to psychomotor performance exam before and a f t e r a 4 weeks l a s t i n g treatment period, using v i s u a l and acoustic sensorimotor reaction time tasks and a battery of motor performance tasks (Mot. Leistungs-Serie). Psychopathological symptoms were recorded by HRSD and BPRS. In t o t a l schizophrenics' l e v e l of performance as compared to depressives was lower, being s i g n i f i c a n t with respect to tapping ( r i g h t and l e f t hand) and pegboard task ( l e f t hand). Schizophrenic as w e l l as depressed patients showed impaired l e f t hand performance, some of which (number of mistakes in l i n e tracing) improved in schizophrenics under treatment. Differences in t h e o r e t i c a l aspects of etiopathogenetic explanations of these dysfunctions w i l l be discussed. Neurologische und Psychiatrische U n i v e r s i t ~ t s k l i n i k e n WOrzburg, FSchsleinstra6e 15, D-8700 WOrzburg

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AN!YAL MODEL FOR STUDY OF CENTRAL CHOLINERGIC SYST~E, N.i.Hariri.~.PS~n.fF.Z.Kuta~.~S.Demir~6ren.tG~eker. ~ B.~dem., A.Aktimttr Aging is characterized by many structural and biochemical alterations in hrain.A decline in cognitive functions in aged humans and animals has also been reported.Although the mechanisms involved in this functional decline is unclear,dysfunction ef the cholinergic system is considered an • contributing factor.Since many features of aging and those of radiation unjury are externally alike, i~z!zing radiation may be a convenient model of both modelling accelarated aging and establishing the causes of aglng.The ~resent study was undertaken to develops an ani~ l model for dementia, for aging or at least for chemicopharmacological testing.Fsur groups of mice were used: 1)Control 2)Hydergine-treated (3 mg~g eraliy once a day for four weeks 3 ) I r r a d i a t e d (head e x p o s u r e V50 fads) 4 ) I r r~!iated and hydergine ~reated.After decapitation the brains were removed and dissected on ice.AchE~ChAT au&MRB (~ascarinic receptor binding H~-QNB) were determined in fr~t~arietal c@rtem, cerebellum hippocampus and corpus s~riatum.Our results sh~" that radiation effects the cholinergic system significan~ly~especially in the deep nucle~ and that the resulting changms are similar t@ th@se observed in aging and dementia.Hydergine stimulated Ach synthesis in normal brain~but did not effect the ChAT levels in irradiated brain.The radiation induced decrease of AchE levels in hippocampus and carpus striatum could be res~red by hydergine.Radia~i~n decreased MHB in corpus s~ri~um while hydergine had n@ effect.Radiatim~+hydergine si~ificantly decreased ~L~_~ in all regions.The results den~e that Ach syntesis csuld not be rest@red by hydergine fsll~ing radiation inj~J. E ~ Univ.Med.Sch.Dept @f Physiolo~Born.v~-IZMIR/qlIRKEY

TARGET ~YNDROT,~ O F PSYCHOPHARMA-COLOGIC'~L INTERVENTION IN PATIE~TTS W I T H ACUTE AL~D ~ R O N I C COURSES OF ~ C ' , ~ A~D V E S T I B U I J ~ DISORDERS. J. Ba~teck~ ~ O. Skovro~sk#, Z. B o l e l o u c k ~ Depression, anxiety, au~onS~ous d i s t u r B a n C e s and other psychopathological syndromes accompany cochlear and vestibular disorders as somatopsyahic r ~ c t i o n ( secondary psychopathology) or take a part in their multifactorlal aetiology and pathogenesis thus representing psychosomatic c o m p o n ~ t of these disorders. Treatma~t with psychctropic drugs has oftau been succesful in some of these diseases~ Therefore since 1981 we tried to assess psychopathology in cochlear and vestibular disorders and searched for psychopathological syndromes and symptoms suitable for psychopharmacological i n t e r v ~ tiono The aim of the present study was to quantify psychopathology by means of the SCL - 90 ( Derogatls and coll., 1973 ) and to search for target syndromes of psychopharmacological intervention in acute and chronic courses of these diseases. A sample of 130 inpatients ( 72 mere with mean age of 43,9 years and 58 women with mean age of 47,9 years ) was investigated. Samples of 45 engine drivers and 192 nurses served as controls for assessma~t of arbitrary borderline values of the psychopathology measured by lO dimensions ( corresponding w i t h psychopathological syndromes ) of the S ~ L - 90. According to our h 2 p o t h e s l s significantly more psychopathology was found in acute courses. Somatic complaints, depression, anr~ety and sleep and eating distortions represented main target syndromes. Some psychotropic drugs in low doses are recommended for the psychopharmaoc!ogical i n t e r v ~ tion. Dept. of Psychistry, Postgraduate Medical and Pharmaceutical inst., ~stavn~" 91, 181 02 Praha8.

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NO EVIDENCE FOR CATECHOL-O-METHYLTRANSFERASE INHIBITION AFTER METOPRINE TREATMENT IN RATS Leena Tuomisto and Ewen MacDonald Metoprine is an i n h i b i t o r of histamine-N-methyltransferase, the main enzyme c a t a b o l i z i n g histamine in the CNS. I is often u t i l i z e d to elevate brain histamine l e v e l s when studying the functions of CNS histamine. Our own e a r l i e r study with metoprine ( I ) showed an i n h i b i t i o n of maximal electroshock convulsions with concomitant e l e v a t i o n of whole brain histamine concentrations. Sound-induced convulsions in susceptible rats were also reduced (2). The p o s s i b i l i t y t h a t metoprine could i n h i b i t another methy l a t i n g enzyme, catechol-O-methyl-transferase (COMT) was examined by administering the drug i . p . at two dose l e v e l s , 5 and 20 mg/kg to rats which were then s a c r i f i c e d at O, I , 4, 24 and 100 a f t e r treatment. The r a t i o of the two dopamine (DA) metabolites was used as an i n d i r e c t i n dex of COMT a c t i v i t y . Dihydroxyphenylacetic acid (DOPAC) is the i n i t i a l metabolite of DA formed a f t e r i t s deaminat i o n by menoamine oxidase (MAO). I t is then f u r t h e r catabolized by COMT to the f i n a l metabolic product, homvanill i c acid (HVA). The deaminated metabolite of serotonin, 5-hydroxyindoleacetic acid (5-HIAA) was also measured in the brain of the t r e a t e d r a t s . The compounds were d e t e r mined by HPLC coupled to a coulometric detector with a s l i g h t l y modified separation procedure from Mefford ( 3 ) . There was no evidence f o r metoprine-induced i n h i b i t i o n of COMT. However, the higher dose of metoprine i n h i b i t e d the formation of DOPAC at e a r l i e r time points. Since there was no corresponding decrease in 5-HIAA l e v e l s , t h i s is i n t e r preted as being due to i n h i b i t i o n of DA release r a t h e r than i n h i b i t i o n of MAO. The e f f e c t of metoprine on DA turnover and i t s possible r e l a t i o n s h i p with the i n h i b i t i o n of histamine metabolism is under i n v e s t i g a t i o n . I . Tuomisto L Tacke U: Neuropharmacology 1986:25:955-958 2. Tuomisto L e t a l . : Agents Actions 1987:20:252-254 3. Mefford IN: J. Neurosci. Methods 1981:3:207-224 Department of Pharmacology and Toxicology, U n i v e r s i t y of Kuopio, POB 6, SF-70211 Kuopio, Finland

OPIATE RECEPTORS: BINDING OF ANTITUSSIVES M.M. Airaksinen and A. Lecklin The use of opioid analgetics including codeine as a n t i tussives has been encumbered by t h e i r abuse p o t e n t i a l . In Finland codeine has been replaced in over the counter preparations by dextrometorphan (DMP), thought to be without euphorizing e f f e c t though occasional abuse was reported u n t i l s o r b i t o l was added to the DMP syrups. Both the a n t i t u s s i v e and addictive effects of opioids may be mediated by opioid receptors (Chau & Harris, Natl. I n s t . Drug Abuse Res. Monogr. Ser. 49, 77, 1984) but a specif i c i t y to certain opiate receptor subtypes might permit the design of antitussives with no addiction p o t e n t i a l . We have compared the binding to opioid receptors of codeine, DMP and a rather potent novel a n t i t u s s i v e vadocaine, a d e r i v a t i v e of lidocaine, by allowing them to compete with t r i t i a t e d ligands in r a t brain homogenate subf r a c t i o n . The ligands f o r ~(mu), 6 ( d e l t a ) , K(kappa)and o (sigma) receptors were dihydromorphine (DHM), D-Ala-D-Leuenkephalin (DADLE), dynorphin and SKF 10047, r e s p e c t i v e l y . I f the a n t i t u s s i v e effects of codeine and DMP are due to the parent molecules, t h e i r only common a f f i n i t y suggests that the C-sites may take part in t h i s e f f e c t . However, a l l the a f f i n i t i e s are low i f compared to those of morphine and the major effects of codeine are probably due to i t s metabolism to morphine. The rather low a f f i n i t y of DMP to C-, K-: and o-sites may or may not explain its occasional abuse. Vadocaine was s i g n i f i c a n t l y bound only to the o-receptor, which is probably not involved in the antitussive effect which might be peripheral and related to i t s local anesthetic effect (M~nnist~ et a l . Arzneim. Forsch./Drug Res. in press 1988). Table. ICsD:s (~M) of antitussives competing with ligands Antitussive DHM DADLE dynorphin SKF-I0047 Codeine 3.5• 15~I 231• 232• Dextromethorphan 356• 30=3 35• 18• Vadocaine 77• . 393• 209• 28• Department of Pharmacology & Toxico|ogy, U n i v e r s i t y Of Kuopio, P.O.B. 6, SF-70211 Kuopio, Finland

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34.01.19

EFFECT OF PHENYLETHANOLAMINE-N-METHYLTRANSFERASE INHIBITOR ON LOCOMOTOR ACTIVITY IN RATS M. Nakagawara, T. Kariya, T. Asada, M. Atobe, M. Kubota and N. Motohashi Recently adrenaline and adrenaline-Torming enzyme, Phenylethanolamine-N-methyl-transferase (PNMT) are found in hypothalamus. This study was undertaken to investigate whether hypothalamic adrenergic function is involved in locomotor activity in rats. Male Wistar Strain rats and male Fischer 344 rats, approximately 70 days old, were used. Fischer 344 were reported to have a= adrenoceptor subsensitivity and higher PNMT activity in hypothalamus. Rats were housed individually under a 12-hr. dark/light cycle (lights on at 6:00 a.m.). The horizontal locomotor activity in rats were measured in photocell-employed activity recording devices (0N-3420). Rats were treated with the PNMT inhibitor, SK&F 64139 50mg/kg, intraperitoneally at i0:00 a.m. In Wistar strain rats the locomotor activity counts were significantly increased after the PNMT inhibitor injection, when compared with the saline injected group. The locomotor activity counts in Fischer 344 rats were also increased after injection. These increased counts of locomotor activity in Fischer 344 rats were significantly higher and continued longer than those in Wistar rats. These results sugsest that decreased central adrenaline levels might induce the increment of locomotor activity in rats.

OPIOID PARTIAL AGONISTIC PROPERTIES OF A RECENTLYABUSED ANALGESIC A.M. Persico, L. J a n i r i , E. Tempesta Lephetamine is a new drug of abuse, displaying central analgesic a c t i v i t y and a spectrum of c l i n i c a l effects of the opioid p a r t i a l agonistic type.On the ground of recent reports on i t s unexpected abuse, the Authors performed a microiontophoretic study in order to evaluate the effects of the drug on the spontaneous and evoked f i r i n g of r a t single neurones. Interactions with putat i v e transmitters and with morphine were also i n v e s t i gated. The study was carried out at the somatosensory c o r t i c a l l e v e l . Opposite patterns of response were e l i c i t e d by lephetamine. E x c i t a t o r y effects on the spontaneous f i r i n g rate were f r e q u e n t l y recorded; other units were s l i g h t l y i n h i b i t e d or showed no response. The l a t t e r pattern of effects always corrisponded to an evident i n h i b i t i o n of glutamate-evoked excit@tory responses. Preliminary data indicate that t h i s anti-glutamate a c t i v i t y , which is t y pical of opiates, is reversed by systemic admi,istrdtion of naloxone (0.15 mg/Kg IP). Non- specific interactions were observed with substances such as norepineohrine, serotonin, GABA and acetylcholine. Our results give i n i t i a l evidence that leohetamine may exert even at the sinole neurone level an o o i a t e - l i k e a c t i v i t y of a p a r t i a l aoonistic type. Drug Dependence Unit, Dept. of Psychiatry - Catholic Univ. S. Heart, Largo A. Gemelli 8, 00168 Rome, I t a l y .

Acknowledgements:We deeply thank Prof. Norbert Matussek (Psychiatric Hospital, University of Munich) for all his helpful suggestions. We thank Smith Klein & French Laboratories (Philadelphia, USA) for the presentation of the SK&F 64139 and Mrs. Chisato Watanabe (Yamanashi Medical College) and Mr. Kiyomi Ohara (Ohara Co. Ltd.) for their invaluable assistance. Dept. of Neuropsychiatry, Yamanashi Medical College iii0 Shimogato, Tamaho-chc, Nakakoma-gun, Yex,anashi-ken 409-38 Japan

368

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THE ROLE OF THE NUCLEUS ACCUMBENS IN MEDIATING HALOPERID0L INDUCED FORELIMB MUSCULAR RIGIDITY IN RATS B.A. Ellenbroek, J. van den Hoven & A.R. Cools Haloperidol is known to produce muscular rigidity in a number of different muscles including forelimbs and hindlimbs (DeRyck & Teitelbaum Exp. Neurol., 79, (1983), 54). Whereas the stiato-nigro-collicular system is known to be involved in the expression of hindlimb rigidity (Ellenbroek et al, Neurosci.Lett. 54, (1985), 189),relatively little is known about haloperidol induced forelimb muscular rigidity. We have investigated whether the nucleus accumbeDs might play a role in this respect. Rats were chronically implanted with two cannulae aimed at either the nucleus accumbens or the neostriatum and with two stainless steel teflon insulated wire electrodes in either the forelimb triceps (TRIC) or the hindlimb gastrccnemius soleus (GS) muscle. Injections of haloperidol into the neostriatum were found to induce rigidity in the GS but not the TRIC muscle. This GS rigidity could be antagonised by apomorphine. On the other hand, injections of haloperidol into the nucleus accumbens were found to induce rigidity within the TRIC but not within the GS muscle. This TRIC rigidity, however, was found to be insensitive to apomorphine, but could be antagonised by intra accumbens injections of phenylephrine. These data suggest that the noradrenergic system within the nucleus accumbens plays a role in regulating forelimb muscle tone whereas the dopaminergic system within the neostriatum plays a r01e in regulating hindlimb muscle tone. Psych0neuropharmacol. Res. Unit, P.O. Box 9101, 6500 HB Nijmegen, the Nether]aDds.

D I F F E R E N T ~ C H A N I S ! . ~ U N D E R L I E THE D E V E L O P M E N T A N D E X P R E S S I O N OF H E R O I N - I N D U C E D PLACE P R E F E R E N C E IN THE RAT T i m o t h y h Hand, L u i s S t i n u s and M i c h e l Le M o a l neroin, a drug s e l f - a d m i n i s t e r e d for n o n m e d i c a l reasons, is k n o w n to p r o d u c e a p r e f e r e n c e for stimuli r e l i a b l y p a i r e d w i t h its a d m i n i s t r a t i o n . This c o n d i t i o n e d p l a c e p r e f e r e n c e (CPP) is k n o w n to p e r s i s t for long p e r i o d s of time after d r u g c o n d i t i o n i n g sessions, llowever, l i t t l e is k n o w n a~out h o w h e r o i n - i n d u c e d CPP d e v e l o p s , and there i~as b e e n no i n v e s t i g a t i o n of w h a t u n d e r l i e s the ~ o s t - c o n d i t i o n i n g e x p r e s s i o n of this CPP. U s i n g a novel 3 - c o m p a r t m e n t place c o n d i t i o n i n g apparatus, we c o n f i r m e d that h e r o i n p r o d u c e s a strong and l o n g - l a s t i n g CPP over a w i d e r a n g e of coses up to 1 mg/kg. P r e t r e a t m e n t on all 6 days of c o n d i t i o n i n g w i t h n a l o x o n e (50ug/kg) or p i m o zide (50 and 200ug/kg) p r e v e n t e d the d e v e l o p m e n t of CPP i n d u c e d b y 2 5 0 u g / k g h e r o i n . P r e t r e a t m e n t w i t h c l o n i d i n e (50ug/kg) r e s u l t e d in an a t t e n u ated but s i g n i f i c a n t CPP. We then d e t e r m i n e d w n e t h e r these same t r e a t m e n t s could d i s r u p t an a l r e a d y e s t a b l i s h e d CPP. A n i m a l s u n d e r w e n t the c o n d i t i o n i n g p r o c e d u r e w i t h 2 5 0 u g / k g heroin, a n d were given n a l o x o n e (50 or 1000ug/kg), c l o n i d i n e (50ug/kg) or p i m o z i d e (50 or 200ug/kg) p r i o r to h~e test s e s s i o n only. S u r p r i s i n g l y , o n l y p i m o zide at the h i g h e s t d o s e d i s r u p t e d the e s t a b lished CPP; n a l o x o n e f a i l e d to do so, e v e n at 1000ug/kg. T o g e t h e r , these r e s u l t s s u g g e s t t h a t w h i l e o p i a t e and c a t e c h o l a m i n e s y s t e m s c o n t r i bute to the d e v e l o p m e n t of h e r o i n CPPs, the p o s t c o n d i t i o n i n g e x p r e s s i o n of these e f f e c t s is n o t o p i a t e - m e d i a t e d , b u t r a t h e r is p a r t i a l l y d o p a ~ i n e - m e d i a t e d . Thus, the m e c h a n i s m s u n d e r l y i n g the d e v e l o p m e n t a n d e x p r e s s i o n of h e r o i n r e w a r d are p h a r m a c o l o g i c a l l y d i s s o c i a b l e . I . N . S . E . R . M . U-259, F - 3 3 0 7 7 B o r d e a u x C e d e x

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EFFECTS OF VARIOUS TREATMENTS INTERACTING WITH THE DOPAMINERGIC TRANSMISSION ON AMINEPTINE-INDUCED H Y P E R A C T I V I T Y IN M I C E .

ENHANCED DOPAMINE RELEASE MAY BE FUNDAMENTAL NEUROPHARMACOLOGICAL BASIS OF CROSS REVERSE TOLERANCE BET~FKEN COCAIN AND METHA~HETAMINE S,Otsuki,T.Hamamura,K,Akimoto.Y.Kazahava

A. CHAGRAOUI, M. VASSE and P. PROTAIS

and M , S a t o It is w e l l k n o w n t h a t a n i m a l s p r e t r e a t e d w i t h methamphetamine(MAP) exhibit behavioral augmentat i o n in r e s p o n s e to a c h a l l e n g e of cocain. C o n v e r s e l y , a c h a l l e n g e of MAP p r o d u c e s i n t e n s e a b n o r m a l b e h a v i o r s in a n i m a l s p r e E r e a t e d w i t h coeain. In v i v o d i a l y s i s t e c h n i q u e was u s e d to study n e u r o p h a r m a c o l o g i c a l basis of this p h e n o m e non in the r a t s t r i a t u m . E x p . l ; B o t h rats p r e t r e a ted w i t h c o e a i n ( 2 O m g / k g i~ 14days) and c o n t r o l ( p r e t r e a t e d w i t h s a l i n e 14 days) r e c e r v e d a chall e n g e of M A P ( 4 m g / k g i.p:)o A f t e r the i n j e c t i o n , r e l e a s e of d o p a m i n e ( D A ) was g r e a t e r in c o c a i n p r e t r e a t e d group (Figol). E x p . 2 ; B o t h rats p r e t r e -

Amineptlne, administered at increasing doses (5-40 mg/kg, i.p.) in mice, induces a dose-dependent hyperactivity (measured either in d~sical acfimeter or in DIGISCAN actimeter) which persists about 8 hours at 20 mg/kg. The hyperactivityinduced by 20 mg/kg amineptine is dose-dependently antagonized by metoclopramide (1.25-120 m~w'kg,i.p.), SCH 23390 (75-8000 ag/kg, s.c.) and amisulpride (1.56-100 rag&g, i.p.). Nevertheless, whereas amineptine-induced hyperactivity is completely antagonized at a relatively low dose of the discriminant banzamide derivative amisulpride (50 mg/kg, i.p.), it is completely antagonized only at a high dose of the selective D-2 antagonist metoelopramlde (80 mg/kg, i.p.) or of the selective D-1 antagonist SCH 23390 (4000 ug/kg, s.c.). Amineptine-induced hyperactivity is significantly reduced (i) by low doses of apomorphine (25-300 ug/kg~s.c.) stimulating dopamine autoreceptors, (ii) by a pretreatment with reserpine (4 mg.fkg,s.c., 24h prior testing) which depletes the vesicular stores of monoamines and (iii) by gammabutyrolactone (100 mg/kg, i.p., 30 rain after amineptine) which inhibits the firing rate of dopaminergin neurons. Similar data are also obtained with the selective dopamine uptake inhibitor GBR 12783 (10 mg/kg, i.p.) but not with dexamphetamine (5 mg/kg, i.p.) whose effects persist in reserpine-pretreated mine and in gammabutyrulactone-treated mice. Fmully, the study of the interaction of increasing doses of amineptlne with dexamphetamine (5 mg/kg, [p.) indicate that a low dose of amineptine (5 mg/kg) potentiates dexamphetamine hyperactivity whereas a high dose of ~mlneptine (40 mg/kg) reduces dexamphetamJneinduced hyperactivity. These data indicate that the stimulation of dop~mine receptors induced by zmineptlne depends at least in great part on the dopamine released from the vesicular stores by the faring rate of dopaminerglc neurons. The similarity of the results obtained with amineptine and with the selective dopamine uptake inhibitor GBR 12783 suggests a common mechanism of action which differs from that of dexamphetamine.

ated with MAP(4mg/kg iop. 14days) and saline pretreated control were administered cocain(20mg/ ~g i.p.). After injection,release of DA was greater in MAP pretreated group (Fig.2) These data suggest that enhanced DA release plays an important role in cross reverse tolerance. F

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369

34.01.24

34.01.25

LOCUS COERULEUS EXCITATION'BY NICOTINE IS

IN VIVO MEASURENENT OF EFFICACY OF THE TWO PARTIAL AGONISTS Ro 16-6028 AND Ro 17-1812. M.-C. P o t i e r , L. Prado de Carvalho, P. Venault, G. Chapouthier and d. Rossier. The imidazobenzodiazepines Ro 16-6028 and Ro 17-1812 bind with high affinity to central benzodiazepine receptors, and have been described as partial agonists: they are anticonvulsant, anxiolytic, without being sedative (Haefely, 1984). Behavioral effects and in vivo binding of Ro 16-6028 and Ro 17-1812 were studied in mice, and receptor occupancies were correlated to behavioral effects In vivo binding studies: Ro 16-6028 and Ro 17-1812 were injected s.c. 27 min before the injection of (3H)Ro15-1788 (50 pCi/kg i.v.), and 30 min before sacrifice. There was a dose-dependent inhibition of (3H)Ro 15-1788 binding to cerebellar, cortical and hippocampal membranes by Ro 16-6028 and Ro 17-1812. Doses of Ro 18-6028 and Ro 17-1812 inhibiting 50% of the specific binding of (3H)Ro 15-1788 (ID~n'S) were found to be 0.1-0.2 mg/kg and 0.2-0.4 mg/kg respectively. Behavioral effects: correlation to receptor occupancies: A dose of 0.2 mg/kg s.c. of Ro 16-8028 or Ro 17-1812, corresponding to 30-60% of receptor occupancy, was suffi-cient to prevent tonic-clonic convulsions induced by pentylenetetrazol (80 mg/kg s.c.). A higher dose (0.3 mg/ kg s.c.) of either ligand, corresponding to higher receptor occupancy (40-70%) were anxiolytic in a conflict test. However, even at 100% receptor occupancy, Ro 16-6028 and Ro 17-1812 (5mg/kg s.c.) did not produce any deficit in a rotarod test. Previous studies of in vivo binding have demonstrated that anticonvulsant and anxiolytic effects of full agonists (diazepam and flunitrazepam) appeared at less than 10%, and ataxic effects at higher level (30%) of receptor occupancy. Thus, higher levels of receptor occupancy seem necessary for induction of the same pharmacological effect by a partial agonist than by a full agonist. Haefely Clinical Pharmacol. 7(1) p.670. (1984) Laboratoire de Physiologic Nerveuse, C.N.R.S. 91190 Gif-sur-Yvette, France.

MEDIATED VIA PRE%t&RY SENSORY AFFERENTS G 6 r a n En~ber~ and M i h # v H~ljos

Previous electrophysiologioal studies have shown that nicotine causes excitation of noradrenergic neurons in the locus coeruleus (LC). In the present study, single unit recording techniques were employed to pharmacolo#cally analyze this effect of nicotine. Low doses of nicotine (40-160 l.tg/kg, i.v.) were found to dose-dependently increase the LC firing rate (20-100 per cent). The effect was instantaneous, shortlasting and no tachyphylaxis was observed. The effect was antagonized by pretreatment with the quaternary ganglionic blockers hexamethonium (12 mg/kg, i.p.) or chlorisondamine (0.3 mg/kg, i.v.). The typical effect of nicotine on LC discharge was, in all essential, mimicked by the quaternary nlco~ic agonist wtramethylammonium (TMA). Also, neonatal treatment with capsaicin, a procedure that is associated with a selective degeneration of primary sensory C-fibre afferents, clearly antagonized the effect of nicotine on LC neurons. We propose that the action of nicotine on central noradrenergic neurons in the LC is primarily executed peripherally via activation of primary sensory C-fibre afferents. Department of Pharmacology, University of Gothenburg P.O. Box 33031, 400 33 Gothenburg, Sweden

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EFFECT OF M I N A P R I N E ON S Y N A P T I C T R A N S M I S S I O N IF THE RAT N E O C O R T E X IN V I V O S. Okuyama and H. A i h a r a The effects of m i n a p r i n e a n d / o r e x c i t a t o r y a m i n o acid a n t a g o n i s t s on t r a n s c a l l o s a l r e s p o n s e s (TCR) were e x a m i n e d in u r e t h a n e a n e s t h e t i z e d rats. The TCR was r e c o r d e d from the sunface of the anterior n e o c o r t e x f o l l o w i n g e l e c t r i c a l stimulation of the c o n t r a l a t e r a l corpus callosum. The TCR c o n s i s t e d of a b i p h a s i c positive - n e g a t i v e w a v e f o r m (S. O k u y a m a and H. Aihara, N e u r o p h a r m a c o l o g y 27, 67 1988). Intravenously a d m i n i s t e r e d m i n a p r i n e i n c r e a s e d the a m p l i t u d e of the p o s i t i v e - and n e g a t i v e waves, in a dose d e p e n d e n t manner. Intracortical m i c r o i n j e c t i o n of ( • phosphonovalerate (APV) and g a m m a - D - g l u t a m y l glycine (DGG) r e d u c e d the a m p l i t u d e of the negative-wave, w i t h no e f f e c t s on the a m p l i t u d e of the positive-wave. L-glutamate diethylester (GDEE) had no effect on the TCR. The m i n a p r i n e induced increase in the a m p l i t u d e of the n e g a t i v e - w a v e was c o m p l e t e l y a n t a g o n i z e d by simultaneous i n t r a c o r t i c a l m i c r o i n j e c t i o n s of APV and DGG which, per se, did not a f f e c t the TCR. In contrast, A P V and DGG had no e f f e c t on increase in the a m p l i t u d e of the p o s i t i v e - w a v e to minaprine. The e n h a n c i n g effect of m i n a p r i n e on the TCR remained u n a l t e r e d in case of an intracortical m i c r o i n j e c t i o n of GDEE. These findings indicate that the n e g a t i v e - w a v e of the TCR may be related to e x c i t a t o r y a m i n o acid receptors. The p o s s i b i l i t y that the p h a r m a c o l o g i c a l a c t i o n of m i n a p r i n e on the synaptic t r a n s m i s s i o n in the n e o c o r t e x m a y be linked to the e x c i t a t o r y amino acid r e c e p t o r s warrants further attention. Research Center, T a i s h o P h a r m a c e u t i c a l Co., Ltd., Yeshino-cho, Ohmiya, Saitama 330, Japan

E F F E C T OF M I N A P R I N E ON I S C H ~ M I A - I N D U C E D CHANGES OF M O N O A M I N E C O N T E N T S IN D I S C R E T E BRAIN REGIONS OF M O N G O L I A N G E R B I L S H. Araki, Y. Tsuyuki, Y. Karasawa and H. Aihara Minaprine [3-2-morpholinoethylamino)-4-methyl6-phenyl p y r i d a z i n e d i h y d r o c h r o l i d e ] protects a g a i n s t i s c h e m i a - i n d u c e d d e s t r a c t i o n and disa p p e a r a n c e of CAI neurons in the h i p p o c a m p u s in m o n g o l i a n gerbils (J. Pharmacol. Exp. Ther. 242, 686, 1987). N e u r o t r a n s m i t t e r s may be involved in the d e s t r u c t i o n of these neurons. Next we clamped the c o m m o n carotid arteries of gerbils for 5 min and the levels of m o n o a m i n e s and their m e t a b o l i t e s were m e a s u r e d using HPLC. Levels of n o r a d r e n a l i n e , d o p a m i n e and s e r o t o n i n (5-HT) in the hippocampus, cortex and striatum remained u n c h a n g e d d u r i n g the ischemia, however, following r e - c i r c u l a t i o n these levels d e c r e a s e d from 5 min-2 hrs. Besides, h o m o v a n i l l i c acid, 5 - h y d r o x y ~ n d o l a c e t i c acid and d i h y d r o x y p h e n y l acetic acid (DOPAC) also did not change d u r i n g ischemia, but these levels increased from 5 min2 hrs after r e - c i r c u l a t i o n . 3-Methoxytyramine (3-MT) i n c r e a s e d d u r i n g ischemia and up to 30 min after r e - c i r c u l a t i o n in the striatum. When m i n a p r i n e in a dose of 50 mg/kg was given for 3 days b e f o r e the occlusion, d e c r e a s e s in 5-HT in the h i p p o c a m p u s and increases in DOPAC in the striatum were s i g n i f i c a n t l y d i m i n i s h e d 5-30 min after r e c i r c u l a t i o n . Further i n c r e a s e s of 3-MT were r e c o g n i z e d d u r i n g ischemia. The p r o t e c t i o n of d e s t r u c t i o n and d i s a p p e a r a n c e of the CAI neurons as induced by m i n a p r i n e m a y be related to the s e r o t o n e r g i c n e u r o n a l f u n c t i o n in the h i p p o c a m p u s .

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Ltd.,

34.01.28

34.01.29

PHARMACOLOGICAL PROPERTIES OF THE ENANTIOMERS OF THE ~2AGONIST HEDETOMIDINE R. Virtanen~ T. Viitamaa and L. Nyman Medetomidine, (~)-4- l-(2,3,dimethylphenyl)ethyl -1H-imidazole, (MED), is a newly developed potent, selective and specific ~2-adrenoceptor agonist which has shown sedative , analgesic and anxiolytic effects in animal models (Lammintausta et el., ACNP Meeting 1986, p. 205; MacDonald et al. Fed. Proc. 46, 699, 1987). The racemic compound has recently been resolved to its d- and 1-enantiomers (HPV-1440 and MPV-1441, respectively) and the present paper describes some pharmacological properties of these two forms. In receptor binding experiments (BH-elonidine and 3H-prazosin displacement) both MED and MPV-1440 showed high affinity on ~2-binding sites (ICSO-values 3.3 and 1.2 nM, respectively) while MPV-1441 was about ~0 times less active. ~2/~i selectivity ratios of 46000, 5000 and &O00 for MPV-1440, MED and MPV-1441, respectively, were obtained in these experiments. In field stimulated mouse was deferens preparation MED and MPV-1440 showed potent e~-agonistic effects while MPV-1441 was 5-4 orders of magnitude less active. In studies with rats and mice MED and MPV-1440 had potent, dose-dependent sedative and analgesic effects which were antagonized by ~2-blockers. MPV1441 was essentially inactive. Furthermore, in narrow dose range, both MED (5-10 ug/kg s.c.) and HPV-1440 (0.51 ug/kg), but not MPV-1441, increased punished responding in a multiple VI-FR conflict procedure in rats. These results show that the ~2-agonistic activity of MED resides almost totally in the d-enantiomer. Farmos Group Ltd, Research Center, P.O. Box a25, SF-20101 Turku, Finland

INVOLVEMENT OF CENTRAL DOPAMINERGIC NEURON SYSTEMS IN BETA-PHENYLETHYLAMINE (PEA)-INDUCED BEHAVIORAL SENSITIZATION OF THE RAT T. K u r o k i r T. T s u t s u m i r M. H i r a n o r T. M a t s u m o t o f H. U c h i m u r a , A. S h i r a i s h i a n d T. N a k a h a r a Beta-phenylethylamine (PEA) is an endogeneous trace amine, which resembles amphetamine b o t h in structure and pharmacobehavioral effect. We studied effects of chronic intermittent treatment of PEA on stereotyped behavior and central dopaminergic n e u r o n s y s t e m s of rats. I n male Wistar rats receiving 25 or 50 mg/kg of PEA intraperitoneally once daily for 28 days, progressive enhancement of s t e r e o t y p e d sniffing and head movement was observed. Rechallenge of different d o s e s (12.5, 2 5 o r 5 0 m g / k g , i.p.) o f PEA to behavioral sensitized rats withdrawn for 7 days reinstated dose-related characteristic f e a t u r e s of e n h a n c e d s t e r e o t y p y . T h i s b e h a v i o r a l sensitization persisted u p t o 61 d a y s a f t e r withdrawal. Thus, we confirmed the formation of long-lasting behavioral sensitization induced by PEA similar to so-called 'reverse torelance' to amphetamine. An in vivo release of striatal dopamine (DA) i n PEA-induced behaviorally sensitized rats was examined by using intracerebral dialysis. Rechallenge of PEA (25 m g / k g , i.p.) r e m a r k a b l y enhanced striatal DA release in the rat r e c e i v e d r e p e a t e d P E A (50 m g / k g , i.p.) t r e a t m e n t after 7 days withdrawal, in parallel with the intensity of the stereotyped behavior. These results suggest that repeated administration of PEA presynaptically alters the nigro-striatal dopaminergic neuron system, possibly, in the s a m e m a n n e r of a m p h e t a m i n e s e n s i t i z a t i o n . Center for Emotional & Behavioral Disorders, Hizen National Mental Hospital, Kanzaki, Saga 842-01, Japan.

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THE ENHANCED DOP.~[LNE(DA) RELEASE AND PRODUCTION BY CARBA}~ZEPINE(CBZ) ON RAT STRIATUM. R.H1shlda,S.Kanek~TM.Matsuna~,and K.Takebe* Effects of CBZ on dopaminergic system have not been fully clarified yet. This study was designed to elucidate the effects of CBZ on metabolism and release of DA in rat striatum(adult male Wistar) by means of measuring DA and its metabolites,in vivo volta~m~etry technique and DA uptake method. (1)CBZ(50mg/kg,dissolved in D ~ O ) or placebo(control) was administered intraperitoneally,and the striatum was removed following the decapitation at 0,1 and 2hr after injection. Catecholamines were extracted with n-butanol and measured by HPLC with ECD. DA and DA+DOPAC+HVA increased significantly lhr after CBZ administration as compared with the predose- and control-|hr values,respectively. The values for DOPAC+HVA/DA,DOPAC/DA and HVA/DA remained unaltered during 2hr after injection, respectively 9 (2) Differential pulse oxidation current(DPOC) in rat striatum was measured by in vivo voltammetry technique. DPOC increased with the peak observed within 30 min postinjection in the CBZ-treated(20mg/kg i.p.)rats,whereas DPOC remained unchanged in the control rats. (3) In vitro with slice of rat striatum,CBZ(10-3,10-4and I0-5M) did not inhibit DA reuptake. As CBZ does not block DA receptor, our results indicate that CBZ primarily enhances both release and production of DA in presynaptic site of dopaminergic neuron. *The Third Dept.of Internal Medicine, **Dept.of Neuropsychiatry, *eeDept.of Neurology,Hirosaki University School of Medicin% 5Zaifu-cho,Hirosaki,036 Japan.

INFLUENCE OF RITANSERIN

AND RO-15.]788 ON FLUNITRAZEPAM

INDUCED CHANGES IN MORPHINE WITHDRAWAL BEHAVIOR. J.Gibert-Rahola, J.Valverde, R.Maldonado, I.Leonse~ui. M.C.Saavedra, J.Esteban r and J.A.Mico. Several BZD, among these f]unitrazepam (FZP), can modify different signs of morphine withdrawal in animals. The pharmacological basis of this effect re,wains unknown.Morphine abstinence syndrome is a complex behavioral pattern mediated by a fine balance of neurotrans~itter systems. Thus, the shaking behavior is related to the serotoninergic system,particularly 5 - H ~ and an inverse relationship between GABAergic activity ahd jumping has been reported. It is known that GABA mediates many pharmacological actions of BZD. However, it seems that other nearotransmitters may also be involved, perhaps indirectly, in same of the behavioral effects of BZD, for example, several findings suggest an involvement of serotonin. Previous work from oar laboratory has established that FZP reduces the number of jamps in morphine dependent mice but inversely exacerbate shaking behavior. The present study examines the mechanisms implicated in these effects Opiate dependence was induced in OF1 mice by administration of morphine s.c twice daily (9 a.m and 6 p.m), the doses were progressively increased from 25 to 150 mg/kg over a period of 5 days and 2 hr. after the last morphine administration,the withdrawal syndrome was induced by i.p injection of naloxone (Smg/kg). The nsmber of jemps and we% dog shakes (WDS)were counted after na!oxone injection for a i0 min. period. Mann-Whitney U test was used to analyze the results. FNZ (I mg/kg) decreased jemp escape attemps (U=I0 p~=.0]) and markedly increased WDS (U=5.5 p < . 0 1 ) . Ritanserin (0.5 and I mg/kg) a specific 5-HT2antagonist, inhibited the effect of FNZ on jumping (0.5 mg/kg U=15.5 p~=.05; 1 mg/kg U=I0 p-=.01) but only inhibited WDS at 1 mg/kg (U=24 p-=.01}. Ro-15.1788 a specific BZD-antagonist inhibited jumping and WDS at 40 mg/kg (jumping: U=I4 p~=.05; WDS: U=I8 p~=.05), 20 mg/kg was completely ineffective. These results suggest that concurrent stimulation of the 5-HT~ receptor and the BZD-receptor may be responsible for ~he observed effect of FZP on morphine withdrawal behavior in mice. Department of Neuroscience. Faculty of Medicine. Plaza de Falla, 11003, Cadiz (SPAIN).

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MEDETOMIDINE AND ATIPAMEZOLE BIND SELECTIVELY TO ALPHA-2ADRENOCEPTORS V. Saano, E. MacDonald and R. Virtanen Medetomidine (MED) is an agonist, and atipamezole (ATI), an antagonist for cK-2-adrenoceptors. In t h i s study the aff i n i t i e s of these compounds for various receptors were investigated using radioligand-displacement technique in v i t r o . The i n h i b i t i o n constant (Ki) of MED f o r Oc-2-receptors was 1.08 nM, and Ki of ATI was 1.56 nM. For other receptors, the a f f i n i t i e s were markedly lower: Ki-value of MED for O~-1-receptors was 1750 nM, f o r benzodiazepine receptors 261900 nM, f o r tryptamine receptors 14370 nM, f o r delta-type opiate receptors 45390 nM, and f o r 5-HT-2 receptors 14360 nM. The Ki-values of ATI, respectively, were 13300, 117500, 130400, 38790, and 27320 nM. Both compounds enhanced the binding of muscimol to GABA receptors by approximately 50% at I @M concentration. To further study the effect of MED and ATI on GABA recept o r s , t h e i r interaction with a GABA receptor antagonist, bicuculline (BIC), was investigated. BIC was infused into mouse t a i l vein and the convulsion threshold f o r three successive stages (I= myoclonic j e r k ; II= clonus of upper limbs; I l l = generalized tonus) was determined. MED at doses ! 30 ~g/kg lowered by 24-32% the threshold f o r stages I and I I tp
EFFECT OF ACUTE MORPHINE ON THE REGIONAL DOPAMINE METABOLISM IN THE MOUSE BRAIN J. Airi% L. Sepp~l~ M. Viitanen and L. Ahtee Morphine (MO) is known to affect the cerebral impulse flow and to increase the concentr:~tions of acidic dopamine (DA) metabolites DOPAC and H~A. Less is known about the regional DA metabolism in the mouse brain, especially concerning 3MT. In the present experiments MO (3, i0 and 30 mg/kg) was administred subcutaneously. 1 h after the acute dose (or 0.5, 1 and 2 h after 30 mg/kg) the mice were decapitated and the brains were dissected into 5 parts: hypothalamus (HYP), striatum (STR), limbic forebrain (LIMB), rest of ferebrain (RFBR) and lower brain stem (discarded). The concentrations of DA and its acidic metabclites DOPAC and HVA, as well as 3MT in STR and LIMB, were measured using HPLC with electrochemical detection. In LIMB 30 mg/kg of MO increased the DA concentration by 34 % and 24 % at 0.5 and 1 h, respectively. The limbic 3MT concentration was not affected by MO, but MO elevated dose-dependently the DOPAC and HVA concentrations, the maximum increase in DOPAC being 129 % at 0.5 h and in HVA 95 % at 2 h after 30 mg/kg of MO. In sT]{ the DA concentration was not altered. The 3MT concentration fell at 0.5 h by 4 1 % and at 1 h by 2 1 % but not at 2 h after 30 mg/kg of MO, whereas both DOPAC and HVA concentrations rose. In RFBR and HYP, the two largest doses of MO increased the DOPAC and HVA concentrations. In LIMB the rise in DOPAC and HVA but not in 3MT concentrations suggests that the predominant effect of acute MO in this brain area could be the activation of the intraneuronal DA turnover. In STR, the initial fall of 3MT concentration suggests reduced neuronal DA release and thus reduction of the impulse flow. In RFBR and HYP, acute MO seems to activate the dopaminergic system as judged from the elevated concentrations of DOPAC and HVA. University of Helsinki, Department of Pharmacy, Division of Pharmacology, Kirkkokatu 20, SF-00170 Helsinki, Finland

34.01:34

34.01.35

M A G N E T I C R E S O N A N C E S P E C T R O S C O P Y (MRS) A N E W M E T H O D FOR IN V I V O I N V E S T I G A T I O N S OF N E U R O L E P T I C S IN THE MAM~[AL BRAIN. K. Mann, M. B a r t e l s , K. A l b e r t and H. R e m b o l d C l i n i c a l e f f e c t s of n e u r o l e p s i c s are not p r e d i c ~ table on the basis of p l a s m a c o n c e n t r a t i o n s . CSF and p l a s m a levels show m a r k e d i n t e r i n d i v i d u a l d i f f e r e n c e s even u n d e r s t a n d a r d dose therapy. NRS p r o v i d e s a new m e t h o d fcr d e t e r m i n i n g conc e n t r a t i o n s of f l u o r i n a t e d p h a r m a c o l o g i c a l agents in the b r a i n of live n ~ n n a l s . In our study rats were e i t h e r fed daily doses of f l u p h e n a z i n e d i h y d r o c h l o r i d e (5-50 mg/kg) by gavage for s e v e r a l w e e k s or t h e y r e c e i v e d one single dose of f l u p h e n a z i n e i n t r a v e n o u s l y . F l u o r i n e - 1 9 s p e c t r a of f l u p h e n a z i n e were recorded at 188.3 MHz on a 4.7 T e s l a s p e c t r o m e t e r (BRUKER MSL 200). Two d i f f e r e n t coils were u s e d (coil a: 60 mm i m a g i n g h e a d w i t h a saddle type i n t e g r a l coil, and coil b: 6 m m probe h e a d w i t h surface coil - 10 x 18 mm). U s i n g coil a, F1 s p e c t r a of the intact rat h e a d were o b s e r v e d at 63 p p m w i t h a w i d t h of 400 Hz (number of scans 48000, m e a s u r i n g p e r i o d i0 h). Fi s p e c t r a i n d i c a t e d b r a i n c o n c e n t r a t i o n s of 5-10 x &0-5 M. The a p p l i c a t i o n of s u r f a c e coil b led to m a r k e d ly n a r r o w e r signal s h a p e s (250 Hz). F1 s p e c t r a were d e t e c t a b l e a f t e r 8 m i n u t e s f o l l o w i n g a single i n t r a v e n o u s a p p l i c a t i o n of f l u p h e n a z i n e (number of scans: 480, c o n c e n t r a t i o n : 0.4 x 10-5 M. The 100 fold r e d u c t i o n in the r e c o r d i n g time is very p r o m i s i n g for a p p l i c a t i o n of F l u o r i n e - J 9 MR S p e c t r o s c o p y in man. U n i v e r s i t y of T G b i n g e n , D e p a r t m e n t s of P s y c h i a t r y and O r g a n i c C h e m i s z r y , O s i a n d e r s t r a ~ e 22, D - 7 4 0 0 T G b i n g e n .

EVIDENCE FOR 5-HTIa-DEPENDENT IPS!L~i~LT CIRCLING IN 6-OKDA-LESI ONED P~.TS D.M.Coward and S.Urwyler Previous studies have shown that the DA D-2 agonis% CV 205-502 can cause paradoxical I P S I L A ~ L circling in 6-0HDA-lesioned rats under certain conditions (D.M.Coward & R.Markstein, In "Studies in Neuroscience", ed. W.Winlow, Manchester Univ. FTess, In Press). i.fenow present data linking this effect to an interaction ~ t h 5-HTla receptors. Lesions and receptor binding studies were carried out by conventional means. Rats exposed to 2.5 mg/kg i.p. damphetamine in post-lesion week 6 and an inactive dose of the D-1 agonist CY 208-243 (0.1 mg/zg i.p.) in weeks 7-9 showed ca. 700 ipsilateral turns/~-h following their first exposure to CV 205-502 in week lO. Repeated "CV" treatment caused diminution of ipsilateral activity and the emergence of conventional contralateral circling. Identical results were obtained when saline treatment was substituted for amphetamine or CY 208-243 exposure. The high affinity of CV 205-502 for both D-2 and 5-HTla receptors prompted us to examine the 5-HTla-agonist 8-0HDPAT in this test paradigm. Weekly exposure to 0.6 mg/kg i.p. 8-OH-DPAT in post-lesion weeks 7-9 resulted in ipsilateral circling after the second and third treatments (ca. 200 turns/90 min., 2p~O. O01). Subsequent CV 205-502 induced ipsilateral circling in these animals was no different from that seen in saline pretreated controls, possibly indicating that sensitisaticn to this paradoxical action of CV 205-502 is maximal under placebo treatment conditions. The findings suggest CV 205-502 - induced ipsilateral circling reflectsa complex interplay between stress, 5-HTla-receptor activation and endogenous dopamine systems. Sandoz Research institute Berne Ltd., P.O.Box 2173, CR3001 Berne, Switzerland.

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34.01.37

NEUROPHARMACOLOGICAL EFFECTS OF L-threo-3,4DIHYDROXYPHENYY.qERINE (L-DOPS) ON NEUROLOGICAL DISEASES. M. Yamamoto and H. Ujike L-DOPS is a synthetic precursor of noradrenalin (NA). This agent i~proved freezing phenomenon in parkinoson's disease and orthostatic hypotension in familial amyloid polyneuropathy. (Narabayashi et al. Pro Jpn Acad 57B,351,1981) In this study,we first administered L-DOPS alone, and then in combir~tion with carbidopa to patients with parkinsonism(n=6) and olivo-ponto-cerebellar atrophy(n=3). NA and 3-methoxy-4-hydoxyphenylglycol (MHPG) in cerebrospinal fluid(CSF) and p~asma were measured. pretreat L-DOPS L-DOPS +carbidopa NA in CSF 61, 29 324e147 55• (n=8,pg/ml) NA in plasma 128• 45 573~491 131• 54 (n=9,pg/ml) MHPG in CSF 7.4• 9.1• 6.3• (n=9,ng/ml) MHPG in plasma 5.0e0.9 4.8• 4.3~i.i (n=9,ng/ml) (mean~SD) NA in CSF and plasma were significantly increased by L-DOPS therapy alone compared to both pretreatment and L-DOPS+carbidopa therapy. M/~PG in CSF showed significant increase by L-DOPS therapy alone. These findings suggest that carbidopa inhibits the conversion of L-DOPS to NA in the periphery and facilitates its transport into the CNS. Clinical effects will be also discussed. Deparment of Neurology,Kagawa Central Hospital, Bancho,Takamatsu 760,JAPAN

IS THE PROTECTION AGAINST PILOCARPINE INDUCED SEIZURES AFTER TRANSIENT OLIGAEMIC HYPOXIACAUSEDBY INCREASED GABALEVELS IN DIFFERENT VULNERABLEBRAIN STRUCTURES ? C. Heim, M. Sieklucka-Dziuba, Z.A. Bortolotto, W. L6scher, E.A. Cavalhelro, K.-H. Sontag BiLateral clamping ot carotid arteries (BCCA) in pentobarbitaI anaesthetized normotensive Han Wist rats for 24 or 36 min leads to decreased seizure susceptibility 14 days after application of pilocarpine (increase of potency rat i o 51% after 24 min of BCCA, 35% after 36 min of BCCA). No tissue damages could be observed. GABA-levels were increased significantly in substantia nigra (17 or 24%), hippocampus (19 or 22%), amygdalaand piriform cortex (15 or 18%), frontal cortex (22 or 21%), parietal cortex (8 or 12%), thalamus (16%), c o i l . sup. (12%); GABA-T a c t i v i ty was decreased significantly after 36 min of BCCA in hippocampus (10%), frontal cortex (11%), thalamus (8%), striatum (19%), cerebellum (13%), hypothalamus (11%); GAD a c t i v i t y remained unchanged. I t may be suggested that the increased C~BA levels in the most vulnerable structures prevent the generalisation of seizure a c t i v i t y , controlled by EEG. But the results demonstrated that not in a l l vulnerable structures the increased GABAcontent is accompanied by decreased GABA-T a c t i v i t y . Furthermore nearly the same GABAcontent 14 days after 36 min of BCCAdid not protect animals to the same extent as animals with 24 min of BCCA. Therefore not only the increased GABAcontent in the most vulnerable brain structures alone should be the limitating factor for seizure a c t i v i t y . Max-Planck-lnstitute for experimental Medicine, HermannRein-Str. 3, D 3400 GOttingen, F.R.G.

34.01.38 RILUZOLE (PK 26124) INDUCESDISCRIMINATIVE STIMULI INRATS. Rataud J., Bardone M.C., Stutzman J.M., Mazadier M., ~Blanchard J.C., Laduron P. Riluzole was found to possess an original p r o f i l e as anticonvulsant drug and seems to interfere with glutamate neurotransmission. Indeed i t protected animals against convulsions induced by nicotine in mice (ED 50=5.8 mg/kg po) and those caused by supra maximal electroshock in mice and rats (ED 50=4.8 mg/kg ip and 1.5 mg/mg po respectivel y ) . Furthermore, i t inhibited post-discharges and behavioral manifestations induced by amygdalastimulation in rats (kindling phenomena ; ED 50=I.25 mg/kg ip). In contrast to benzodiazepines, which are known to i n h i b i t the seizures induced by pentylene tetrazole (PTZ) or picrotoxin, r i l u z o l e (20 mg/kg po) did not antagonizeclonic seizures induced by these agents. Nevertheless, i t protected animals against tonic seizures like carbamazepine.But unlike benzodiazepines, i t did not antagonize PTZ stimuli in rats (LAL test). This product is not a true sedative agent although i t was able to induce at low doses(2mg/kg ip) slow wave and REM sleep in rats. Owing to i t s original p r o f i l e and preliminary positive clinical results observed in schizophrenic patients, we decided to test the possible discriminative properties of riluzole. Male rats were trained to discriminate the interoceptive effecz of r i l u z o l e (4 mg/kg po) from saline in a standard two levels operant conditioning procedure. Only 50 percent of the rats learned to discriminate this compound from saline. The stimulation was not dependent of the route of administration and the ED 50 value after inzraperitoneal injection was 1.5 mg/kg. In contrast MK801 did not generalize to the r i l u z o l e discriminative cue. All these results suggest that r i l u z o l e possessesdiscriminative properties and although the precise mechanism of its antiglutamate action remains to be elucidated, this compoundmarkedly differs from MK 801 which is a well known non competitive NMDAantagonist. RHONE-POULENC SANTE, Centre de Recherches de Gennevil]lers, 35, quai du Moulin de Cage, 92231 Gennevilliers (France)

34.01.39 NMDA R E C E P T O R S

MAY MEDIATE

TONIC

INHIBITORY

CONTROL OF DOPAMINERGIC TRANSMISSION MEDIAL FRONTAL CORTEX T.Nishikawa, N.Hata and K.Takahashi.

IN R A T

The e f f e c t s of b i l a t e r a l infusion of e x c i t a t o r y amino a c i d e r g i c drugs into the m e d i a l frontal c o r t e x on c o r t i c a l d o p a m i n e (DA) m e t a b o l i s m have b e e n e x a m i n e d in c o n s c i o u s rats. Local inj e c t i o n of N - m e t h y l - D - a s p a r t a t e (NMDA) r e c e p t o r antagonists, 2-amino,5-phosphonovalerate (APV) and 2 - a m i n o - Y - p h o s p h o n o h e p t a n o a t e (APH), inc r e a s e d the amount of 3,4-dihydroxyphenylacetic acid (DOPAC) and the D O P A C / D A ratio in the medial frontal cortex. Furthermore, APV, APH and 3-((~)-2-carboxypiperazin-4-yl)-propyl-lp h o s p h o n a t e (another N M D A r e c e p t o r antagonist) locally a p p l i e d to the m e d i a l frontal cortex, f a c i l i t a t e d c o r t i c a l DA u t i l i z a t i o n after inhib i t i o n of D A s y n t h e s i s induced b y i n t r a p e r i t o neal a d m i n i s t r a t i o n of ~ - m e t h y l - p - t y r o s i n e (a t y r o s i n e h y d r o x y l a s e inhibitor). In contrast, J n t r a - m e a i a l frontal c o r t e x i n f u s i o n of g l u t a mate d i e t h y l e s t e r (a q u i s q u a l a t e r e c e p t o r antagonist), r - g l u t a m y l - a m i n o m e t h y l s u l p h o n a t e (a quisqualate/kainate r e c e p t o r antagonist) and NMDA f a i l e d to affect the c o r t i c a l D O P A C / D A ratio a n d DA u t i l i z a t i o n . These f i n d i n g s are c o n s i s t e n t w i t h the v i e w that N M D A r e c e p t o r s m a y be i n v o l v e d in tonic i n h i b i t o r y r e g u l a t i o n of d o p a m i n e r g i c t r a n s m i s s i o n in the m e d i a l frontal cortex. D i v i s i o n of M e n t a l D i s o r d e r Research, N a t i o n a l I n s t i t u t e of N e u r o s c ~ e n c e , NCNP, 4-1-1, O g a w a Higashi, Kodaira, T o k y o 187, Japan.

373

34.01.40

34.01.41

NEUROENDOCRINE EFFECTS OF INTRAHIPPOCAMPAL KAINIC ACID LESIONS: AN EXPERIMENTAL MODEL FOR STUDYING EPILEPSY AND PREGNANCY. D. Amaro, I o T . N . V e r r e s c h i and M.P.P. B e r z a g h i I n t r a h i p p o c a m p a l k a i n i c a c i d l e s i o n s o f f e r an e x p e r i m e n t a l model o f e p i l e p s y which i s c h a r a c t e r i z e d by the l a t e appearance o f spontaneous r e c u r r e n t s e i z u r e s (SRSS). E x p e r i m e n t a l s t u d i e s d e m o n s t r a t e d t h a t pregnancy and n u r s i n g d e c r e a s e t h e f r e q u e n c y o f SRSs in r a t s a f t e r KA a d m i n i s t r a t i o n in dorsal hippocampus. Data o b t a i n e d from s e v e r a l s t u d i e s have f i r m e l y s t a b l i s h e d t h e n e u r o e n d o c r i n e e f f e c t s o f n e u r o e x c i t a t o r y amino a c i d s . These f i n d i n g s prompted us t o s t u d y s i s t e m a t i c a l l y a p o s s i b l e e n d o c r i n e i n f l u e n c e on t h e d e v e l o p m e n t o f our e x p e r i m e n t a l model o f l i m b i c e p i l e p s y . I n t r a h i p p o c a m p a l KA i n j e c t i o n s in f e m a l e r a t s m a r k e d l y a f f e c t e d the e s t r o u s c y c l e . P r o g e s t e r o n e l e v e l s 24 h f o l l o w i n g KA ( A c u t e P e r i o d ) , were s i m i l a r t o t h o s e found i n no t r e a t e d r a t s . However, two weeks l a t e r ( S i l e n t P e r i o d ) , i t was clearly observed a significant d e c r e a s e in p r o g e s t e r o n e l e v e l s among KA t r e a t e d f e m a l e . These data s u g g e s t t h a t o u r e x p e r i m e n t a l model o f e p i l e p s y in pregnancy i s o f p a r t i c u l a r i n t e r e s t in u n d e r s t a n d i n g the r e l a t i o n s h i p between s e i z u r e s a c t i v i t y and n e u r o e n d o c r i n e status.

~H-PN

S u p p o r t e d by FAPESP, FINEP and CNPq from B r a z i l . L a b o r a t S r i o de N e u r o l o g i a E x p e r i m e n t a l da E s c o l a P a u l i s t a de M e d i c i n a Rua B o t u c a t u , 862 - Caixa P o s t a l 20265 BROIO00 - SAO PAULO (SP) - BRAZIL

200-110 BINDING SITES ASSOCIATED WITH SLOW C A L C I U M C H A N N E L S IN C U L T U R E D N E U R O N E S J.N. O c t a v e and J.M. M a l o t e a u x S e v e r a l t r i t i a t e d l i g a n d s of the d i h y d r o p y r i d i n e chemical group have bee_n used to c h a r a c t e r i z e the slow calcium channels in rat brain. The specific binding of = H - P N 2 0 0 - 1 1 0 was s t u d i e d u s i n g homogenates from rat c u l t u r e d neurones. The Scatchard analysis a l l o w e d to c a l c u l a t e a Bmax value of 22.7 fmoles/mg protein and a Kd v a l u e of 0.206 • 0.055 nM w h i c h was in the same r a n g e t h a n the Kd v a l u e of 0.571 nM o b t a i n e d in rat brain homogenates. Competition experiments of ~ H - P N 2 0 0 - 1 1 0 s p e c i f i c b i n d i n g w e r e p e r f o r m e d using several calcium entry b l o c k e r s and the c a l c i u m a c t i v a t o r BAY K-8644. The ICmo v a l u e s d e m o n s t r a t e that the d i f f e r e n t drugs w h i c h have been used i n t e r a c t with a c o m m o n b i n d i n g site. The 4 ~ C a = - u p t a k e into neurones has b e e n s t u d i e d in 5and 50 mM K" d e p o l a r i z i n g medium. The 4~Ca=" u p t a k e i n c r e a s e d r a p i d l y in d e p o l a r i z i n g codition, reaching 235 % of the basal u p t a k e a f t e r I m i n u t e incubation. The c a l c i u m a n t a g o nists nitrendipine, verapamil, diltiazem, f l u n a r i z i n e and p i m o z i d e did not d e c r e a s e e i t h e r the basal or the 50 mM K" i n d u c e d 4~Ca =§ u p t a k e in c u l t u r e d neurones. BAY K-B644 significantly enhanced the 4 m C a =§ uptake in depolarizing conditions and this effect was completely inhibited by 1 uM nitrendipine or by I0 ~M flunarizine. In c u l t u r e d neurones, calcium antagonists only inhibit the effect of BAY K-8644, w h e r e a s in p e r i p h e r a l t u m o r a l cells from n e u r o n a l origin, these c a l c i u m a n t a g o n i s t s are also a b l e to block the K ~ induced c a l c i u m uptake. U n i v e r s i t ~ C a t h o l i q u e de Louvain, l a b o r a t o i r e de N e u r o c h i m i e , UCL 1352, B - 1 2 0 0 Brussels, Belgium.

34.01.42

34.01.43

UNALTERED HIPPOCAMPAL ~-CONOTOXIN GVIA AND DIHYDROPYRIDINE BINDING SITES AFTER REPEATED ELECTROCONVULSI\~ SHOCK IN RATS D.J. Dooley Although the efficacy of eleetroconvulsive treatment (ECT) in human depression is indisputable, the relevant physiologic changes effected by this therapeutic approach remain controversial and elusive. Since ECT undoubtedly affects some of the processes underlying calei~-dependent neurotransmitter release, there is the possibility that ECT-induced alterations in hippocampal voltage-sensitive calcium channels (VSCCs) may contribute to the antidepressant effect. The existence of such alterations was addressed by repeatedly administering electmoconvulsive shock (ECS) (ear-clip electrodes; BO mA, 0.5 s, 50 Hz sinusoidal; 1 x i0 days) to rats [SpragueDawley, ~, 120-130 g], sacrificing these animals 24 h after the last ECS, and preparing crude hippocampal membrane suspensions for use in r a d i o l i g ~ binding assays for N-~y~e VSCCs (0.I-I0 pM or 4 pM I-~-conotoxin qVIA ( I-~-C~)), L-type VSCCs (lO-lOOC pM or i00 pM ~H~isradipine (H-ISR)), ~nd beta, adrenoceptors (0.25 nM ~H-dihydroalprenolol). Saturation experiments yielded ~ l a r K and B values for the sham and ~CS groups ( I - ~ - ~ : ~0.4mpa~, ~ 600 fmol/mg protein) (~HISR: ~60 pM, ~i000 fmol/mg protein). Betal-adrenoceptor binding (positive control) was significantly decreased by ~30 %, whereas beta2-sdrenocepto{2~inding was unchanged. Interaction exper-lments with --~I- ~-CT and various ~ubstances (i.e., calcium, cadmium, neomycin) and with R-ISR and several substances (i.e., (+)-202-791, flunarizine, fostedil, MDL 12330 A) provided further evidence for the unaltered state of the respective binding sites. These findings suggest thatlp~ippocampal N-3 and L-type VSCCs, as assessed using ---I-~-CT and -H-ISR, are unaltered by ECS, and that changes in these VSCCs are not a prerequisite for the antidepressant effect of ECT. Dept. of Pharmacolog~v, GSdecke Research Institute, Mooswaldallee 1-9, D-7800 Freiburg, F.R.G.

INFLUENCE OF SOCIAL ISOLATION OF TIME-DEPENDENT CHANGES IN PENTOBAPH3ITAL RESPONSE OF MICE

374

H. W a t a n a b e and N. O g a w a Introduction Hypnotic effect of sodium pentobarbital (PB) v a r i e s w i t h i n a day and is influenced by socio-psychological condition. We e x a m i n e d the r o l e of p h a r m a c o k i n e t i c facet in these p h e n o m e n a . M e t h o d s A f t e r PB i n j e c t i o n (50 mg/kg, i.p.) at 0300, 0900, 1500 and 2100, the s l e e p i n g time (onset and duration) and the drug levels at the awakening in b r a i n w e r e observed. Mice were h o u s e d in g r o u p of 5 or singly for 2M p r i o r to the e x p e r i m e n t with food and w a t e r ad lib. Automatically-controlled artifical illumination provided alternating 12 h p e r i o d s for light (0700-1900) and d a r k n e s s (1900-0700). R e s u l t s The t i m e - d e p e n d e n t variations in the d u r a t i o n s of s l e e p i n g and in the d r u g levels at the a w a k e n i n g in b o t h groups of m i c e w e r e well fitted cosine-curve (p<0.01). In both groups of mice, the d u r a t i o n s w e r e s h o r t e r and the drug levels at the a w a k e n i n g w e r e h i g h e r in the d a r k p h a s e (both p<0.01, ANOVA). The duration in i s o l a t e d m i c e was significantly r e d u c e d as c o m p a r e d to that of the a g g r e g a t e d mice (p
34.01.44

34.01.45

A PHASE ADVANCE OF THE LOCOMOTOR RHYTHM IN METHAMPHETAMINE PRETREATED RATS H.Takagi~ S.Yamada~ H.Eojima~ Y.Noda~ S.Rarajiri~ S.Nishi I and K.Inanaga2 Effects of chronic pretreatment with methamphetamine(MAP) and its withdrawal on wheel running and open field activities in rats were investigated. MAP (1.6 mg/day) was infused continuously by osmotic minipump for 28 days. During MAP infusion, locomotor activity in an open field apparatus for 3 min was significantly enhanced. In contrast, the withdrawal of MAP caused a significant reduction in locomotor activity for more than 2 weeks. Ten days before or 4 days after the drug withdrawal, the animals were housed individually in a running wheel cage and the number of cage revolutions were continuously recorded until the 28th day after the drug withdrawal. During the MAP infusing period, rats markedly increased the number of cage revolutions and such a hyperactivity continued for more than 28 days after the drug withdrawal. However in the rats which were housed from the 4th day after the drug withdrawal, there was no significant difference in the number of revolutions between the control and MAP-treated groups during the dark period (19:00 to 7:00). On the other hand, during the light period (7:00 to 19:00) MAP-treated rats showed a greater number of revolutions than the control rats. This increased activity continued up to 2 weeks following drug withdrawal. Moreover, the highest activity of the MAP group appeared 2 hours earlier than that of the saline group. These data indicate that the withdrawal of chronic MAP treatment advances the onset of active phase which normally coincides with the beginning of the dark phase.

THE MCID

Institute of Brain Diseases I, Department of Neuropsychiatry 2, Animal Center 3, Kurume University School of Medicine, Xurume, Fukuoka 830, Japan

34.01.46 PLASMA DHPG DOES NOT REFLECT REDUCTION OF NORADRENALINE RELEASE AFTER ALPHA2-ADRENOCEPTOR AGONIST ADMINISTRATION IN MAN A. Kallio, M. Koulu, R. Ponkilainen, H. Scheinin,M.Scheinin MPV-1440, the pharmacologically active d-isomer of medetomidine, is a highly selective alpha2-adrenoceptor~ agonist. It effectively reduces the concentration of noradrenaline (NA) in plasma presumably by activating inhibitory alpha2-receptors on sympathetic nerve endings and in the CNS. In this study, increasing i.v. doses of MPV1440 were given to five healthy male subjects in order to investigate the effect of reduced sympathetic nervous activity on the plasma levels of DHPG, an important metabolite of NA. MPV-1440 powerfully and dose-dependently decreased the concentration of NA in plasma. After the highest dose, the decrease was 92 %, on the average. Plasma NA levels remained below 25 % of baseline between 15 and 90 minutes after drug administration. However, there was only a slight (up to 25 %) reduction in plasma DHPG (p<0.001), and this reduction was not clearly dosedependent. The modest decrease in plasma DHPG despite almost total inhibition of NA release (as indicated by disappearance of NA from plasma) may be a result of continued intraneuronal NA metabolism by monoamine oxidase. Thus, the concentration of DHPG in plasma may actually reflect intraneuronal noradrenaline metabolism and turnover rather than release of the transmitter. This conclusion is supported by the rapid decrease of plasma DHPG levels after administration of the MAO-A inhibitor moclobemide (Scheinin et al, this meeting). Department of Pharmacology, University of Turku, Kiinanmyllynkatu 10, SF-20520 Turku, Finland.

IM_~GE A N A L Y S I S S Y S T E M OF F L U O R E S C E N T T I S S U E ON B R A I N A M I N E S T. S h i b u y a and K. Sate Using the M C I D s y s t e m ( I m a g i n g R e s e a r c h Inc. Canada ) to e x a m i n e f l u o r e s c e n t t i s s u e s p e c i m e n s of b r a i n a/r.ines, we s t u d i e d the c o l o r a t i o n and the q u a n t i f i c a t i o n of f l u o r e s c e n t intensity. The a n i m a l s u s e d in this e x p e r i m e n t w e r e m a l e W i s t a r rats. A f t e r e x c i s i n g the b r a i n tissue, fluorescent tissue specimens were prepared a c c o r d i n g to the f o r m a l d e h y d e method. F l u o ~ e s cent s t a n d a r d s w e r e p r e p a r e d w i t h c o n c e n t r a t i o n s of 0.5, 5 and 10 p g / u l n o r a d r e n a l i n e or d o p a m i n e in a 1% a l b u m i n solution. A c o n v e r s i o n t a b l e of optical d e n s i t y and f l u o r e s c e n t i n t e n s i t y was compiled. To a n a l y z e f l u o r e s c e n t images, p h o t o g r a p h i c slides w e r e p l a c e d u p o n an i l l u m i n a t o r for c o n v e r s i o n to a s h a d i n g g r a d a t i o n v i d e o image by a CCD camera. The s h a d i n g level r e c o g nition was f u r t h e r f a c i l i t a t e d by a p s e u d o - c o l o r d e p i c t i o n (256 colors). By a p p l y i n g this m e t h o d , it is ~ = ~ ^ to m e a s u r e m i n u t e q u a n t i t a t i v e c h a n g e s in the b r a i n c a t e c h o l a m i n e levels, such as those c a u s e d by i n c r e a s e d i n t r a c r a n i a l p r e s sure p r o d u c e d by the drug, M i d o d r i n e . This m e t h o d o f f e r s an image a n a l y s i s of a m i n e s in the brain or in the a d r e n a l m e d u l l a and it can d e t e r m i n e v a r i a t i o n s of amine f l u o r e s c e n c e in the blood. B a s e d on the above results, this m e t h o d can a n a l y z e l o c a l i z a t i o n and m o v e m e n t of brain amines on the c e l l u l a r level. M o r e o v e r , an a c c u r a t e q u a n t i t a t i v e p r o t o c o l s i g n i f i c a n t l y increase the u t i l i t y of the f l u o r e s c e n t a s s a y for c a t e c h o l a m i n e s . D e p a r t m e n t of P h a r m a c o l o g y , T o k y o M e d i c a l College, 6-i-I, Shinjuku, S h i n j u k u - k u , Tokyo 160 J A P A N

34.01.47 PLASMA HVA AND GROWTH HORMONE RESPONSE TO METHYLPHENIDATE INFUSION R.P. Sharma, 3.I. 3avaid, R. Kartan, M. Easton, G. Pandey Methylphenidate is a non-amphetamine psycho-stlmulant with predominantly dopaminergic properties, and is a potent activator of schizophrenic symptoms. Recent work indicates that plasma HVA may be a valid index of central dopamine release. We set out to measure the behavioral response to methyJphenidate in conjunction with measures of postsynaptic receptor stimulation (growth hormone response), and presynaptic dopamine release (plasma MVA response). 13 research inpatients (RDC diagnoses included $ schizophrenics, 2 schizoaffectives, 5 major depressions and 2 bipolars) underwent a washout period of 17 day (SD=4 days). A placebo randomized, i.v. methylphenidate injection (0.5 mg/kg) was administered a f t e r the washout period. 7 blood samples (15 mls) were obtained from patients on both placebo as well as active days (-#0,15,+30,+60,+90,+120 minute% +24 hours.). Pulse rate and blood pressure recordings were obtained before and after

infusion on either day. Clinical s y m p t o m s were rated by the BPRS (lg item) and GAS. A preliminary analysis indicates a robust behavioral and growth hormone response to methytphenidate, and a t e n t a t i v e association between increases in suspiciousness and plasma HVA.

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34.01.49

34.01.48 OXIR~CETAM ANTAGONIZES

~E

EFFECT~

L E A R N I N G A N D M E M O R Y ON T H E RADIAL A R M

O?

SCOPOLAMINE M A Z E IN THE RAT

ON

O. Pozzi, M. Magnani and S. Banfi Since it has recently been reported that the nootropic drug oxiracetam (OXI] can prevent scopolamine (SCOP) amnesia in a passive avoidance paradlgm by interacting wlth central chollnergic mechanisms, the present experiments were deslgned to investigate whether OXI exerted a slmilar effect against the disruptive action of SCOP on cholce accuracy in the radial maze. Male Wlstar rats (n=15), 2 months of age, 250 g body weight, were malntalned at about 80% of their free-feeding body weight and trained in a 8-arm radial maze using the Olton procedure untll they performed the task without errors. Thereafter, the rats were assigned, on separate days, to each of the following treatments: (a) SCOP 0.2 mg/kg s.c., (b) OXI 30 mg/kg i.p. plus SCOP 0.2 mg/kg s.c., (c) methylscopolamine (MethscoP) 0.2 mg/kg s.c., (d) OXI 30 mg/kg i.p., (e} SCOP 0.2 mg/kg s.c. plus physostigmine (PHYS) 0.3 mg/kg s.c. Performance during eachsession was assessed in terms of efflciency of respondlng and running tlme. SCOP induced a slgnificant decrease in the efflclency of respondlng while MethSCOP, which does not cross the blood brain barrier, was devoid of any effect. OXI and PHYS completely antagonized the disruptive effect of SCOP on the efficiency of response. On the other hand SCOP produced a pronounced increase in running tlme which was not evident after the administration of MethSCOP and was antagonized by PHYS but not by OXI. Since both these effects seem to be mediated through central cholinergic systems, as MethSCOP is unable to induce any of them while P~YS suppresses both, it can be suggested that OXI selectlvely enhances those cholinergic mechanisms whlch are involved in learning and memory. ISF - Laboratories for Bxomedlcal Research Via Leonardo da Vincl I - 20090 Trezzano s/N. (Milano) Italy

34.01.50 CERbq_s AN~D HALOPERIDOL DECRE~SED INSULIN LEVELS AND LXCRK%SED DOPAC/DA IN LIMBICFOREBRALN J.Manzanares, P. Gomez-Polledo, C. Grande~ J. Saiz-Ruiz, J. Benedi and F. Zara$oza Experiments were performed on female Wistar rats with a body weight of 250-270 g.animals were divided in six groups with n=20 each. Group I: Control (Saline 0.9%). Group II (Haloperidol 0.05 mg,TLg/day) given intraperitoneally for 10 consecutive days. Group IIk (Ceruletide 0.03 mg.'I
376

EFFECTS OF DANTROLENE ON BRAIN NEUROTRANSMITTERS J. T a k e u c h i , Y. K i u c h i , T. K o b a y a s h i , H. S h i m i z u H. O g a t a a n d M. T o r u T h e n e u r o i e p t i c m a l i g n a n t s y n d r o m e is s u c c e s s f u l l y t r e a z e d w i t h d o p a m i n e a g o n i s t s , s u c h as bromocriptine, amantadine, levodopa / carbidopa. Dantrolene, which relaxes muscle tone by interf e r i n g w i z h t h e r e l e a s e of c a l c i u m i o n s f r o m t h e sarcoplasmic reticulum, has been used effectively for m a n a g e m e n t of t h i s s y n d r o m e . It is w e l l k n o w n t h a t the p a t i e n t s t r e a t e d w i t h d a n t r o l e n e show central side-effects, s u c h as s l e e p i n e s s , dizziness, fatigue, insomnia, headache, speech disturbance, depression, mental confusion, epileptic seizure, enphoria, nervousness, etc. T h e e f f e c t s of d a n t r o l e n e o n b r a i n n e u r o t r a n s m i t t e r s w e r e s t u d i e d b y u s i n g rats. T h e r a t s were killed by decapitaltion a n d the b r a i n s w e r e divided into prefrontal cortex, striatum, anterior hypothalamus and posterior hypothalamus. N o s i g n i f i c a n t c h a n g e w a s f o u n d in G A B A , gulunamic acid ana noradrenaiine concennrau• in 4 b r a i n a r e a s 60 min. a f t e r i.p. i n j e c t i o n of d a n t r o l e n ( 5 , i0, 2 5 m g / k g ) . D o s e - d e p e n d e n t i n c r e a s e in 3 , 4 - d i h y d r o x y p h e n y l a c e t i c acid concentration in a n t e r i o r h y p o t h a l a m u s was noted. D e p a r t m e n t of P s y c h i a t r y , Shinshu University S c h o o l of M e d i c i n e , 3-.I-1 A s a h i , M a t s u m o t o , J a p a n 390

34.01.51 CHRONIC LITHIUM TREATMENT ENHANCES THE 5-HTIA-MEDIATED SEROTONIN SYNDROME PRODUCED BY 8-OH-DPAT VIA CATHECHOLAMINERGIC SYSTEM, NOT VIA POST-SYNAPTIC 5-HTIA RECEPTORS Y. Uchitomi, S. Yamawaki, I. Hide, N. Yokota, H. Havakawa and K. Sarai. Previously, Goodwin et al(Psychopharmacol. 90, 488, 1986) reported that subacute lithium treatment enhanced the serotonin(5-HT) behavioural syndrome produced by 8OH-DPAT, a 5-HTIA agonist in rats, and suggested that lithium had its effect on the 5-HTIA-mediated behaviour by a post-synaptic action since depletion of 5-HT with PCPA did not prevent it. Recently, clonazepam, an anticonvulsant, and zotepine, a nenroleptic, have been reported to have an antimanic efficacy in mania as well as lithium and carbamazepine. In a presen~ study, we re-examined the previous report and also investigated the effects of carbamazepine, clonazepam, and zotepine on the 5-HT]A-mediated behaviour and at 5-HTIA binding sites in rats. Administration of lithium chloride(3mEq/kg) for 14 days enhanced the intensity of forepaw treading, one component of the 5-HT syndrome produced by 8-OH-DFAT. However its effect was abolished by monoamine depletion with reserpine or cathecholamine depletion with AMPT, not by PCPA. Carbamazepine, clonazepam, and zotepine had no effect on the 5-HT syndrome. Radioligand binding studies using [3H]-8-OH-DPAT showed that zotepine possessed weak affinity for 5-HTIA receptor(IC50=4uM); others lacked affinity. The density of 5-HTIA binding in rat hippocampus was reduced by chronic lithium treatment, not by others. In conclusion, these results suggest that lithium enhances the 5-HTIA-mediated motor function via cathecholaminergic system while it causes 5-HTIA receptor down-regulation. And it is also suggested that these antimanic drugs have no common effects on postsynaptic 5-HTIA receptors. Department of Psychiatry, Kure National Hospital, Aoyama 3-1, Kure, Hiroshima 737, JAPAN.

34.01.52

34.01.53

EFFECT OF CHRONIC ANTIDEPRESSANT TREATMENT ON PROTEIN PHOSPHORYLATION IN DISCRETE BRAIN AREAS. D. Tinelli, J. Perez, S. Ciancio, I. Zucchi and G. Racagni. Considerable evidence indicate that several neurotransmitters produce many of their biological responses by regulating the intracellular concentration of cyclic AMP (cAMP), cyclic GM~ (cGMP) or calcium (Ca++), thus modifying the activity of protein kinase enzymes responsible for the phosphorylation of substrate proteins. A chronic antidepressant administration is associated with a number of adaptive changes in the central monoaminergio system. Aim of the present study was to analyze the pattern of protein phosphorylation in the frontal cortex and hippocampus of rat after a treatment with desipramine (DMI), a tricyclic antidepressant. Only in the soluble f r a c t i o n of cerebral cortex we observed a higher incorporation of 32p in a protein band of apparent molecular weight of 280 KDa in basal and stimulated conditions. The high molecular weight and the cAMP dependent protein kinase phosphorylation could s u r e s t that this .protein may represent a microtubuleassociated protein. Since an acute administration of DMI doesn't seem to induce 8ny modification the change in the phosphorylation of this protein could be related to the biochemical modifications induced by a chronic treatment with trioyclie antidepressants. Center of Neuropharmacoloy=y, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.

MET-ENKEPHALIN, GIVEN ONLY EARLY STAGE OF STRESS, ATTENUATES STRESS-INDUCED INCREASES IN NORADRENALINE TURNOVER IN RAT BRAIN REGIONS M. Tanaka, Y. Ida, A. Tsuda and M. Yoshida By measuring levels of noradrenaline ~NAT-and i t s major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-S04), we investigated effects of Met-enkephalin (Met-ENK) administered at the three d i f f e r e n t stages of stress on increases in NA turnover caused by stress in rat brain regions. Het-ENK e i t h e r at 50 ~g or at 150 ug, or saline, was injected i . c . v . 0 min, 5 min, or 10 min a f t e r exposure to 1-hour immobilization stress in male Wistar rats. Levels of NA and MHPG-S04 in the six brain regions were measured f l u o r o m e t r i c a l l y . Immobil i z a t i o n stress caused s i g n i f i c a n t increases in MHPG-S04 levels in the hypothalamus, amygdala, hippocampus, thalamus, midbrain and locus coeruleus (LC) region, which suggests that stress increases NA turnover in these brain regions. Met-ENK 50 pg injected immediately before stress exposure s i g n i f i c a n t l y attenauted stress-induced increases in MHPG-S04 levels in the amygdala, thalamus and LC region but the peptide injected neither 5 min nor 10 min a f t e r stress exposure. S i m i l a r l y , Met-ENK 150 ug injected at 0 min s i g n i f i c a n t l y attenuated these increases in a l l brain regions examined, however, the peptide injected neither 5 min nor 10 min. Number of defecation and weight loss caused by stress were also s i g n i f i c a n t l y attenauted by Met-ENK injected only at 0 min. These results suggest that the attenuating effect of Met-ENK on stress-induced increases in NA turnover is greatly affected by the time of the peptide administration and that Met-ENK may i n h i b i t increases in NA turnover in the brain regions caused by stress by affecting the i n i t i a l phase of stress. I t is further suggested that these attenuating effect of the peptide may be related to the r e l i e f of fear and/or anxiety of the animals exposed to stress. Department of Pharmacology, Kurume Univeristy School of Medicine, Kurume 830, Japan.

34.02.01 CDRTISOL,

POSTER PRESENTATION 34.02

Neuropharmacology of Hormones

ACI~

AND BETA-ENDORPHIN DURING COLD PRESSOR TEST IN PARKINSC~ DISEASE Rabey JM, Scherf M (i), Oberman Z and Graff E (2). (1)-Dept of Neurology and (2)-Dept of Pathol Chem, Tel-Aviv Med Center and Sackler School of Med, Tel-Aviv University, Tel-Aviv, Israel.

Stress stimulates several adaptive hormonal responses. Prominent among them are the secretion of catecholamines from the adrenal medulla, corticosteroides from the adrenal cortex and adren~cor rico tropin (ACIH) and beta-endorphin from the pituitary. In Parkinson disease some of the 9 neurotrans-~it ters (dopamine and norepinephr ine ), which modulate the response at hypothalamic hypophyseal level may be altered. In order to evaluate the impact of hSe disease to the system we administrated the Cold p ressor test (hand immersion for 2 minutes in ice Water) to seventeen parkinsonian patients (twelve "old" aged 60-80 and five "young" 40-50) and twelve controls (six "old" and "young" age matched). Blood pressure, heart rate and blood samples for cortisol, ACIH and beta-endorphin determination (by radioimmunoassay) were taken at -15,0,2,4,8 and 15 minutes during the test. During the paradigma the increase of beta-endorphin s ~nol,/! (p<0.0005) and cortisol Z =2.6 ug/dl (p<0.005) was significantly lower among the p~-rkinsoni~n old patients compared with the matched controls ( ~ =16.2 pmol~ /i and 9.1 ug/dl respectively). The ACTH response in old patients was similar among both groups (A =17.0 pg/ml and n =40 pg/ml) (p<0.0003). Young parkinsonians patients also showed a l o w e r response of all the parameters during the test. Peripheral responses as measured by heart rate and blood pressure were different among groups. In conclusion, the altered response observed, indicates that the mechanism regulating the central release of scx~e hormones in " t h e hypo thalami c-hypophysea i pathway during stress is deranged in Parkinson's disease affecting the peripheral response.

377

34.02.02

34.02.03

DOPAMINERGZC CONTROL ON PLASMATIC ~ - M S H SECRETION IN MAN. I.Rainero, P.Limone, C.Merlini, T.De Gennaro, D.Piazza, G.M.Molinatti and L.Pineesi. Several studies in rats have shown that G(-MSH is synthetized in the neurointermediate lobe {NIL) os the pituitary by post-translational processing of pro-opiomelanocortin. The release os the pep=ide from rat NIL into plasma is under direct inhibitory dopaminergic (DA) control. The existence os DA control os @(-MSH release in man has never been investigated. We therefore measured the effects os acute administration os metoclopramide, DA antagonist, on plasma o~-MSH concentrations. 5 male healthy subjects (mean age Z SD = 30.0~3.2 yrs) were selected for the study. Each subject received metoclopramide (10 mg.iv) and placebo. Blood samples were drawn at 0,15,30,45,60,90 a n 4 120 min. following the administration os the drug. Plasma ~ - M S H - l i k e immunoreactivity ( ~ - M S H - L I ) was measured with a specific RZA kit. The antibody cross-reacted in equal amount with acetyl-~(-MSH and des-acetyl-MSH. The assay sensitivity was 4 pg/ml. Basal -MSH-LI concentration {mean ~ SD) was 9.8 + 3.8 pg/ml. Metoclopramide induced a biphasico(-MSH increase, characterize~ by a first peak at 15' ( l a . Z = 4 . 7 pg/ml p
DETERMINATION OF RAT ADRENAL CATECHOLAMINES BY LIQUID CHROMATOGRAPHY/ELECTROCHEMICAL DETECTION (LCEC) CONFIRMS A LACK OF POSTMORTEM CHANGE IN LEVELS OF COMPOUNDS Y. Maruyama~ Y. Ikarashi and S. Tadokoro We present a simple, rapid and specific method for the determination of adrenal catecholamines in rat through LCEC by direct sample injection, with no al~mina extraction. The time required to obtain a full chromatogram(20 min) was significantly shorter than that needed when alumina extraction procedure was employed(90-120 min). Direct assay of sample was accomplished by setting a low oxidation potential, of 0.4 V. Although the sensitivity of norepinephrine, epinephrine and dopamine at +0.4 V was decreased by 57, 53 and 89 %, respectively, from the response at the optimal potential of +0.6 V, individual amounts in the adrenal tissue were sufficient for detection. The levels of norepinephrine(96 Ng), epinephrine(465 ~g) and dopamine(3 pg) obtained by direct sample injection exhibited an exellent agreement with those obtained via alumina extraction procedure. Direct sample injection method was employed to examine postmortem change in levels of adrenal catecholamines in rat. The adrenal tissue was kept at room temperature(23~C) following decapitation. No significant postmortem change in the level of each compound was determined during 60 min after sacrifice. Levels of enzymes collaborating with these compounds are also discussed. Division for Behavior Analysis, School of medicine, Gurur~a University, Gunma 371 Japan

34.02.04

34.02.05

BLUNTED PROLACTIN RESPONSE TO DOMPERIDONE IN SCHIZOPHRENIA u and N.Eato Prolactin(PRL) response to domperidone(DPD) (lOmg,per os), that is reported not to enter the blood brain b a r r i e r and d i r e c t l y a c t on the p i t u i t a r y grand, was evaluated in 38 s c h i z o p h r e n i c p a t i e n t s and 9 normal v o l u n t e e r s . Blood samples were c o l l e c t e d a t 0,30,60, 120 and 180min a f t e r the a d m i n i s t r a t i o n . Plasma PRL concentrations were measured by RIA. In c o n t r o l s , the peak PRL l e v e l was observed a t 30 and 120min, female(mean l e v e l 420ng/ml) and male(mean l e v e l 85ng/ ml), r e s p e c t i v e l y . In s c h i z o p h r e n i c s , the b a s e l i n e PRL level was from 64 to 370ng/ml. Ten p a t i e n t s showed no PRL i n c r e a s e a f t e r DPD a d m i n i s t r a t i o n (blunted response) and 4 patients showed delayed response. Thyrotropin releasing hormon(TRH) test was performed in 8 patients with blunted response and 2 patients with delayed response, and normal PRL response, which peak time at ]Smin, was revealed in all patients. One unmedicated patient showed blunted response to DPD and normal response to TRH. After treatment of haloperidol, PRL response to DPD was still blunted. These data indicate the possibility that blunted response to DPD did not due to increase of PRL basal ]eve] by antipsychot~c drugs but due to subsensitivity of dopamine receptor on the pituitary cell.

THE DEXAMETHASONE SUPPRESSION TEST IN PARKINSON'S DISEASE - RELATIONSHIP TO SEVERITY OF DEPRESSION O. A u e r t , R. R u p p r e c h t , K. P. L e s c h t G. Fuchs~ H. P r z u n t e k and W. Kuhn The s a t u r e os d e p r e s s i o n i n P a r k i n s o n ' s D i s e a s e (PD) i s not c l e a r a t p r e s e n t . The Dexamethasone S u p p : e s s i o n T e s t (DST) has been e x t e n s i v e l y s t u d i e d i n d e p r e s s i v e d i s o r d e r s . However o n l y few c a t a are a v a i l a b l e i n p a r k i n s o n i a n p a t i e n t s w i t h d e p r e s s i v e symptoms. We compare t h e r e s u l t s o f t h e DST i n 35 u n t r e a t e d (de novo) p a t i e n t s w i t h PD, 20 p a t i e n t s w i t h endogenous d e p r e s s i o n , 20 p a t i e n t s w i t h non-endogenous d e p r e s s i o n and 28 h ~ a l t h y c o n t r o l s u b j e c t s . S e v e r i t y o f d e p r e s s i o n was assessed by the H a m i l t o n R a t i n g S c a l e for depression. Cortisol values ~ere obtained at 8 a.e. and 4 p.m. after oral administration of l mg dexamethasone at ll p.m.. Cortisol nonsuppression was defined as a failure to suppress both postdexamethasone levels to below 5 ul/dl. Cortisol nonsuppression occurred in 66 % of the endoeenous depressives, in 28 % of the parkinsoni~n patients, in 25 % of the non-endogenous depressives and in 17 % of the controls. The mean Hami&ton score was 25 in endogenous depression, 16.5 in PD, 21 in non-endogenous depression and 5.5 in controls. As parkinsonian patients mostly have lower Hamilton scores but higher nonsuppression rates than non-endogenous depressive patients, the abnormal DST results obtained in PD do not only reflect severity of depression. Neurologische Universit~tsklinik, Oosef-Schneider-Str, ll, D-8700 WOrzburg.

Chichibu Psychiatric Hospital, 1404 Terao, Chichibu, Saitama 368, JAPAN.

378

34.02.06

34.02.07

ACUTE EFFECTS OF MONOAMINERGIC DRUGS ON THE LEVELS OF fl-ENDORPHIN IN RAT HYPOTHALAMIC NUCLEI A. Nohtomi, M. Itoh, H. Kawasaki and K. Nohtomi

C O R T I C O T R O P I N R E L E A S I N G H O R M O N E (CRH) S T I M U L A T E S H Y P O T H A L A M I C O P I O I D R E L E A S E BOTH IN V I V O A N D IN VITRO K.E. N i k o l a r a k i s , O.F.X. Almeida, D.J.S. S i r i n a t h s i n g h j i * and A. Herz D i s t u r b a n c e s of the h y p o t h a l a m o - p i t u i t a r y - a d r e nal axis are a s s o c i a t e d w i t h several p s y c h o t i c disorders. H y p e r s e c r e t i o n of c o r t i c o s t e r o i d s in d e p r e s s i v e p a t i e n t s has b e e n e x t e n s i v e l y e x a m ined and h y p e r a c t i v i t y of CRH n e u r o n s is w e l l e s t a b l i s h e d . On the other hand, e n d o g e n o u s o p i o ids m o d u l a t e n e u r o n a l t r a n s m i s s i o n and t h e r e is e v i d e n c e i n d i c a t i n g their i n v o l v e m e n t in the p a t h o p h y s i o l o g y of a f f e c t i v e psychoses. The i n t e r a c t i o n b e t w e e n CRH and o p i o i d n e u r o n s were e x a m i n e d b o t h in v i v o and in v i t r o e x p e r i ments in rats. E x o g e n o u s CRH a p p l i e d to h y p o t h a lamic slice p r e p a r a t i o n s in v i t r o i n d u c e d a 2 fold increase in the r e l e a s e of B - e n d o r p h i n , dynorphin and m e t - e n k e p h a l i n . B l o c k a d e of e n d o g e nous CRH by the specific CRH r e c e p t o r a n t a g o n i s t u - h e l i c a l CRF9_41 both in v i v o (push-pull method) and in v i t r o was f o l l o w e d by a s i g n i f i c a n t dec r e a s e in B - e n d o r p h i n and d y n o r p h i n release.

P r e v i o u s s t u d i e s have shown t h a t dopamine i n h i b i t s the r e l e a s e of B - e n d o r p h i n - l i k e immnnoreactiv i t y (B-ENDi) from r a t hypothalamus in v i t r o (I. Vermes et a l . , g r a i n Res.,326:41,1985). However. l i t t l e is known as to the acute e f f e c t of monoa~in e r g i c drugs on the l e v e l s of B-ENDi in r a t hypothalamus in vivo. In the p r e s e n t study, the levels of B-ENDi were determined in the hypothalamic nuc l e i of the r a t s acutely t r e a t e d with the monoami n e r g i c drugs. In the median eminence, s n l p i r i d e (20 mg/kg) or domperidone (2.5 mg/kg) decreased the l e v e l s of B -ENDi, and L-DOPA (200 l g / k g ) increased the levels of B-ENDi. In the nucleus arcuatus, i s o p r o t e r e n o l (25 ~ g / k g ) increased the l e v e l s of B-ENDi, and p r o p r a n o l o l (2.5 mg/kg) r e v e r s e d the e f f e c t . Conc u r r e n t i n j e c t i o n of 5-HYP (B0 mg/kg) with f l u o x e t i n e (10 mg/kg) increased the l e v e l s of B-ENI)i in the nucleus a n t e r i o r hypoth&lali, nucleus p e r i v e n t r i c u l a r i s and nucleus p a r a v e n t r i c u l a r i s . These r e s u l t s s u g g e s t t h a t dopamine, n o r a d r e n a l in and s e r o t o n i n Ray r e g u l a t e B - e n d o r p h i n e r g i c neurons in r a t h y p o t h a l a l u s . Department of Neuropsyehiatry, Faculty of Medicine, Kyusyu University, Fukuoka 812. JAPAN.

These results indicate that e x o g e n o u s CRH stimulates o p i o i d release, while h y p o t h a l a m i c o p i o i d neurons are t o n i c a l l y s t i m u l a t e d by CRH r e l e a s ing neurons. These C R H - o p i o i d i n t e r a c t i o n s m a y thus have i m p l i c a t i o n s in the p a t h o p h y s i o l o g y of a f f e c t i v e disorders. Max-Planck-Instiut f~r P s y c h i a t r i e , Dept. N e u r o p h a r m a c o l o g y , Am K l o p f e r s p i t z 1 8 a , D - 8 0 3 3 Planegg. F.R.G. *AFRC I n s t i t u t e of A n i m a l Physiology, C a m b r i d g e , England.

34.02.08

34.02.09

TRH STIML~LATION TEST IN PRIMARY DEGENERATIVE DE>ENTIA (PDD) AND CONTROLS M.W. Dysken, A. Falk, M. Kuskowski, and D. Krahn Previous TRH stimulation studies in PDD patients vs. controls have shown no difference in ~TSH (Peabody et al, Biol Psych 21, 553,'86; E1 Sobky et al, Acta Psych Scand 74, 13,'86), a blunted~TSH in patients (Sunderland et all Psych Res 16, 269,'85; Thomas et al, Acta Psych Scand 76, 158,'87), no difference in~PRL (Thomas et al, v.s.), an augmented ~PRL in patients (Peabody et al, v.s.; E1 Sobky et al, v.s.), and a blunted~PRL in patients (Newhouse et al, Biol Psych 21, 963,'86). We performed TRH stimulation tests in 18 DSM-III PDD patients (10M, 8F; age=68• 7) and 12 controls (7M, 5P; age=61• Patient MiniMental State~ExamiGation scores ranged from 2 to 28 with ll!SD=18• control scores were all equal to 30. Patient HAM-D scores ranged from 2 to I0 (M=6). Protirelin (500 ug) was injected IV and blood was sampled at 0,15,30,45, 60, and 90 min for TSH and PRL. There were no significant differences between patients and controls in baseline T4,T3 uptake, or TSH; TRH stimulated TSH at all times; TP~ stimulated PRL at all times; and AUC for TSH and PRL. Duration of illness, M24SE, and HAM-D scores did not correlate significantly with stimulation test results There was, however, a significant relationship between gender and stimulated TSH and PRL. The TSH peak (30 min) for women (patients=20• controls=9• was significantly greater (F=8.3, p(0.01) than for men (patients=12• controls=7• The PRL peak (15 min) for women (patients =66• controls=31• was significantly greater (F=7.1, p~0.02) than for men (patients=53• controls=23• GRECC Program (IIG), Minneapolis VA Medical Center, One Veterans Drive, Minneapolis, ~ , USA.

THE C E N T R A L A C T I O N OF C O R T I C O T R O P I N - R E L E A S I N G F A C T O R - A B E H A V I O R A L A N D B I O C H E M I C A L STUDY I.V~TSUZAKI, Y . T A K A M A T S U and T . M O R O J I Corticotropin-releasing factor that consists of 41 amino acids and releases b o t h A C T H and 6-endorphin from the a n t e r i o r p i t u i t a r y gland. Recently, CRF and its r e c e p t o r s h a v e b e e n r e p o r t e d to to be w i d e l y d i s t r i b u t e d throughout m a m m a r i a n brains. In the p r e s e n t study, effects of CRF on b e h a v i o r s and turnover rates of c a t e c h o l a m i n e s in d i s c r e t e various regions of the f o r e b r a i n w e r e e x a m i n e d when i n j e c t e d i n t r a c e r e b r o v e n t r i c u l a r l y (i.c.v.) in rats at a dose level of 1.0 or i0 ug/10~l. CRF of 1.0 ug i n c r e a s e d l o c o m o t o r activity, w h i l e CRF of i0 ug i n d u c e d stereotypy c h a r a c t e r i z e d by grooming. CRF injected i.c.v, caused a d o s e - d e p e n d e n t increase in the turnover rate of d o p a m i n e (DA) in the frontal c o r t e x (FC). D A t u r n o v e r rates in the striatum, h i p p o c a m p u s (HIPP) and amygdala were increased, but not in a dose dependent manner. These findings, taken together w i t h b e h a v i o r a l changes observed, indicate that the b e h a v i o r a l c h a n g e c h a r a c t e r i z e d by g r o o m i n g may be a s s o c i a t e d w i t h the activity of the m e s o c o r t i c a l D A system. The turnover rate of n o r e p i n e p h r i n e in the FC and H!PP was i n c r e a s e d s i g n i f i c a n t l y but not d o s e - d e p e n d e n t l y , s u p p o r t i n g the h y p o t h e s i s that CRF in the b r a i n m a y be an endogenous a n x i o g e n i c factor. D e p a r t m e n t of P s y c h o p h a r m a c o l o g y , P s y c h i a t r i c R e s e a r c h I n s t i t u t e of Tokyo, 2-1-8 Kamikitazawa, Setagaya-ku, 156, T o k y o

379

34.03.01 AN I'~ S'II~Y ON S

POSTER PRESENTATION 34.03

Neuroimaging in Neuroscience and Psychiatry

~

I

~

MASAYK~KI U}~MATSU~ M.D. AND H I ~ KAIYA, M.D. All subjects consenting to this study were physically healthy male adults under 50 years of age. Since the size of the corpus callosum is thought to be gender-related, only male subjects were used. The group of normal controls consisted of 17 volunteers(all right-handed, mean_+ SD age of 31.5_+ 5.5 years old) in whom mental disorders and a history of brain lesions could be excluded. Forty patients(39right-handed, I undetermined, mean+_SD age of 32.2+_ 6.7 years old) were diagnosed as having schizophrenic disorders based on DSM-III criteria (APA, 1980). An MRI system(Picker, Vista MR) with a 0.5 tesla superconducting magnet and a radio frequency coil, 30 cm in diameter, was used in this study, The images were constructed on a 256)< 256 matrix display. Slice thickness was approximately 10 mm, with a special resolution of I.Tx 1.7 am. The image in a mid-sagittal cut was made using an i n v e r s i o n r e c o v e r y pulse sequence(inversion time: 500 msec, repetition time: 2000 msec). Each d e m o g r a p h i c v a r i a b l e was d o c u m e n t e d for all patients. Each clinical measure on the Brief Psychiatric Rating Scale(Blm~S)(Overall and Gotham, 1962) and negative and positive symptoms(Andreasen and Olsen, 1982) were also obtained for all schizophrenic patients. All data were input into a microcomputer and treated statistically. Results, schizophrenic patients had a higher septum pellucidum : brain ratio(PBR)(t=2.92,p<0.01) and a higher anterior one third of the corpus callosum : brain ratio(ACBR)(t=2.17,p<0.06) than normal controls. There were no significant differences in corpus callosum : brain ratio(CBR), callosum width ratio(CWR), length of the corpus callosum between schizophrenics and normal controls. However, ~ithin the schizophrenic group, there was a correlation between certain morphological measures and distinct clinical features of the disease. Department of Neurology and Psychiatry, Gifu University School of Medicine, 40 T s u ~ a c h i , Gifu, Japan.

34.03.02

34.03.03

A SPECIFIC METABOLIC PATTERN RELATED TO THE HALLUCINATORY ACTIVITY IN SCHIZOPHRENIA J.D. Buret, A. Lesur, J.L. Martinot, B. Mazoyer, S. Pappata, A. Syrota, J.C. Baron, T. Lemp~ri&re The cortical metabolic pattern of 12 schizophrenic inpatients experiencing either true or pseudohallucinations was studied using positron emission tomography (PET) and 18-fluoro-deoxyglucose. All patients fullfilled the DSM III criteria for schizophrenia and their clinical symptomatology and the evolutive aspects of their illness were carefully investigated. A specific hypothesis concerning the hallucinatory activity was elaborated before data analysis. This hypothesis involved a particular imbalance between the activities of the posterior associative (PA) and of the non-associative sensory cortex (NAS). Variables thought to be the most representative of this hypothesis were a priori selected for the statistical analysis: the regional glucose metabolic rates (rCMRGIu) in the PA region and in the NAS regions together with the ratio of these two values. 18F-DG PET studies were also performed in a group of 6 agematched control subjects. The analysis revealed a significant decrease of the CMRGIu in the PA cortex (pc.05, Kruskal and Wallis test) together with a marked increase of the ratio NAS/PA (pc.004) in the schizophrenic group. We also found a significant increase of the metabolic index (the ratio of the rCMRGIu to the whole cortex metabolic rate) in the NAS visual cortex (p<.0001) in the schizophrenic group. These results are in good agreement with recent PET studies showing a reduction of the rCMRGIu in the posterior associative area in schizophrenic patients. Moreverp the apparent imbalance between the PA and NAS cortex activities offers a functional approach of the hallucinatory phenomena whatever their sensory modality could be. This particular pattern is also in agreement both vith the clinical phenomenology of schizophrenia and with some psychophysiological theories developped about hallucinations. Serv. Bosp. F. Joliot, CEA, 91406 0rsay,France

C O M P U T E R I Z E D T O M O G R A P H Y IN A F F E C T I V E D I S O R D E R S : IRELATIONSHIPS WITH PSYCHOMOTOR RETARDATION S.SCHLEGEL, W.MAIER, D.NIEBER, K.KRETZSCHMAR In 44 p a t i e n t s w i t h a m a j o r d e p r e s s i v e episode, according to D S M III, CT i n v e s t i g a t i o n s were performed. CT m e a s u r e m e n t s : V e n t r i c u l a r b r a i n r a t i o (VBR) was measured with three different methods, linear d i s t a n c e s of the third v e n t r i c l e , the frontal horns , the b i c a u d a t e diameter, S y l v i a n and i n t e r h e m i s p h e r i c fissures w e r e p e r f o r m e d . Correlation analyses with different rating scales showed most significant correlations w i t h those scales w h i c h o b t a i n e d " r e t a r d a t i o n " r e l a t e d items, e.g. B e c h - R a f a e l s e n - D e p r e s s i o n Scale (BRMS), Brief P s y c h i a t r i c R a t i n g Scale, Global A s s e s s m e n t Scale, w h e r e a s the H a m i l t o n D e p r e s s i o n R a t i n g Scale and d i f f e r e n t a n x i e t y r a t i n g scales did n o t c o r r e l a t e s i g n i f i c a n t l y w i t h any CT m e a s u r e m e n t . The item a n a l y s e s of BRMS items demonstrated most significant a s s o c i a t i o n s with lowered mood, verbal, motor, emotional, and i n t e l l e c t u a l retardation. Such relationships were not found for the items: anxiety, somatic complaints, sleep d i s t u r b a n c e s and suicidal impulses. Based on these data we d e v e l o p e d the h y p o t h e s i s t h a t only the "retarted" s u b t y p e of d e p r e s s i o n is a s s o c i a t e d with m i l d brain atrophy. In order to r e c o n s i d e r these results on the basis of measurements of verbal, m o t o r and i n t e l l e c t u a l retardation, a study of a new sample of patients is in progress. First data of this i n v e s t i g a t i o n will be presented. D e p a r t m e n t of Psychiatry, U n i v e r s i t y of Mainz, Untere Zahlbacherstr.8, D-6500 Mainz, F.R.G.

380

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34.03.05

VOLUME, SHAPE, LOCATION AND GRAY/WHITE TISSUE ANALYSIS OF BRAIN MAGNETIC RESONANCE IMAGES H.H. Holcomb, H.L. Loats~ C.A. Tamminsa~ A. Summerfelt and A. Slusarcick Computer assisted stereotaxic measurements of brain tissue is a prerequisite for assessing the role of abnormal brain morphology in neuropsychiatric illness. Magnetic resonance images (MRI), obtained with a 1.5 Tesla magnet, 3 millimeters thickness, TR=3000, TE=20 and 80, were acquired of the entire brain in an initial sample of three normal volunteers and six patients with psychiatric illness. These images were digitized and subjected to a series of measurements and transformations on a biomedical image analysis system. First, using the glabella-inion axis, we determined the x,y,z stereotaxie coordinates of all image pixels. Centroid coordinates and volume estimates of selected subcortical structures (caudate, putamen, amygdala) were determined. Lateral and third ventricle volumes were also measured in association with a serial slice analysis of shape. The latter was accomplished using a Fourier expansion of the structure's perimeter. The shape was described using the amplitudes and phase angles of the first eight harmonic terms. Trend analysis and principal component analysis provided estimates of harmonic term influence over rostro-caudal and dorso-ventral axes. In each slice gray/white tissue contributions were assessed using optical transmission thresholding. By using the cingulate cortex or superior frontal pole as an internal control, we were able to determine the precent of brain tissue that provided magnetic resonance signals characteristic of gray matter, white matter, or cerebrospinal fluid. This set of morphometric analyses will substantially improve the quantitative assessment of brain tissue shape, volume, topology, and gray/white characteristics. University of Maryland Psychiatric Research Center; Johns Hopkins Medical Institutes; and Loats Associates, Inc.; Baltimore, MD 21228, USA.

Corpus Callosum Imaging in Schizophrenia M. Casacchia, A. IRossi, P. Stratta, V. Di Nichele, 5. Ceccoli, R. Fassariello~, M. Gallucci*. Clinica Psichiairica, *Catiedra di Radiologia Ospedale S.H. Collemaggio. University of L'Aquila. 67100 L'Aquila -ITALY

34.03.06

I> lqosenihal R., Bigelow L.B. (i972): Quantitative brain measurements in chronic schizophrenia. Br. J. Psychiatry 12,259. 2) ~cssi A., Stralia P., Casacchia N. et al (1988): Brain morpholog~ in schizophrenia by Magnetic Resonance Imaging (MR)). Acta Psych)air. Scandinavica (in press).

34.03.07

~ m p a i r m e n t of s a c c a d i c schizophrenics. A. Mackert,

Available evidences indicate t h a t schizophrenia may be associated with morphological brain changes. Among others, the possible existence of structural callosal pathology in schizophrenia was firs~ suggested in i972 by lqosenihal and Bigelow who reported finding a significant increase in the "thickness" of the Corpus Callosum (CC) in post-mortem brains of schizophrenics compared to a psychiatric control group (i) .' With the advent of Magnetic Resonance Imaging (MRI) technology the problems of posi-moriem studies may be overcome because we are able to obtain detailed images of the brain in multiple planes with an e~celleni delineation of morphology of the CC in vivo. We underlook a MR) controlled s~udy in schizophrenia by means o~ an Ansaldo Esatom 5000 scanner operating at 0.5 Tesla magneli~ field (2). A midsagillal slice (5 mm thid0 and 8 axial slices (10 mm thid0 were obtained. Several midsagittal and axial measurements were performed on 30 palienis and 30 strictly matched controls, Schizophrenics showed a sial)st)tally significant larger Venlricular Brain ratio and lower Corpus Callosum to brain ratio. Structural callosal differences may be useful for further exploration of functional organization in the normal human brain and of possible alteration in normal cerebral organization thai a~-e associated wiiJl the paiophysiology of schizophrenia.

eye m o v e m e n t s

in

C. W o y t h

S c h z z o p h r e n l c s have w e l l k n o w n d i f i c i e n c i e s in smooth p u r s u l t eye t r a c k i n g . T h e p r e s e n t inves t i g a t i o n f o c u s s e s on s a c c a d i c eye m o v e m e n t s r e s p o n s i b l e for r a p i d l y d i r e c t i n g the fovea to a t a r g e t in v i s u a l space. 47 acute s c h i z o p h r e n i c s w i t h o u t n e u r o l e p t i c s f u l f i l l i n g RDC c r i t e r i a p a r t i c i p a t e d in the study. The BPRS, SANS and P r o g n o s t i c Scale s e r v e d as i n s t r u m e n t s for p s y c h o p a t h o l o g y . The c o n t r o l group i n c l u d e d 28 age and sex m a t c h e d h e a l t h y v o l u n t e e r s . A l u m i n o u s t a r g e t w a s disp l a c e d u n p r e d i c t a b l y from 7,5 to m a x i m a l 2o ~ in b o t h d i r e c t i o n s . S a c c a d i c eye m o v e m e n t s w e r e r e c o r d e d by e l e c t r o o c u l o g r a p h y in the h o r i z o n t a plane. S c h i z o p h r e n i c s p r o d u c e d s i g n i f i c a n t l y m o r e dysm e t r i c saccades u n d e r s h o o t i n g the t a r g e t m a i n l y for small a m p l i t u d e s (7,5 and Io~ Signiflcant c o r r e l a t i o n s w e r e found in p a t i e n t s w i t h e a r l y m a n i f e s t a t i o n and d i s a d v a n t a g e o u s c o u r s e of illness. There w e r e no signs of l a t e r a l asymm e t r i e s in the g r o u p of s c h i z o p h r e n i c s . The m o s t likely e x p l a n a t i o n for the h i g h e r r a t e of h y p o m e t r i c s a c c a d e s in s c h i z o p h r e n i c s is a d y s f u n c t i o n of the c o m m a n d c e n t e r s l o c a t e d in the c e r e D r a l cortex. D e p a r t m e n t of P s y c h i a t r y (Head: Prof. Dr. H. H e l m c h e n ) , Free of Berlin, E s c h e n a l l e e 3, D - l o o o B e r l i n 19

University

MRI AND CT IN CHRONIC A L C O H O L I S M - E F F E C T S OP A B S T I N E N C E CN ! N T R A C R A N I A L CSF V O L U M E AND BRAIN DENSiUY. G. Mundle: K. Mann~ D. Petersen~ H.W. S c h i e d ~ G. S c h r o t h an~ H. H e ) m a n n A l c o h o l i c b r a i n shrinkage has b e e n c o n s i d e r e d to be due to d e h y d r a t i o n of the b r a i n w h e r e a s its r e v e r s i b i ! i ~ y f o l l o w i n g a b s t i n e n c e has b e e n att r i b u t e d t o r e h y d r a t i o n . We t e s t e d this h y p o t h e sis u s i n g ccm~uted t o m o g r a p h y (n=45) and m a g n e tic resonance i m a g i n g (n=10) in chronic a l c o h o lics before and after a six weeks d e t o x i f i c a t i o n program. Intracranial volumetry revealed a highly signif~ cant r e d u c t i o n of CSF volume (p> 0.001) after abstinence. Uhe p a r t i a l volume effect could be better resolved by MR!. T 2 - r e l a x a t i o n times for withe m a t t e r were e s t i m a t e d by l i n e a r r e g r e s s i o n from 16 echoes of a CPGM sequence. S i g n i f i c a n t increases which one w o u l d expect from h i g h e r free water content (i.e. r e h y d r a t i o n ) could not b e verified. CT density m e a s u r e m e n t s were p e r f o r m e d in 45 patients. Brain density i n c r e a s e d s i g n i f i c a n t l y in the d o r s c - n e d i a l part of the thalamus, w h e r e a s c a k a t e nucleus, inner capsula, and frontal white and grey m a t t e r did not differ significantly. C o r r e l a t i o n b e t w e e n density increase in thalamus and volume change of the v e n t r i c l e s was -0.77. These results are in c o n t r a d i c t i o n with the " r e h y d r a t i o n hypothesis". Other influences, such as a r e g e n e r a t i o n of the neuropil, might be more important th~n p r e v i o u s l y thought. D e p a r t m e n t s of P s y c h i a t r y and N e u r o r a d i o l o g y , U n i v e r s i t y cf ?~bingen, F.R.G. O s i a n d e r s t r e Z e 22, D-7400 THbingen.

381

34.03.09

34.03.08 CT SCANS AND NEUROLEPTIC RESPONSE SCHIZOPHRENIA: A MULTIDIMENSIONAL A P P R O A C H

IN

W. F. Gattaz, W. Rest, K. Kohlmeyer, K. Bauer, C. v. K. Hfibner and T. Gasser Structural brain abnormalities in schizophrenia have been reported by several computertomographJc (CT) studies. However the prevalence and the localization of the abnormalities vary widely among studies. These differences might stem from samples h e t e r o g e n e i t y , f r o m t h e c h o i c e o f t h e CT p a r a m e t e r t o be i n v e s t i g a t e d o r f r o m t h e u s e o f d i f f e r e n t c r i t e r i a for d e f i n i n g abnormalities. To overcome these d i f f i c u l t i e s we i n v e s t i g a t e d 12 CT p a r a m e t e r s in 80 schizophrenic patients (mainly acute schizophrenia} and in 30 s e x and age-matched controls and evaluated the data simultaneously through Multidimensional Scaling (MDS). MDS p r o v i d e s a graphic representation in which subtle deviations in the different CT parameters can be detected, independently of predetermined criteria for the definition of abnormalities. In o u r s a m p l e MDS i d e n t i f i e d 18 p a t i e n t s w i t h d e v i a n t m e a s u r e s f r o m t h e c o n t r o l s i n o n e o r m o r e CT p a r a m e t e r s . F i v e of t h e s e 13 p a t i e n t s w e r e f i r s t o n s e t s c h i z o p h r e n i c s . Patients with deviant CT p a r a m e t e r s showed significantly poorer response to a standardized haloperidol therapy over 3 weeks as compared with patients without d e v i a n t CT p a r a m e t e r s . Our results suggest that the multidimensional approach used here might be useful to identify more precisely patients with and without structural brain abnormalities for the further study of the features that could characterize these subgroups. Central Institute of Mental Health Mannheim P. O. Box 5 9 7 0 , 6 8 0 0 M a n n h e i m 1, F. R. G.

COMPUTED TOMOGRAPHY SCAN ~iD MEDICATION RESPONSE IN BIPOLAR AFFECTIVE DISORDER S. Pu• M. Berpsewicz, E. Bidzi~ska,,, A. K a l i n o w s k i , T. K r y s t , P. K o z t o w s k i , M. Zatuska, E. Bos B. Habrat, Using computed tomography v e n t r i c u l a r and s u l c a l measurement were completed i n 40 depressed p a t i e n t s w i t h b i p o l a r a f f e c t i v e d i s o r d e r s / w i t h l o n g - t e r m course of i l l n e s s / . Amongst 67 % p a t i e n t s c o r t i c a l a t r o p h y , enlargement o f lateral ventricle and/or ventricle asymmetries were found. Findings suggest that above brain changes are more frequent in patients with severe course if illness. Detailed analysis of psychotropic drugs efficacy during last 3 years /antidepressants. lithium carbonate, neuroleptics/ showed no significant differencies in cortical atrophy and ventricular enlargement amongst responders and nonresponders. All patients with ventricular asymetry belong to subgroup of nonres-

ponders. I n s t i t u t e o f P s y c h i a t r y and N e u r o l o g y , A1. S o b i e s k i e g o 1 / 9 , 02-957 Warsaw, Poland

34.03.10

34.03.11

GREATER LEFT CEREBRAL HEMISPHERIC METABOLISM IN BULIMIC PATIENTS AS ASSESSED BY POSITRON EMISSION TOMOGRAPHY J. C. WU, B. Blinder, M. S. Buchsbaum, M. Derrfler, J. Haqman, W. Y. Tai, E. Hazlett and N. Sicotte We now report for the first time a study of the functional neuroanatomy of bu!imic behavior as assessed by positron emission tomography (PET) study of regional cerebral glucose metabolism. Eight DSM-III diagnosed bulimic subjects (mean age 28.6!6.5 yrs, all women, six right-handed and two left-handed) and eight normal controls (mean age 28.9 • 7.7 years, all women, all right-handed) had a PET scan according to methods previously described (Buchsbaum et al, 1984). The PET scan procedure involved the administration of 4 to 5 millicuries of 18-fluoro-deoxyglucose. There was a significant three-way interaction (hemisphere by quadrant by group, F=2.82, D.F.=3,42, p=.05) which confirmed a finding of hypofrontality. The bulimic left-sided subcortical structures were higher than the normal left sides structures, whereas the bulimic right-sided structures were less than the normal right-sided structures. Clinical correlations with structural metabolism: Significant negative clinical correlations were found for striatal and thalamic structures relative metabolism with the EAT. Significant positive correlations were found for the limbic structures. Department of Psychiatry, University of California, Irvine, Med Sci I, Room D404, Irvine, California 92717

NEURO-IMAGING OF PAIN RELATED POTENTIALS IN TH FREQUENCY DOMAIN B. Bromm and E. Scharein I n s t i t u t e of P h T s i o ] o ~ ,

Hamburg U n i v e r s i t y , FaG

~ n c r e a s i n g l y , cerebral p o t e n t i a l s evoked by painf u l s t i m u l i are i n v e s t i g a t e d as an assessment to e x p e r i m e n t a l l y induced p a i n . S i g n i f i c a n t c o r r e l a t i o n s between l a t e components of somatosensory evoked cerebral p o t e n t i a l s (SEPs) and painfulness of the applied stimulus have been documented. The present paper describes the t r a n s f o r m a t i o n of SEPs (500 ms) i n t o the frequency domain with the param e t r i c spectral e s t i m a t o r based on the maximum ent r o p y method (MEM, l ) as a new approach to monitor the time course in e f f i c a c y of c e n t r a l l y acting drugs. Imipramine was chosen as an example of a t r i c y c l i c a n t i d e p r e s s a n t , and meperidine ( p e t h i d i he) as a s y n t h e t i c o p i o i d with strong analgesic p r o p e r t i e s . The i n f l u e n c e of the treatments on SEP spectra were monitored over 4 hours in a sample of 24 h e a l t h y s u b j e c t s . Results: Most of a l l the PSDs o f the SEPs impress by an immense power peak in the 2-4 Hz range ( d e l t a ) . A second peak r i s e s between 4-8 Hz ( t h e t a ) , and a 3rd accumulation of a c t i v i t y can be observed in the alpha band (8-12 Hz). Pain r a t i n g s as well as d e l t a power of the SEP spectra were diminished by a s i n g l e dose of imipramine to an e x t e n t s i m i l a r to t h a t by the n a r c o t i c meperidine. Differences in time course of e f f i c a c y could be a t t r i b u t e d to the d i f f e r e n t pharmacokinetics of the two drugs. The SEP spectra obtained by MEH are shown to be a good t o o l in d i f f e r e n t i a t i n g the cerebral h i e - a v a i l a b i l i t y of the drugs a p p l i e d . (1) Scharein E. et a l . (1984), i n : Pain Measurement in Man, B. Bromm (ed.) pp. 189-202, Elsev i e r , Amsterdam.

382

34.03.12

34.03.13

PET-SCANNING WITH C 11 LABELED METHYL SPiPERON AND PROLACTIN PROVOCATION TESTS IN THERAPY RESISTANT PSYCHOTIC PATIENTS H.J.Coppensl.2 r C.J.Slooff 4, A.M.S.PaansSr W.Vaalbur~ 3, J.W.Louwerens 4 and J.Korf I It is generally assumed that neuroleptics require a blockade of cerebral dopamine-D2-receptors for their antipsychotic action. We studied whether this is a necessary condition in therapy resistant schizophrenics. Therefore D2-receptor binding with C 11 labeled methyl spiperon in vivo was performed with PET-scanning, the psychological condition was assessed by the present state examination (PSE) and the extrapyramidal side effects were evaluated by the Chouinard scale. Six patients (between 22 and 40 yrs old) who were all diagnosed as schizophrenics, according to the DSM III criteria (APA'80), having positive psychotic features, were treated with a megadosis of neuroleptics during at least six weeks. Despite the high dosis the psychosis did not change significantly. We found that all patients had a maximal D2-receptor blockade. In a second test patients were "provocated" with 500 mg L-DOPA (plus 50 mg Carbidopa) and with i0 mg haloperidol subsequently, to study changes in the prolactin blood concentrations. L-DOPA lowered significantly prolactin concentrations, but b aloperidol was without effect. The results with PET and the haloperidol provocation tests indicate that the megadose treatment leads to a complete D2-receptor blockade. The persistent effect of the DOPA provocation may indicate that under this condition not all (D2)agonistic activity is suppressed. If so, therapyresistance may be related to remaining D2-activation by endogenous dopaminergic neurons. (This investigation was in part supported by SQUIBB Ned) Departments of Biological Psychiatry I , Clinical Psychiatry 2 and Nuclear Medicine ~ of the Groningen University, and Psychiatric Hospital Licht en Kracht, Assen 4, the Netherlands.

T O P O G R A P H I C A L E E G FLAPPING A N D N E U R O P S Y C H O LOGICAL PARAMETERS IN P A R K I N ~ N ' S D I S E A S E ~.ND DEMENTIA OF ALZHEIMER TYPE L. F r ~ l i c h , R. Ihl, W. Kuhn, K. M a u r e r Topographical EEG mapping shows differences of electrical brain activity in patients with d e m e n t i a of the Alzheimer Type compared to h e a l t h y controls. S o m e p a t i e n t s s u f f e r i n g from M. P a r k i n s o n a l s o d e v e l o p a d e m e n t i v e syndrom. T h e a i m of t h e s t u d y w a s to u n c o v e r d i f f e r e n c e s in t h e t o p o g r a p h i c a l EEG pattern of both diseases. These differences might b e of r e l e v a n c e for an a d e q u a t e pharmacological t r e a t m e n t . I0 p e r s o n s (2 men, 8 women) with idiopathic Parkinson's disease volunteered to p a r t i c i p a t e in our study. The characteristics of this s a m p l e w e r e as f o l l o w s : mean age = 64.2 years; d u r a t i o n of illness = 5.4 years. All patients were receiving levodopa/benserazid and some combination of bromocriptine, deprenyl. b u d i p i n e and a m a n t a d i n e . Parkinsonian symptoms w e r e a s s e s s e d by t h e C o l u m b i a R a t i n g S c a l e and t h e Z u n g Scale. I0 patients with probable DAT (2 men, 8 women)(mean age = 64.8 years; duration of illness = 4.8 years) free of psychotropic drug treatment were investigated for comparison. To evaluate the degree of dementia brief cognitive rating s c a l e (BCRS) was applied. For further characterization of the memory impairment "Syndrom-Kurz-Test" was used. Differences were found between patients with M. Parkinson and patients with DAT. D e m e n t i v e s y n d r o m e ~ in M. P a r k i n s o n d i f f e r e d in b r a i n e l e c t r i c a l a c t i v i t y f r o m p a t i e n t s w i t h M. Parkinson without dementia as well as f r o m patients with DAT. Dept. of P s y c h i a t r y , University of Wdrzburg, FQchsleinstr. 15, D - 8 7 0 0 W Q r z b u r g

34.03.14

34.03.15

T~E I N F ~ OF P S ~ I S F H A T ~ TO~C DIST~ON OF ~ AND ~

ON THE

TOPOGRAPHY OF EVENT-RELATED POTENTIALS BEFORE

300.

AND AFTER ANTIOEPRESSIVE THERAPY G . C a r l , R . D i e r k s , K . M a u r e r , G.Laux

Th. Dierks, K.Maurer Six healthy subjects volunteered in a study to investigate the influence of phosphatidylaerine on the electrical activity of the brain

as

measured

by

phcsphatidylserine w e r e

electrical brain mapping. 6 ~ administered intravenously.

topogra~h/c distributian of

~G

was

The

measured prior to

administration, 30, 60, 90 and 120 rain afterward. The audibly evoked P300 was elicited ~efore, 60 and 120 min after the application of the substance. ~

results showed a ~mlnution of

delta and slow theta activity (0-5.5 Hz), whereas the fast theta and slow al~ha (6.0-9.5 Hz) activity underwent an increase. two frequency bands also showed a high correlation with time when using Kendal's Thau as correlation coefficient. The auditory elicited P300 didn't exhibit any cha~es regarding amplitude and latency in the recordings after drug administration compared to baseline values. However a s ~

influ~ce up~

latencies

becsme visible (shorter latencies) compared to amplitudes whic~ had the teedescy to maintain their values.

The ~

Endogenously depressive (DSM III, IC0-9) p a t i e n t s (3 f e m a l e s , 2 m a l e s ; a g e d 37-60) w e r e t r e a t e d for 28 days w i t h t h e MAOinhibitor moclobemid (300 m g / d a y ) . The a v e r a g e H R S D - s c o r e was 31 p r i o r to t r e a t m e n t . On day 28 the m e a n H R S D - s c o r e was 14. On the day b e f o r e t r e a t m e n t and on day 28 t h e topographical distribution of t h e e v e n t related acustically evoked potentials were r e c o r d e d . N 100 and P 300 l a t e n c i e s and amplitudes were compared with the differences on the p s y c h o m e t r i c s c a l e s b e f o r e and a f t e r treatment. Improvements in t h e H R S D - s c o r e s during treatment correlated significantly as far as s t a t i s t i c s are c o n c e r n e d (p
was

explored with variance analytic statistics (ANOVA) to elucidate sign/ficant changes over time. Statistical methods ta~ng spatial distribution into account, like spatial standard deviation were used for evaluation of changes in the topograph/c distribution pattern of the A~300. Dept. of Psychiatry, Univ. of Wuerzburg, Fuechsleinstr. 15, D- 8700 W u e r z ~ , FRG.

383

34.03.16

34.03.17

EFFECTS OF FIVE MONO,~MINE-INFLUENCING DRUGS ON THE APPEARANCE OF FRONTAL MIDLINE THETA ACTIVITY (Fme).

FRONT.~L MIDLINE THETA ACTIVITYAND PLATELET MAO IN HUMAN SUBJECTS.

J.NAKAMURA, H.MUKASA, M.HASHIMOTO, M.OTSLrKAAND K.INANAGA The distinct e rhythm which appears in the frontal midline area during the performance of mental tasks is called Fme. The appearance of Fme shows individual differences and seems to be re&ated to certain personality traits or the anxiety level of the subjects. In the present study, I) placebo, 2) L-DOPA (200 and 600 mg), 3) dopamine (DA) releaser; a TRH analog (DN~1417:80 mg), 4) noradrenaline (NA) precursor; L-threo-DOPS (600 mg), 5) DA receptor blocker; sulpiride (150 mg) and 6) MAD inhibitor; safrazine (15 mg) were administered to healthy male students for 5 days respectively. The subjects were all extrovert and did not show neurotic tendencies as measured by Maudsley Personality Inventory (MPI) and Karolinska Scales of Personality (KSP). EEG recording, determination of the changes in the background activity of EEG, and Spielberger's State-Trait Anxiety Inventory-1 (STAI-I) were carried out before, during and after the each drug administration. The appearance of Fme showed significant increase after the administration of L-DOPA (600 mg) an~ DN-1417 (80 mg). But the appearance of Fm~ had not been changed by placebo, L-DOPA (200 mg), L-threo-DOPS (600 mg)~ sulpiride (150 m g ) a n d safrazine (15 mg). As to the anxiety level, the scores of STAI-I showed no significant change during the experiments. From these results, we consider that the change of the appearance of Fm@ due to drug administration ocurrs not via NA but through the mediation of DA, and not necessarily associates with the change of the anxiety level. Department of Neuropsychiatry, Kurume University, School of Medicine, 67 Asahi-machi, Kurume 830, JAPAN.

H.MLrKASA, M.HASHIMOTO, J.NAKAMURA, S.YAMADA AND K.INANAGA The distinct theta rhythm which appears from the frontal midline during the performance of mental tasks has been designated as frontal midline theta (Fm0). Fm8 shows individual differences and seems to be related to certain personality traits or anxiety level of the subjects. In several studies, it has been indicated that low platelet monoamine exidase (MAD) activity is also associated with certain personality traits. In the present study, we have investigated the correlation between the appearance of Fm~ and platelet MAO activity. The subjects were 22 male students. The serial addition task was continued for 5 min and an EEG" #ecording was made during this period. The same procedure was repeated every other week up to a total of 3 times. MPI, MAS.and STAI were used in order to assess the personality traits and anxiety level of the subjects. The platelet MAO activity was assessed by the method of Jackman et al. Results were as follows: there was negative correlation between the appearance of Fm~ and the platelet MAD activity. The person with marked extroversion showed high amounts of Fm@ and low MAO activity. But no correlation was found between the anxiety level and platelet MAD activity. These results indicated that FmS, an electrophysiological marker, may be useful in the investigation of monoamine functions in the central nervous system by way of platelet MAD activity, a biological marker. In other words, the biological backgrounds of individual differences in Fm8 appearance may be ascribed to the contribution of the central monoamine system. Furthermore, the correlation of such markers as platelet MAO activity and Fme with personality traits as measured by various psychological tests may prove to be of great importance in the exploration of the biological bases of personality. Department of NeuropsyChiatry, Kurume University, School of Medicine, 67 Asahi-machi, Kurume 830, JAPAN.

34.04.01

POSTER PRESENTATION 34.04

Neuroimmunomodulation

Hyperbilirubinemia in Schizophrenic Psychosis P. Schiller, N. MUller, M. Ackenheil It was observed, that patients suffering from schizophrenia (ICD 295.0 - 6) frequently show a slight increase of b i l i rubin. In a retrospective study, the b i l i r u b i n blood concentration of every patient, who was admitted to the psychiatric hospital in 1985, was recorded. Excluded were patients with a l i v e r disease and patients suffering from alcoholism or drug abuse. A hyperbilirubinemia - comparable to the incidence of the Gilbert's syndrome is expected to occur in approximately 5-I0% of the general population. All patients having a b i l i r u b i n concentration of l , l mg% or more were l i s t e d . We found l l 4 out of 858 patients with a hyperbilirubinemia (see Table below). In schizophrenics, there were~significant more patients with a hyperbilirubinemia (CH~- = 20,7; p~O,OOl) compared to a l l other patients. Compared to the patients suffering from affective psychosis or a neurosis/ personality disorder, schizophrenics showed an extraordinary high ra~e of hyperbilirubinemia cases (CHI2 = 15,5; p< O,OOl; CHI~ = 18,5; pLO,OOl). In most cases, the hyperbilirubinemia was evident on admission to hospital and disappeared gradually during treatment. Two aspects should be discussed. l) Is there an increased coincidence of Gilbert disease and schizophrenia, which would point to a genetic linkage or 2) an increased v u l n e r a b i l i t y of erythrocytes in schizophrenics? reg. pat. h.-bilirubinemia part

9atients schizophrenie a f f e c t i v e psychoses neuroses others

858 187 393 2D5 72

114 47 39 18 I0

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~ab]e: general view over registered patients, diagnoses and hyperbilirubinemia Psychiatric Hospital of the University of Munich

384

34.04.02

34.04.03

UTAH MOLECULAR gENETIC STUDY OF }ta_XIC-DEPRESSION W Byerley, J-M Lalouel, M Leppert, P O'Connell, J Holick, D Stauffer, K.Bullen, F Reimherr, P Wender B Grosser, R White Recent studies indicate that a g e n e on the short arm of the llth chromosome and an allele on long arm of the Xchromosome determine the expression of manic-denression in some but not all families (Egeland et al Nature 783, 325, 1987, Baron et al Nature 289, 326 1987 and Mendlewicz et al Lancet 1230, i, 1987). As part of the Utah Molecular genetic Study of ~nic-Depression and Schizophrenia, we identified several multigenerational pedigrees afflicted with manic-depression. Each family has multiple persons affected by either Bipolar I or II disoraer or recurrent major depression. Diagnoses were made according to modified Research Diagnostic Criteria. In a preliminary investigation, we tested for linkage between one large Utah manic-depressive family and 6 polymornhic DNA markers (H-ras, piNS-310, pADJ762, JWI51, FTHLF, and pTT42) localized to the short arm of chromosome #ii and 6 DNA probes (Stl4 DXI3, D52A. p19-2, pYh~3, and pDXY$1) on the long arm of the X-chromosome. Close linkage, however, was ex&luded for H-ras (lod score -0.76 at 8=0.10) as well as for Stl4 (lod score -0.7] at 8=0.10). Work in progress will use the human linkage map to identify loci that confer susceptibility to manic-depression in the Utah families. Dept of Psychiatry and Howard Hughes Medical Institute, Univ of Utah Med Ctr., Salt Lake City, Utah 84132 USA

2 - D - E L E C T R O P H O R E SIS O F PROTEINS IN L Y M P H O C Y T E S F R O M P A T I E N T S WIT~[ PSYCHIATRIC DISORDERS. D.B.Wildenauer, W.Hoech~len, D.Waldinger, M.Ackenheil ............................................ Alterations in the composition of lymphocyte proteins Were studied in patients with schizophrenic disorders and compared to h e a k h y controls. Proteins were labeled

by t r e a t m e n t of lymphocytes with 8 8 S - m e t h i o n i n e and separated by two dimensional polyacrylamide g e l e t e c t r o phoresis according to O'Farretl. The polypeptides were detected by autoradiography. The e l e c t r e p h o r e s i s pa~tern of 29 p a t i e n t s with schizophrenic disorders and of 24 h e a l t h y controls were analyzed for variations.. 14 areas, as localized by reference proteins, were found with variations, i.e. spots were missing, new s p o t s appeared or the position was changed. One of the variations appeared to be predominant in schizophrenics: an additional polypeptide was detected in the pattern of 12 (n=22) schizophrenics with the subtype 295.1 (hebephrenic), 295.8 (paranoid) and 295.6 (chronic), but only in one of the controls and not in 6 patients with schizoaffective disorder (295.7). The respective molecular weight and isoelectric point of the protein is 40KD and 5.8. Correlation with biological variables as well as significance for schizophrenic disorders needs to be investigated. Psychiatric Hospital of the University of Munich, D - 8 0 0 0 Mfinchen 2, NuabaunstraSe 7, F R G (Head: Prof.Dr.H.Hippius)

34.04.04

34.04.05

STRESS-INDUCED MODIFICATIONS OF SOME IMMUNOLOGICAL PARAMETERS IN THE RAT. P. Foresta, C. Albertoni, A. Caprioli, M.T. Ramacci and *L. Angelucci The purpose of this study was to evaluate in the rat the effect of repeated stress on the responsiveness of spleen cells to mitogen stimulation; the activity of splenic phagocytes; and the cytotoxicity of peritoneal macrophages. These paramete_rs were examined in correlation with their respective hemocytometr ic analyses. Male Sprague-Dawley rats, aged 8 months, were used. They were subdivided into 3 groups: one control group (n=8) and two stressed groups (n--4 per group), with stress consisting in the immersion of the animals into 4~ water for 3 rain for 6 consecutive days. Then, they were subjected to examination at 30 rain and at 24 hr after completion of

HYPC ~RZACTIVITY TO ]]~&~ERFERON INDUCTiCN IN PERIPHERAL HLOCD MONON~CLEAR LEHCCCYTES OF PSYCP~ATR IC PATIENTS.

the stress cycle to ascertain stress-induced immunological modifications, if any. In 30-rain samples, an increase in phagocytosis (C. albicans) accompanied by total WBC increment, and a decrease in mitogen-induced proliferation (PHA and LPS) were found, whereas no change was observed in the animals sacrificed 24 hr later. The cytotoxic capacity of peritoneal macrophages showed no statistically significant modification at any time. Biological Research Labs, Sigma Tan S.p.A., 00040 Pomezia, Rome, Italy and *Pharmacology II, School of Medicine, "La Sapienza" University of Rome, Italy.

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We have observed that peripheral blood mono-: nuclear leucocytes / P ~ / of patients with schizophrenia ~nd affective disorders have a reduced capacity to produce interferons upon induction with Newcastle diseases virus/~V/, ohytohemagglutinin/PHA/,phcrbol myristate acetate/P~[A/ or !ipopolysaccharide/LPS/.Whole blood technique was used and interferon antiviral-activity was measured by a microbicassay using E~tC virus as challenge. T.~e response of P~.% to h~V or LPS was more suppressed than the response to P H A + P ~ . W e have investigated whether the hyporeactivity was corrected with mode of treatment.ln 20 pts subjected to ECTtherapy we did not found any effect of ECTtherapy on the induced interferon levels. The effects of psychotropic drugs and possible transmission of hyporeactivity by serum is under investigation. Psychiatric Clinic of the Medical University 25,St.Kraszewskiego,50-229 W~OCLAW,pCLAND

385

34.04.06

34.04.07

LACK OF CORRELATION BETWEEN REDUCED NK ACTIVITY AND INCREA SED ACTH AND CORTISOL VALUES IN MAJOR DEPRESSION D: Nerozzi, A. Santoni, G. Bersani, A. Magnani, G. Frajese Recent reports have pointed out the reduced functional capacity of the immunocompetent system in depression (S. Schleifer, Arch. Gen. Psych.41,484,1984). We evaluated the cytotoxic activity of Natural Killer cells (NKCA) since this immunological parameter is involved in surveillance against neoplastic disease (R.B.Herberman, Ad. Canc.Res.27, 305,1978) and since depression may elevate the risk of death from cancer (R.B.Shekelle, Psychos.Mad.43,117,1981). The aim of the study was also to verify the relevance of ACTH and cortisol on NKCA in depression. Twenty-two patients free from medical disorders, diagnosed as major depressive with melancholia, were selected in a drug-free state and compared to 22 sex- and age-matched healthy controls. NKCA studies were performed as previously published (A.Santoni, J.Immun.iS4;2799,1985). ACTH and cortisol values were measured by RIA methods. Statistical analysis was performed using the Student's T teat (two tailed). T h e NK activity was reduced in the depressed group while ACTH and cortisol values were enhanced compared to controls (see TAB). All tests of correlation and linear regression performed between hormonal and immunological parameters we re negative. Since alterations in various neurotransmitter systems in depression are well documented, a direct ac tion of neurotransmitters on the immune system can not bo excluded.

LY~:/~HOCYTE SUB-POPULATIONS IN MAJOR AFFECTIVE DISORDERS

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34.04.08 ABNORMAL NEUTROPHIL FUNCTION IN DEPRESSION : A POSSIBLE STATE-DEPENDENT MARKER? Bernadette O'Neill and B.E. Leonard. Several studies have linked depression to an increased incidence of cancer (Shekelle et al., Psychosom; Med., 45, 117, 1981), allergies (Nest et al., 3. Affect. Dis., 3, 2~I, 1981) and autoimmune disorders (Rogers et al., ~sychosom. Med., 41, 147, 1979). Kronfol e t a l . , (Life Sci., 55, 241, 1983) have sheen that there is a reduced response of lymphocytes to mitogen stimulation in depressed patients. Our preliminary studies have sho~n that neutrophil activity may also be decreased in a statedependent manner in patients with endogenous depression (O'Neill and Leonard, IRCS Med. Sci., 14, 803, 1986). In the present study we have investigated a larger patient population undergoing treatment with mianserin, fluoxetine or ECT. The results of this study show that neutrophil activity was reduced in drug free depressed patients'but returned to control values in response to effective therapy. This only occurred ~hen the patients own serum was used to opsonize the zymosan u s e d t o initiate phagocytosis, suggesting that a Factor may be present in the serum which is responsible for the suppression of phagocytosis. Experimental evidence suggests that increased serum prostenoids might be responsible. The specificity of the neutrophil test for depression was investigated by assessing neutrophil responses of panic disorder, schizophrenic, alcoholic and anxiety patients. It was found that panic disorder patients exhibited a similar decrease in neutrophil activity to depressed patients ~hich was reversed only in response to effective antidepressant treatment and was independent of anxiety symptoms. Serum cross-over studies confirmed the findings in depressed patients that the reduction in neutrophil activity was due to a serum defect rather than a cell defect. The other psychiatric groups sho~ed no differences compared to controls. Pharmacology Department, University College, Galway, Republic of Ireland.

386

P.P. Pani, L. rondo, C. Burrai, L. Scamonatti, G.F. Floris, P.E. Manconi Although the interrelationship between Immune System and CNS is still far from being clear, there are several clinical and pre-clinical observations showing the existence of a relationship between psychopathological states and immune functions. Among psychiatric disorders depressive states are the most oftenaccompanied by abnormalities in the number and function of lymphocytes. In particular the followinghave been noticed: A decreased proliferative response to mitogens after bereavment (i); a negative correlation between cellular NK activity and Depression score at the MMPI (2); a total decrease of T and B lymphocytes a n d a decrease proliferative response to mitogens in patients with Majo Depressive Disorders (3). However some of these results have been disputed. The present study deals with abnormalities in lymphocyte sub-populations in patients with Major Depressive Disorder vs. a control group. Subjects have been evaluated using the MMPI and a clinical interview. All of them were totally drug-free. Lymphocyte sub-populations were studied by monoclonal antibodies using a flow cytofluoremeter. l) Scheifer S.J., Keller S.E., Camerino M., et el. Suppression of Lymphocyte stimulation following bereavment. JAMA ,250, 374-377, 1983. 2) Heisel J.S., Locke S.E., Kraus L.J., Williams R.M. NK Cell Activity and MMPI Scores of a Cohort of College Students. Am. J, Psychiat. 143, 1382-1386, 1986. 3) Scheifer S.J., Keller S.E., Meyerson A.T., Rastin M.J. Lymphocyte Function in Major Depressive Disorders. Arch. Gen. psychiat. 41, 484-486, 1984. Clinics Psichiatrica, Via Liguria 13, 09127 Cagliari,ITALY /

34.04.09 IS THERE AN INFLUENCE OF NEUROLEPTICS ON CELLULAR

IMMUNE RESPONSE? NEUMANNi N.-U., LANZINGER, 0., SANCHEZ-DELGADO, E.. Increased c e l l u l a r immune response was found in 81 p a t i e n t s receiving n e u r o l e p t i c treatment. In order t o q u a n t i f y changes in the immune function we measured the delayed cutaneous h y p e r s e n s i t i v i t y r e a c t i o n s with standardised " M u l t i t e s t - M e r i e u x " . H y p e r s e n s i t i v i t y skin reactions were s i g n i f i c a n t l y stronger and the average number of p o s i t i v e reactions to antigens were higher than in normal c o n t r o l s . The increased c e l l u l a r immune response found in these p a t i e n t s could be explained, et l e a s t in part, by the i n h i b i t o r y e f f e c t s of neuroleptic drugs on histamine release from mast c e l l s (calmodulin antagonism), since histamine a c t i v a t e s suppressor-T-cells through H~-receptors This blockade of suppressor a c t i v i t y , with r e s u l t i n g s t i m u l a t i o n of cell-mediated immunity, could be of c l i n i c a l relevance in immune d e f i c i e n c i e s , malignancies and i n f e c t i o u s desease. Bezirkskrankenhaus GDnzburg, Abteilung P s y c h i a t r i e I I der U n i v e r s i t ~ t Ulm, Ludwig~Heilmeyer-Stra6e 2, D~8870 GOnzburg .

.

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.

34.05.01

POSTER PRESENTATION 34.05

Neuropeptides Basic and Clinical Aspects

PLASMATIC SOMATOSTIN, A STATE-MARKER OF PSYCHOPATHOLOGY IN SCHIZOPHRENIA? J. Saiz-Ruiz, J. Manzanares, J.L. Carrasco, A. Hernanz, M. Mart ln & C. Grande. Since the recognition of Somatostatin (SMT) in 1982, several roles including neuromodulation and behavioral actions have been p00posed for this peptide. Research related to schizophrenic patients has been performed on brain and CSF samples.The results were controversial and the only paper which atteapted to correlate psychopathology and CSF-SMT demonstrated a negative relationship (Gattaz et al.,Psychiatry Res 17/1,1,1986). Blood levels of SMT have not been investigated in schizophrenic populations. We have studied 50 patients that fulfil DSM-III criteria for Schizophrenic Disorder (Age,mean:27.8;s.d. :6.9 yrs. ; 38 male,12 female). Morning blood samples were taken from fasting subjects. Determinations of SMT and Insulin were performed by RIA methods. The evaluation of psychopathology was made by t h e Spanish version of Andreasen Scales (S.A.P.S. & S.A.N.S.). SMT plasma=tic levels in our group of patients were significantly increased ~ e d to a control group matched in age and sex (Student's Test,P 0.001). The results show also a positive correlation (P 0.05, Spearman Ccef. ; Factorial Analysis) between plasmatic levels of SMT and positive schizophrenics symptomatology indexes, specially Hallucinations and Delusions. On the contrary, there was no correlation with plasmatic glucose, insulin~ hepatic enzymes activity, sex, body weight, type or length of neuroleptic treatment and other considered variables %~ne results should be further discussed considering the lack of knowledge about the physiology of peripheric SMT and possible interaction with central SMT.Other factors, such as ackninistration of psychotropic drugs and stress perhaps could explain the findings. Hospital Rar~n y ~Cajal (SQ de Psiquiatrla). iC~ Colmenar, Ks. 9,1. E-28034. Madrid (Spain).

34.05.02

34.05.03

NOREPINEPHRINE (NE) PLASMA CONCENTRATION AFTE~ PLACEBO, D E S M E T H Y L I M I P R A M I N E (DMI) A N D R E C E P T O R B L O C K E R S PLUS DMI IN H E A L T H Y SUBJECTS. R. Lehle, G. L a a k m a n n , K. Zygan, A. Weiss, M. Wittmann, M. A c k e n h e i ] , N. M a t u s s e k The t r i c y c l i c a n t i d e p r e s s a n t DMI m a i n l y i n h i b i t s NE a n d less s e r o t o n i n reuptake. It stim~!ates growth hormone (GH). Since r e c e p t o r b l o c k e r s in f l u e n c e GH stimulation differently, NE plasma concentrations after placebo, DMI a n d DMI plus r e c e p t o r b l o c k e r s w e r e compared. In 7 d i f f e r e n t g r o u p s of 5 h e a l t h y m a l e s u b j e c t s each the NE p l a s m a c o n c e n t r a t i o n was assayed. At t=0 m i n one g r o u p ' r e c e i v e d p l a c e b o (NaC1) i.V., the other groups DMI 50 mg i.v. Five DMI g r o u p s were p r e m e d i c a t e d w i t h e i t h e r m e t h y s e r g i d e 12 mg p.o. (5-HT r e c e p t o r blocker) or p r o p r a n o l o l 15 mg i.v. (B-blocker) or p h e n t o l a m i n e 60 mg i.v. (~-i/~-2 blocker) or y o h i m b i n 10 mg i.v. (~-2 blocker) or p r a z o s i n 1 mg p.o. (~-I b l o c k e r ) . The areas under the seven NE m e a n c u r v e s (AUC) between~t=-30 and t=-0 m i n and b e t w e e n t=0 and t=120 m i n were c o m p a r e d . N e i t h e r p l a c e b o nor DMI i n f l u e n c e d N E c o n c e n t r a tion. P h e n t o l a m i n e and yohimbin increased NE concentration significantly, w h i c h was further i n c r e a s e d by DMI. Prazosin, p r o p r a n o l o l or met h y s e r g i d e plus DMI did not i n f l u e n c e NE c o n c e n tration. Thus it was:ishown that p a r t i c u l a r l y ~-2 blockade causes an i n c r e a s e in p e r i p h e r a l NE c o n c e n t r a t i o n which' i n c r e a s e s f u r t h e r after NE reuptake i n h i b i t i o n by DMI. In spite of p e r i p h e r a l HE increase D M I - i n d u c e d GH s t i m u l a t i o n was i n h i b i t e d by p h e n t o l a m i n e and y o h i m b i n . This i n d i c a t e s that GH s t i m u l a t i o n is m e d i a t e d by postsynaptic ~-2 r e c e p t o r s w h i c h remain ~nhibited a f t e r their b l o c k i n g d e s p i t e the NE increase. Psychiatrische Klinik der U n i y e r s i t ~ t MGnchen, Direktori Prof. Dr. H. Hippius, N u B b a u m s t r . 7

J.TOPINKA, B. BINKOV~ INFLUENCE OF ANTIOXIDANTS ON FREE RADICALS DAMAGE OF LYMPHOCYTES. Oxidative damage in biological systems can occur ~ue to the presence of high level of super0xid~-, hydroxyl- free Tadicals and hydrogen perdxide, which oxidize susceptible target molecules in living cells. They iniciate the process of membrane lipid peroxidation ,~and they react als0 with DNA causing modification of molecular structure of genetic material. Natural and artificial antioxidants can play a protect~ve role against free radical action in cells. In our experiments "in vitro" w i t h h u m a n pheripheral lymphocytes from healthy volunteers was measured unschedulded DNA synthesis (UDS) in the relation to degree Of lipid peroxidation (LPO) induced by Catalytic system FeII/ascorbate. The degree of induced LPO was measured spectrophotometrically by thiobarbituric acid assay. UDS was determined by scintillometric measurement cf incarporated H3-thymidina into DNAo Protective action of fatsoluble vitamin E (alphs-tocopherol) and some nootropics drugs on both LPO and UDS was studied~

Psychiatric Research Institute, Ustavnl 91, 181 o3 Prague 8, Czechoslovakia

387

34.05.04

34.05.05

EXCITATORY EFFECTS OF CYCLIC CCK ANALOGS $ELECTIVE FOR

EFFECT OF AGE ON BINDING SITES FOR CALCITONIN GENE-RELATED PEPTIDE (CGRP) IN THE RAT CENTRAL NERVOUS SYSTEM A. Pecile, F. Guidobono, C. N e t t i , V. S i b i l i a and I. Villa S p e c i f i c binding s i t e s f o r CGRP have been documented in the CNS and t h e i r d i s t r i b u t i o n in a v a r i e t y of brain and spinal cord areas is suggestive of a r o l e of the peptide in CNS control mechanisms. Considering t h a t possible age-related changes of CGRP binding might help in understanding the p h y s i o l o g i c a l s i g n i ficance of the peptide in CNS f u n c t i o n ( s ) we compared the binding s i t e d i s t r i b u t i o n s of CGRP in the CNS of aged rats (24 months old) with those of young rats (3 months old) in brain and spinal cord preparations using an in v i t r o autoradiographic technique. Coronal sections, 16 ~m, from unfixed and frozen r a t CNS were mount~ on gelatine-coated s l i d e s , incubated with 3xlO --M l125-Tyr r a t CGRP in 50 mM Tris-HCl containing 5 mM MgCLp; 2 mM EGTA, 0.05% b a c i t r a c i n and I% BSA. incubation was at room temperature f o r 2 h. N~n s p e c i f i c binding was assessed in the presence of IO--M r a t CGRP. The r e s u l t s showed t h a t in old animals while CGRP binding s i t e s disappear in the c o l l i c u l u s s u p e r i o r and are markedly reduced in the dorsal horns of the spinal cord, they s t r i k i n g l y increase in the cerebellum. The increased binding s i t e s in the cerebellum with age is suggestive of an important r o l e of CGRP in the a c t i v i t i e s c o n t r o l l e d by t h i s brain area and of an adaptive process p o s s i b l y due to a d e c l i n e of the peptide synthesis with age. Dept. of Pharmacology, Chemotherapy and Medical Toxicology, U n i v e r s i t y of Milan, 32 Via V a n v i t e l l i , 20129 Milan, I t a l y

CENTRAL (B-TYPE) RECEPTORS IN RAT BRAIN SLICES

G.A. B6hme, J . M . Stutzmann, J.C. Blanchard, B. Charpeniier (*), B.P. Roques (*) and P.M. Laduron . Cyclization o f t h e N - t e r m i n a l p a r t o f CCKB led t o BC 197 [ S o c - D . A ~ p - T y r ( S O 3 H ) - N l e - D . L ~ s - T r p - N l e - A s p - P h e - N H 2] a n d BC 254 [Boc-D. G f u - T y r ( S O 3 H ) - N l e - D . L } s - T r p - N l e - A s p - P h e - N H p ] , two synthetic analogs showing both high affinity (Ki = 5 1 and 0 . 4 9 nM, r e s p e c t i v e l y ) and h i g h s e l e c t i v i t y (Ki p a n c r e a s / Ki b r a i n = 179 and 1979, respectively) for central (B-type) CQ< r e c e p t o r s i n g u i n e a p i g . B e c a u s e o f their v e r y lo~ a c t i v i t y in p e r i p h e r a l t e s t s ( p a n c r e a t i c a m y l a s e r e l e a s e a n d ileum contraction), we d e c i d e d t o e v a l u a t e t h e p o t e n c i e s o f BC 197 and BC 254 f o r e n h a n c i n g t h e s p o n t a n e o u s a c t i v i t y o f n e u r o n s in r a t h i p p o c a m p a l s l i c e s , an e l e c t r o p h y s i o l o g i c a l response known to involve central CCK-B r e c e p t o r s . Extracellular recordings of spontaneous action potential discharge frequency were obtained i n CA1 a r e a o f r a t hippocampal slices maintained completely submerged in oxygenated artificial cerebrospinal f l u i d . Neurons s h o ~ i n g reproducible excitations without tachyphylaxis Iollowing repeated bath-applications o f CCKB Were tested with BC 254 a n d / o r BC 197. A p p l i c a t i o n s o f b o t h p e p t i d e s r e s u l t e d in r e v e r s i b l e and c o n c e n t r a t i o n - d e p e n d e n t excitation. When t h e maximal f i r i n g rate increase of individual neurons was e x p r e s s e d as p e r c e n t o f t h e r e s p o n s e o f t h e same n e u r o n s t o 0 . 5 vM s u l f a t e d CCK8 ( t a k e n a s IO~A), b a t h - a p p l i c a t i o n s o f 0 . 5 , 2 and 8 ~M BC 254 p r o d u c e d 81• (n=4), 62~7% (n=5) and 92• (n=4) e x c i t a t i o n , respectively. Similarly, after 2, 5 and 10 ~M BC 197 t h e mean e x c i t a t o r y r e s p o n s e s w e r e 23• (n=4), 49• (n=6) and 71• (n=5), respectively. Potency comparisons with the excitation a c h i e v e d by t h e n a t i v e p e p t i d e show t h a t BC 254 was 16 t i m e s l e s s p o t e n t t h a n Cs 8. BC 197 a p p e a r e d s l i g h t l y l e s s p o t e n t t h a n BC 254. T h e s e r e s u l t s a r e c o n s i s t e n t w i t h an e x c i t a t o r y activity oI BC 197 and BC 254 on f u n c t i o n a l p r o c e s s e s in t h e r a t b r a i n . Rhfne-Poulenc Sant6, Centre de Recherches de [/]try, 94400 Vit~v-Sur Seine, FRANCEand (~) D~partement de chimZe o r g a nJque, INSERM U 266 CNRS UA 498, Facult6 de PharmacJe, 755YPGParJs, FRANCE.

34.05.07

34.05.06 CAERULEIN SUPPRESSES ENDOGENOUS DOP~\IINE RELEASE ViA VAGAL AFFERENT SYSTEM,STUDIED BY IN VIVO INTRACEREBRAL DIALYSIS T,Hamamura,K.Akimoto,Y.kazahaya,M.Sato, and S.Ozsuki Caerulrein(CLN),a cholecystokinin-related peptide,has been reported to posess neuroleptic like activity. In vivo intracerebral dialysis technique was used to study the effect of CLN (2,20,2O0ug/kg) on release of endogenous dopamine(DA) from rat striatum. After administration of CLN(200ug/kg),DA decreased between 0.5 and 5h. Maximal reduction of DA(by 29%) was observed at 2-2.5h. CLN(20~g/kg) also decresed DA by 21% at 1.5-2h. CLN(2~g/kg) did not change DA level. Subdiaphragmatic vagotomy reversed this inhibitory effect of CLN. These data suggest that peripherally administered CLN suppresses ~ndo~no~s CA r~lease via vagal afferent system.

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EFFECTS OF THE NEUROPEPTIDE ACTH 4-10 ON NRITING PRESSURE AND SPEED IN HEALTY SUBJECTS * K.C.Steinwachs & H.L. Fehn Nemerods i n v e s t i g a t i o n s has documented the e f f e c t s of ACTH and ACTH fragments on animals and human behavior. These e f f e c t s have been discussed in r e l a t i o n t o d i f f e rent psychological constructs such as a n x i e t y , motivat i o n , a t t e n t i o n , memory and f a c i l i t a t i o n of s i g n a l det e c t i o n . ACTH 4-1D-analogs increased muscle AP amplitude and decrease f a t i g u e in i n t a c t and hypophysectomized r a t s . I t appeard promising t o i n v e s t i g a t e peptide e f f e c t s on psychomotor behavior and koordination in human. As a s e n s i t i v e method f o r the r e g i s t r a t i o n of subtle motor v a r i a t i o n the recording of w r i t i n g pressure curves were used. In a rondomized cross-over double-blind study with 10 healthy male subjects in each group the e f f e c t s of 200 ug ACTH 4-10 ( s n i f f ) on w r i t i n g pressure curve parameters such as v ~ i t i n g time, f i n a l maximum pressur and pressur amplitude were i n vestigated. Paraoeters were recorded from a pressure s e n s i t i v e pad during standardized testword v ~ i t i n g - momon - before administration 1,2 and 3 hours a f t e r a d m i n i s t r a t i o n . Compared t o the placebo ACTH 4-10 increased the spontaneous action speed of automated ~ i t i n g (ANOVAP p ( 0 , 1 ) and increased the f i n a l v ~ i t i n g pressure (ANOVA P s 0,01) The v ~ i t i n g pressure patterns were o p e r a t i o n a l l y i n t e r preted as an i n t e g r a l out put of c e n t r a l nervous motor a c t i v i t y , which were t r a n s m i t t e d by musculartension and muscular c o n t r a c t i o n s . The r e s u l t s suggested an peptid e f f e c t on w r i t i n g performance in healthy subjects. Labor f o r Neuroendokrinologie, U n i v e r s i t y of Ulm FRG, *Bezirkskrankenhaus Erlangen, Am Europakanal 71, 8520 Erlangen FRG.

34.05.08

34.05.09

RESPONSE OF GH TO GRH AND TRH " I N V I T R O " IN GHS E C R E T I N G A D E N O M A S : E V I D E N C E FOR TWO D I F F E R E N T T U M O U R CELL TYPES.

TEMPORAL ASSOCIATION BETWEEN THE SECRETION OF LUTEINIZING HORMONE AND DSIP IN PLASMA FROM NORMAL HUMAN MJ~LES R. Knabe, A. Ernst, M. Hugentobler, P. Dick, p. schulz Delta sleep-inducing peptide (DSIP) shares the same topographical distribution as luteinizing hormone releasing hormone (LH RH) in rabbit and human brain (Y. Charnay, personal communication). It was recently shownthat DSIP could release luteinizing hormone (LH) from rat hypothalamus. Moreover , in rats the secretion of DSIP shows a temporal association with that of corticosterone. These and other results suggest that DSIP might have a role in the function of biological clocks. We therefore studied whether the secretion pulses of LH and DSIP were synchronous in human plasma. Four young male volunteers participated. Plasma was sampled every 30 minutes during 24 hours of either complete bed rest or normal daily activity. Both hormones were measured with immunoassays. Depending on the subject, there were 0 to 6 major pulses of DSIP and 4 to 8 m a j o r p u l s e s of LH secretion during 24 hours. Overall, LB showed a higher pulsatile amplitude than DSIP in all subjects. Less than one third of LH pulses were accompagnied by a DSIP pulse. However, half of the DSIP pulses were synchronous to a LH pulse. We therefore obtained some evidence of a temporal association in the secretion of these two peptides in human plasma. Service de la recherche biologique et de psychopharmacologie clinique, 8 ch. Petit-Bel-Air, CH - 1225 Ch~ne-Bourg, Switzerland and Medizinisches Centrum Mariastein, CH - 4115 Mariastein, Switzerland

B.Oiivan.~O.A.Cabranes.~I.Torres.~P.Mata.~O.~Uria. M.Fern~ndez. TA.Duran.~E.Bordiu.,A.L.Charro. The d i f f e r e n t p a t t e r n s of "in v i v a " r e s p o n se to d i a g n o s t i c t e s t s o b s e r v e d in G H - s e c r e t i n g t u m o u r s t o g e t h e r w i t h the v a r i a b i l i t y in c l i n i c a i r e s p o n s e of a c r o m e g a l i c p a t i e n t s t r e a t e d w i t h di verse pharmacological agents, both suggest hereto g e n e i t y in the p a t h o g e n e s i s of this d i s e a s e . The c u r r e n t s t u d y ~as u n d e r t a k e n to a s s e s -and c h a r a c t e r i z e GH r e s p o n s e to s y n t h e t i c GRH and TRH in an " in v i t r o " s u p e r f u s i 6 n s y s t e m in 7 GH secreting pituitary adenomas obtained following t r a n s s p h e n o i d a i or t r a n s f r o n t a I s u r g e r y . 3 of t h ~ se t u m o u r s also p r o d u c e d PRL, as d e m o s t r a t e d by inmmunohistochemicsI techniques. The a d m i n i s t r a t i o n of 200 n g / m i of GRH y i e l ded a s i g n i f i c a n t i n c r e a s e in the GH c o n t e n t of the s u p e r f u s i 6 n l i q u i d in all four (lO0~) of t h e _ pure G H - p r o d u e i n g s d e n o m a s (PA) and in 1 of 3 -(33,3~), of the m i x e d G H - P R L - p r o d u c i n g t u m o u r s (MA I00 ng/ml of TRH r e s u l t e d in s s i g n i f i c a n t e l e v a tion of the GH c o n c e n t r a t i o n in the s u p e r f u s i 6 n liquid in 2 out of 3 (66,6%) of the PA, and in 1/3 (33,3~) of the MA. We c o n c l u d e t h a t in the t u m o u r s s t u d i e d , PA cells were more r e s p o n s i v e to GRH than MA cells. F u r t h e r m o r e , PA c e l l s t e n d e d to h a v e a s t r o n g e r r e s p o n s e to TRH than MA cells. Our r e s u l t s s ~ p o r t the p o s s i b i l i t y that PA c e l l s and MA c e l l s c h a r a c t e r i z e 2 s e p a r a t e t y p e s of a c r s m e g a l y , w i t h d i f f K rent m e c h a n i s m s of G H - s e c r e t i o n . Hospital

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de San C a r l o s .

28040-MADRID SPAIN

34.05.10

34.05.11

BIOLOGICAL Ah~ PSYCHOLOGICAL EFFECTS OF RESTRICTED ENVIRONMENTAL STIMULATIONS THERAPY (REST) IN NORMAL HUMANS Ch.H. Kaspar, P. Schulz, J. Widmer, M. Hugentobler, P. Dick, R. Tissot REST consists in placing an individual during 60 minutes in a special environment with a very low level of external stimulation. The individual floats in an insulated chamber containing highly salted water at 35 C. This has been reported to produce deep relaxation with a sensation of wellbeing and some metabolic changes. We measured the subjective response to REST and the concentration in plasma of thyroid stimulating hormone (TSH), lutefnizing hormone (LH), prolactin (PRL), cortisol and homovanilic acid (HVA). Urinary matabolites of monoamines were also studied. Subjective responses were evaluated with analogue visual scales. Biochemical studies were done using immunoassays or BPLC. The variables were studied in five normal males once before, during and after 60 minutes of REST and once during a control situation consisting of relaxing on a bed. Before participating to the study, the subjects got used to the practice of REST on three Occasions scheduled during two weeks. Both the REST and control sessions led to a decrease in the values Of all biochemical variables, with the exception of LH. Compared to the control session, during REST, a deeper relaxation with some euphoria was observed in all subjects. This was accompagnied by a trend towards a greater decrease in TSH and cortisol concentrations in plasma and a greater decrease in vanil-mandelic acid in urine. Different relaxation techniques are known to induce biological changes opposite to those observed during stress. Our study confirms other authors' results. Service de la recherche biologique et de psychopharmacologie clinique, 8 ch. Petit-Bel-Air, CH - 1225 Ch~ne-Bourg, Switzerland

CHOLECYSTOKININ-LIKE-I~MUNOREACTIVITIES IN SCHIZOPHRENIC POST-MORTEM BRAINS H__~.S h i b u y a * f F__~.F u k a m a u c h i * r R__t. T a k a h a s h i * r H__~. M i t s u s h i o * * r K__~.Noda** r M__t.T a k a s h i m a * * r M. T o r u * * Cholecystokinin-like-immunoreactivities ( C C K - L - I ) i n t h e p o s t - m o r t e m b r a i n s f r o m 13 schizophrenics a n d 10 c o n t r o l s w e r e a s s a y ed. Schizophrenics were classified by DSMIII as d i s o r g a n i z e d (7), undifferentiated (4), p a r a n o i d (I) a n d c a t a t o n i c (I). The b r a i n t i s s u e s w e r e h o m o g e n i z e d in 3 v o l s of 0.32 M s u c r o s e a n d b o i l e d f o r 20 m i n . CCK was extracted with distilled water and followed with 0.5 N acetic acid. CCK-L-I in water extract consisted of 74% of CCK-8 and 21% of C C K - 3 3 , h o w e v e r , 6 7 % a n d 20% o f C C K L - I in a c e t i c a c i d e x t r a c t w e r e identified as CCK-33 and CCK-8 , respectively; CCK-L-I of schizophrenic group showed in general the t e n d e n c y of h i g h in w a t e r e x t r a c t and low in acid extract. In schizophrenic brains, CCK-L-I in acid extracts were sign i f i c a n t l y l o w in t h e s u b i c u l u m , the corticomedial n u c l e i of t h e a m y g d a l a a n d the posterior p o r t i o n of t h e p y r i f o r m cortex. B e s i d e s , d e c r e a s e d C C K - L - I in a c i d e x t r a c t s were observed in the lateral occipitotemporal cortex and the premotor area of the frontal cortex from the off- and ondrug schizophrenics. Our results suggest the alteration of C C K s y n t h e s i s in these parts of schizophrenic brain. *Dept. of Neuropsychiatry, Tokyo Medical and Dental Univ. I-5-45, Yushima, Bunkyoku, T o k y o 113, **Dept. of Psychobiology, National Center for Mental and Nervous D i s o r d e r s , K o d a i r a - s h i , T o k y o 187, J A P A N

389

34.05.12

34.05.13

NEUROTENSIN RECEPTOR SHARES THE COMMON MECHANLSMS FOR THE STIMULATION OF CYCUC GMP FORMATION AND OF INOSITOL PHOSPHATEs RELEASE WITH LOW-AFFINITY MUSCARINqC RECEPTOR (M1) IN NEUROBLASTOMA CLONE NIE-115 Kiyoke S. Kanha, Shigenobu Kanba, Elliott Richelson and Shuichi Shibata Murine neuroblastoma clone NIE-I15 cells possess various receptors including two-subclasses of muscarinic receptors and neurotensin receptor. Ix these cells, neurotensin-mediated biochemical responses are'very similar to lowaff'mity (putative M 1)muscarinic receptor-mediated responses: both neurotensin and carbachel, muscarinic agonist, stimulate the formation of intracellular cyclic GMP and the inositol phosphates. We have reported that an active tumor promotor, 4/9-phorbol 12-myristate 13-acetate (PMA), selectively inh~its low-affinity muscarinic receptor-mediated inositol phosphates release and cyclic GMP formation in NIE-115. Some inhibitors of metabolic pathway for arachidonic acid also inhibit carbachol-st~nulated cyclic GMP formation in these cells. In this study, we exanuned effect of PM#. and inhibitors of metabolic pathway for arachidonic acid on neurotensin receptor-mediated second messenger activation. When neuroblastoma ceils were stimulated by 10nM neurotensin after preincubation with PMA for 45 rain, stimulation of cyclic [aH] GMP formation was irdl~ited in the dose-dependent manner. The release of [3Hi inositol phosphates by neurotensin was also inhibited by PMA in the identical manner to that for cyclic G~tP formation. ICso for PMA for the inhibition of cyclic [SH] GMP formation and the release of [3Hi inosital phosphates stimulated by neurotensin was 35+-6nM and 35-+8rLM,respectively. These lCse values are in reasonable agreement with those for muscarimc receptors stimulated by carbachol. IJpoxygenase inhibitors and phopfi'o!ipase A2 inhJbitors inhibited neurotenshi-stimulated cyclic [SH] GMP formation with similar ICso values to those for carbachol. The effect of extracellu!ar Ca2§ and temperature were also examined. All these pharmacological aspects of nedrotensin receptor-mediated second messenger systems are similar to tose for inw-affinity muscarinic receptor. We concluded that neurotensin receptor shares" the common mechanism for the stimulation of cyclic GMP forrhation and of inositat phosphates release with low.affinity muscaxinic receptor. Dept. of Neuropsychiatry, Tokyo Women's Medical College, 8-1. Kawada-cho,

BIDIRECTIONAL TRANSFER PHEN0~W~ON BETWEEN CHEMICAL KINDLING WITH METHIONINE ENKEPHALIN ~ND CARBACHOL KINDLING OR ELECTRICAL KINDLING. H. Takeshita, T. Tanaka, T. Sakanoto, J. Takasu, R. Kawahara and H. Hazama Bidirectional transfer phenomenon between chemical kindling with methionine enkephalin ( ~ ) and carhachol or electrical kindling was investigated to elucidate the neurochemical involvement o f M E on kindling phenomenon. Male Wistar rats were stereotaxically implanted with guide cannulae for ME or carbachol injection and bipollar electrodes i n t o the right amygdala. ME (i0 L~) or carbachol (2.5 nmo!e or 20 nmole) dissolved in 1 ~LI of sterile saline was repeatedly injected into the right amygdala every 48 hours through the guide cannulae. Electrical stimulation of after discharge threshold was supplied to the right amygdala once a day. Bidirectional transfer phenomefion was investigated between chemical kindling with ME and carbachol or electrical kindling. As results, transfer was found in the ME kindled rats from ~ kindling te electrical kind!ing as well as to earbacho! kindling. In contrast the transfer phenomenon was not found from electrical kindling or carbachol kindling to ME kindling. These results suggest that the ~-enkepalinergic system may play an impgrtant role in the kindling phenomenon, but is not involved in the essential nervous system for the completion of the rat amygdaloid kindling. Department of Neuropsychiatry, Tott0ri University School of Medicine, 56 Nishimachi, Yonage 683, Japan

Shtnjuku-ku,Tokyo 162, JAPAN

34.05.14

34.05.15

EXCITATORY ACTIONS OF X~-qqOPSIN, NEUROTENSIN AND RELATED PEPTIDES ON DOPAMINERGIC NEURONES IN VITRO M.F. Pozza, E. Kueng, S. Bischoff and H.R. Olpe The actions of the octapeptide xenopsin (a natural analogue of neurotensin), neurotensin (a tridecapeptide) and structurally related peptides were tested on the activity of single dopaminergic neurones of the substantia nigra slice preparation. Extracellular recordings were made ~n the pars compacta region of the rat substantia nigra. ~ne spontaneous firing rate of identified dopaminergic cells (Grace and Bunney, 1983} was displayed aS the composite number of spikes within 30 s periods (Pinn0ck, 1985). Xenopsin (0.I 0-M) strongly excited dopaminergic neurons by 58 % (n = 6). Ala increased firing rate was also found with neurotensin (NT), NT (8-13) and D-Trp (II)-NT (all 0.i 0-M), whereas NT (1-8) had no effect even at i0 ktM. Dopamine (i00 gM) reduced the firing rate by 55 % (n=10}. Xenopsin showed similar efficacy as D-Trp (II)-NT but NT and NT (8-13) were slightly less efficacious. Injection of depolarizing current through the recording electrode (intracellular experiments)~ elicited repetitive firing of the dopaminergic neurones. The frequency was decreased by dopamine (I00 ~M) and increased by xenopsin and NT ( 0 . i ~LM). These data confirm the original findings of Pinnock that NT and NT (8-13)exert excitatory effects on nigral dopaminergic cells. In addition they provide evidence t h a t xenopsin can mimic functional properties of (NT). Surprisingly D-Trp (ll)-h~ which possesses low affinity for NT receptors (Quirion e t a ! . , 1982) also strongly excites dopaminergic neurones. The strong effect of D-Trp(II)-NT could be related to the presence of a D-Trp in the key position ii which may protect this NT analogue from degradation. Grace, A.A. and Bunney, B.S. (19~3) Neuroscience 10/2, 301-315 Pinnock, R.D. (1985) Brain Res. 338, 151-154 Quirion e t a l . (1982) Peptides 3, 757-763 Biology Research Laboratories, Pharmaceutical Division, Ciba-Geigy Ltd., CH-4002 BASLE, Switzerland

E F F E C T S OF B O M B E S I N A N D R E L A T E D P E P T I D E S ON S C R A T C H I N G B E H A V I O R IN R A T S Akira Masui and Nobumasa Kato qBombesin(BBS), a t e t r a d e c a p e p t i d e originally isol a t e d f r o m a m p h i b i a n skin, h a s p o t e n t b i o l o g i c a l e f f e c t s s u c h as h y p o t h e r m i a , gastrointestinal hormone secretion and anorexia. Recently, the excessive grooming after intracerebroventricular (icy) a d m i n i s t r a t i o n o f B B S is o f t e n d e s c r i b e d . B B S - i n d u c e d g r o o m i n g is c h a r a c t e r i z e d as t h e h i n d limb scratching compared with the bodily grooming by other peptides(substance P, C R F ) . However, the c o m p a r i s o n a m o n g B B S - r e l a t e d peptides, which s h a r e the c o m m o n c a r b o x y t e r m i n u s , o n t h e s c r a t c h ing behavior has poorly been mentioned. In t h e p r e s e n t study, 10 B B S - r e l a t e d peptides(BBS, neurom e d i n B, g a s t r i n r e l e a s i n g p e p t i d e ( G R P ) [I-27], GRP[14-27], GRP[18-27], Ac-GRP[20-27], Leu-phyll~litorin, Phe-phyllolitorin, and des-Trp analogs of phyllolitorins). m a l e W i s t a r rats, w e i g h i n g 2 5 0 - 3 0 0 g , w e r e u s e d . 'Cannulation was performed stereotaxically in t h e third ventricle under light anesthesia. The a n i m a l w a s icy i n ~ e c t e d w i t h e a c h p e p t i d e a t 'least 5 d a y s a f t e r t h e s u r g e r y in d o s e g r a d i n g 'from 0.i ug, 1.0 u g to i0 u g / i0 ul / m i n . The a n i m a l w a s p l a c e d in a p l a s t i c c a g e a n d s c r a t c h ing b e h a v i o r w a s d e t e r m i n e d cumulatively in sec / m i n for 3 0 - 1 8 0 min. T h e r e s u l t s w e r e as f o l l o w s ; I)BBS, n e u r o m e d i n B, G R P [ I - 2 7 ] , [14-27], [18-27] w e r e all p o t e n t in e l i c i t i n g t h e b e h a v i o r , b u t the e f f e c t of B B S w a s the m o s t p r o l o n g e d . 2)The e f f e c t s of p h y l l o l i t o r i n s were significantly less t h a n BBS and d e s - T r p a n a l o g s w e r e t o t a l l y inactive. The study suggests that thebiological a c t i v i t y of B B S - r e l a t e d p e p t i d e s r e s i d e s in its C-terminal heptapeptides, and that Trp-residue a p e a r s to b e e s s e n t i a l . Dept. of P s y c h i a t r y , S h i g a U n i v . o f Med. Sci. Otsu 520-21, JAPAN

390

34.05.16

34.05.17

MODULATION OF DOPAMINE RECEPTORS BY YHTROTROPIN-RELEASING HORMONE IN THE ~4T BRAIN K. S. Funatsu and K. Inauaga Wide distribution of thyrotropin-releasing hormone (TRH) in the mammalian brain is known. Is is also known that TRH potentiates the central dopaminergic system. There are evidences that TRH stimulates the release of dopamine (DA) from the nerve-ending in the rat nucleus accumbens. However it has not yet been known whether TRH modulates DA receptors. We therefore investigmted whether there is a receptor-receptor interaction between TRH and DA using the radioligand binding technique. Rat striatum and the limbic forebrain that includes the nucleus aecumbens and the septum were used. These regions are known to contain abundant DAergic nerve-endings and DA receptors. Membrane preparations of these regions were preincubated with 100nM TRH. After the ~emoval of TRH the ~embrane preparation was incubated for H-apomorphine or ~H-spiperone binding. TRH caused a significant decrease of H-apomo~phine binding sites (by 30%) in both regions whereas ~H-spiperone binding was not af#ected. The binding of DA agonists and antagonists to T~H r~ceptors was also tested. DA and apomorphine displaced H-TRH binding partially, suggesting the presence of TRH receptor subpopulation that has a high affinity to DA agonists. DA receptor antagonists (neuroleptics) had virtually no affinity to TRH receptors. These findings suggest the possible interaction between TRH receptors and a certain type of DA receptors having a high affinity to DA agonists, like DA autoreeeptors. Although the binding study cannot identify the function of receptors, it is possible to speculate that this type of DA receptors are DA autoreceptors that are present On the nerve-ending and that TRH potentiates the release of DA through the inhibition of DA autoreceptors. (Ref.) Funatsu and Inanaga, Peptides 8, 319-325, 1987. Department of Psychiatry. Kurume University Hospital, Asahi-machi 67, Kurume 830, Japan.

PRESYNAPTIC OPIOID RECEPTORS IN T H E S A P H E N O U S ARTERY OF THE RABBIT A n i k o K o v a c s , T. F r i e d m a n n , Z. F u r s t Opioid peptide receptors Were detected first by K n o l l (1). T h e s ~ p a t h e t i c a x o n s of t h e d i f f e r e n t a r t e r i e s of t h e r a b b i t p o s s e s s b o t h d e l t a a n d k a p p a r e c e p t o r s (2,3). O u r e x p e r i m e n t s on isolated, p e r f u s e d , e l e c t r i c a l l y stimulated saphenous a r t e r i e s of t h e r a b b i t show: - M u r e c e p t o r a g o n i s t s (DAGO, m o r p h i n e ) are ineffective; -Delta receptor agonist (DADLE) has strong agonist potency (ID50:7.93 nM); -Kappa receptor agonists (ethylketocyclazocine /ECK/,U-50488H, N-cyclopropyl-methyl-norazidodihydro-isomporphine/CAM/, bremazocine) are e f f e c t i v e h a v i n g t h e f o l l o w i n g r a n k o r d e r of agonist activity: ECK>U-50488H>C~{>bremazocine; -This tissue shows very rapid habituation to t h e e f f e c t of k a p p a a g o n i s t s . O u r ' d a t a i n d i c a t e t h e p r e s e n c e of d e l t a a n d k a p p a r e c e p t o r s in t h e s a p h e n o u s a r t e r y . A s C ~ M s h o w e d agonist activity this preparation seems to have o p i o i d "A" t y p e (4). T h e p r e s e n c e of "A" r e c e p t o r type makes this artery different from the central ear a r t e r y c h a r a c t e r i z e d b y "B" r e c e p t o r t y p e (5~ I. K n o l l , J . 1976, Eur. J . P h a r m . 39, 403. 2. I l l e s , P . et al., 1985, J. P h a r m a c o l . Exp.

34.05.18

34.05.19

EFFECTS OF NALTREXONEON INFANTILE AUTISM M. LESOYEI~*. M P BOUVARD**. M DUGAS** It h~ r.~_nsu&~ted that abnormaht~ of the endogeneousopioid s,/stem may underhe someof the devianced~spi~veoby auhstic children. Indirect support for

Nerve growth factor ootentlates the h o r m o n e stimulated intracellular accumulatlon of inosltolphosDhates and Ca2+ I n rat pheochromocytoma cells. Comparison w l t h the e f f e c t s of e p i d e r m a l a r o w t h factor.

an er,3orphin theory of autism cem~ from the foilowing two observations : I ) Ben~ioural featuresof autism ~?e similar to features in opiateaddictionand anai.ogoustc symptoms observed Jr,op,atetreatedanimals ( PANKSEPP 1979); 2) Peri~,nera]measures of opiaidlevelsin autisticchildrensuggestthe presence of abnormalitiesi GILLBE~G 1980). This hypothesiscan be further explc'~ from a therapeuticalperspective:Opiateantagonisttherapy with a long l~sting c-allyeff~tive.drug,NALTPEXONE(Du Pont De Nemours Pharmaceutical). 'Naltrex~e has been specificellyt~.edon self-iniur]ousbelqavioursof ment~,ly retardedsubjacts(GERM/~4 ~987) and on one autisticboy( BERNSTEIN 1987). in an open and ecute-Oose range trial,we tested the response of naitr~xone on two autisticgirls, 12 &nrl I0 years old.Both of them met DSM-Ill cmtema for autism.They displayed ~mous self-injuriousbehaviours (BIB) sincethe age of 7, pain insensitwity,and reducedcrying. During the present exper,,ment,neurolepticswere-notdiscontinued.After 2 days placebo,each childreceived a singledoseof naltrexonewhich was increa~%~devery two days ( i m~!Kg/dav, 1,B mglkg/day ; 2 mg/KglG~iy ). Behavlour w ~ assessedby ratine me B$E ("Behavioral Summ&-L-~. Evaluation" )(LELORD, in press) one hour d~er oral administration of placebo, of naltrexone, three days and six days after L~4"nning of therapy. Sessionsw e e videotapedfor assessment. Naltrexore had a strikingly similar profile af action on the two children : a remd and marked reduction af hyperactivity and an improvment ]n social bandY,our(eye contact, smiles and inte?actions). The reduction of BIB was anly cieer at the beginning of treatm~t ( ! and 1.5 mg/kg/doy), but this effect dic no~ lest at 2 mg/kg/day. No Sideeffects were observed. As a whole, naltre.
Ther. 232, 526. 3. Von Kugelgen etal., 1985, Eur. J.Pharm. 118, 97. 4, Knoll,J. 1977, Pol. J.Pharmacol.Pharm. 29, 165. 5. Kovaes,A. et al., 1985, Varna, Symp. of Physiol. Pharmacoi. of Smooth Muscle p 70. Semmelweis University of Medicine, Pharmacology, Budapest, Nagyvarad P.O.B. 370, 1445-Hungary.

D i e t r i c h van Roll H e u m a n n

Calker #

*Psychiatric Munich NuBbaumstr.

*.

Hospital 7

D-8000

Kyoya

of

the

M~nchen

Dept. ter 4.

Takahata

$ and

University 2

of

of

F.R.G.

# Max P l a n c k I n s t i t u t of P s y c h i a t r y Am K l o p f e r s p i t z I, D - 8 0 3 3 M a r t i n s r i e d

F.R.G.

The e f f e c t s of n e r v e g r o w t h f a c t o r (NGF) a n d e p i d e r m a l g r o w t h f a c t o r (EGF) on the intracellular aocumulation of i n o s i t o l o h o s p h a t e s and C a 2 + - i o n s were s t u d i e d in rat P C - ~ 2 pheochromocytoma cells. B o t h NGF and EGF p o t e n t i a t e in t h e s e c e l l s the i n c r e a s e in t h e accumulation of i n o s i t o l p h o s p h a t e s and C a 2 + ions that is e l i c i t e d by b r a d y k i n i n and carbachol. The e f f e c t of NGF. but not that os EGF. is a b o l i s h e d , w h e n the c e l l s are preincubated with 5'-deoxy-5'-methylthiosdenosin. an i n h i b i t o r of S - a d e n o s y l h o m o c y s t e i n hydrolase. T h e s e r e s u l t s s u g g e s t that a n increased r e s p o n s e to h o r m o n e s , w h i c h act via phosphoinositides-derived second ~essengers m a y be i m p o r t a n t in the m e c h a n i s m of a c t i o n of NGF

and

EGF.

391

34.05.20

34.05.21

ELEVATED CSF LEVELS OF DYNORPHIN A [1-8] IN TOURETTE'S SYNDROME J.F. Leckman. M.A. Riddle. W.H. Berrettini. G.M. Anderson, M Hardin. P. C~u~Doell. G. Bissette. C.B. Nemeroff. W.K. Goodman. and D J Cohen A recent neuropathological study has reported decreased levels of dynorphin A immunoreaotivity in striatal fibers projecting to the globus pallidus in the brain of a patient with severe Gilles de la Tourette's syndrome (TS). This observation taken with the neuroanatomic distribution of dynorphin and its broad range of motor and behavioral effects has led to speculation concerning its role in the pathobiolog~ of TS. We report on the presence of elevated levels of dynorphin A [1-8] in the CSF of 7 adult, dzt~g-free TS patients (Mean + SD: TS: 294 + 57 fmol/ml vs. Ctrls: 223 +_ 64 fmol/ml, p =.036). Three of four drug-naive patients had distinctly elevated levels of 372, 324, and 322 fmol/ml. The increase in CSF dynorphin was found to be associated with the severity of the obsessive con~olusive sy~toms but not the level of tic severity in these patients. Although CSF su~dies lack the precision necessary to address questions of selective involvement of neuronal systems in specific CNS locations, these findings suggest that endogenous opioids are involved in the pathobiolog~ of TS and related disorders. Child Study Center and the Departments of Psychiatry and Pediatrics Yale University School of Medicine, New Haven, C'f 06510

N E U R O P H Y S I O L O G I C A L E F F E C T S OF S Y N T H E T I C COMPETITIVE A N T A G O N I S T OF C O R T I C O T R O P I N R E L E A S I N G FACTOR. A.Tartara,F.Savoldi,E.Marchioni,M.Maurelli C o r t i c o t r o p i n R e l e a s i n g Factor (CRF), a 41 residue peptide, has b e e n d o c u m e n t e d to induce E l e c t r o e n c e p h a l o g r a p h i c (EEG), b e h a v i o r a l and autonomic e f f e c t s w h e n i n t r a c e r e b r o v e n t r i c u l a r l y (i.c.v.) a d m i n i s t e r e d in v a r i o u s animal species including rabbit. A CRF c o m p e t i t i v e a n t a g o n i s t s y n t h e t i z e d by Rivier et al has been found to be active in vivo on ACTH s e c r e t i o n in the rat (Science,224,889,

1984). In the p r e s e n t study we have tested in 12 N e w Zealand rabbits the e f f e c t s of a CRF a n t a g o n i s t (alpha-Helical CRF 19,41 - S i g m a ) , i n j e c t e d into the m e s e n c e p h a l i c v e n t r i c l e on E E G , b e h a v i o r and autonomic parameters. The cortical EEG a c t i v i t y has been q u a n t i f i e d on line by m e a n s o f Fast Fourier Transform; the b e h a v i o r has b e e n evaluated by c o u n t i n g E M G r a p h i c a l l y r e c o r d e d movements and heart rate, r e s p i r a t o r y rate and colonic t e m p e r a t u r e have been c o n t i n u o u s l y recorded on a polygraph. CRF antagonist induced a s i g n i f i c a n t increase in the total power of the cortex; the EEG p a t t e r n was opposite to the cortical changes we o b s e r v e d in the same species after CRF a d m i n i s t r a t i o n . The autonomic p a r a m e t e r s were not s i g n i f i c a n t l y modified. Neurological Institute, U n i v e r s i t y of Pavia, 27100 Pavia, Italy

34.06.01

POSTER PRESENTATION 34.06

Pharmacoendocrinology

392

INFLUENCE OF GROWTH HORMONE RELEASING HORMONE (GHRH) ON T H E G R O W T H H O R M O N E (GH) S E C R E T I O N IN ENDOGENOUS DEPRESSED FEMALE PATIENTS IN C O M PARISON TO HEALTHY FEMALE SUBJECTS

A. Hinz,

G. L a a k m a n n ,

F. K r u p p

Pharmacoendocrine studies showed a significantly lower G H - s t i m u l a t i o n after desimipramine (DMI) administration in e n d o g e n o u s depressed female p a t i e n t s compared with healthy female subjects. The p i t u i t a r y GH s e c r e t i o n is c o n t r o l l e d by (GHRH) and r e l e a s e d by the h y p o t h a l a m u s . The aim of our study was to find out w h e t h e r there is a d i f f e r e n c e in the G H R H i n d u c e d GH stimulation between endogenous depressed female p a t i e n t s and h e a l t h y f e m a l e subjects. We e x a m i n e d 15 e n d o g e n o u s d e p r e s s e d f e m a l e inp a t i e n t s of normal w e i g h t (mean age 44.7 years) who had been g i v e n G H R H 100 ~g i.v. and 13 h e a l t h y female s u b j e c t s (mean age 24.5 years) GHRH 100 ~g i.v. The c o m p a r i s o n of the GH p e a k s shows a higher GH i n c r e a s e (32.5 • 7.4 ng/ml) in h e a l t h y f e m a l e s u b j e c t s t h a n in e n d o g e n o u s d e p r e s s e d p a t i e n t s (12.0 • 2.4 ng/ml). From these groups we s e l e c t e d 6 f e m a l e p a t i e n t s (mean age 26,7) and 6 age matched healthy female subjects (mean age 23.3 years) and c o m p a r e d the GH s t i m u l a t i o n . The GH s t i m u l a t i o n in the g r o u p of e n d o g e n o u s depressed female patients (n=6) is smaller (13.6 • 5.0 ng/ml) t h a n in the g r o u p of h e a l t h y female s u b j e c t s (n=6, 32.2 • 8.5 ng/ml). This study shows that GH s t i m u l a t i o n a f t e r G H R H in h e a l t h y f e m a l e s u b j e c t s (n=13) as well as in the g r o u p m a t c h e d for age (n=6) is c l e a r l y higher than in endogenous depressed female patients.

34.06.02

34.06.03

THE I~FI/JENCE OF CLZ~,~fTEROL, A BETA-ADRE~RGIC AGONIST ON DESIPRAME~E ]]';EI,~'C=~_DGP~3~fH HOP~;3NE ((~), PI~3LACTIN (PRL) AND CORTISOL (COH) STI/~IATION U. Voderholzer, T. M.~.z, A. Hinz, G. LasMnann Previous studies on pituitary hormone secretic~q in healthy subjects using desimipramine (DMI) in conbir~tion with the beta-adrenergic antagonist propranolol suggested that beta-receptors are inhibitory to [~-induced GH and PRL release t~Jt have no influence on F~]-induced A C ~ - and COR secretion (Laakmann et al., PsycF~neuroendocs ii, No. 4. 447-461, 463-474, 475-489. 19@6). To further clarify the role of noradrenergic beta-receptors we investigated ~ effect of a pretreatment with the beta-adrenoceptor agonist clenbuterol (0.04 mg p.o given 60 rain prior to i.v.-infusion of 50 ~ F2#J) on G~, PRL and COR release in comparison to I~tI alone in 12 young healthy male subjects (18-35 years). ~an AUC (x • SE~.:) of ~ secretion f o l l o w ~ D~[I (1127 :~ 226 nglml x 120 rain) was significantly inhibited by clenbuter01 pretrea~ent (465 + 93 nglml x 120 rain; p --<0.01; student t-test). Clenbuterol had no effect on PRL secretion which ~ s nearly identical after combined application of clenbuterol and DMI (30789 :~ 442 ~Ulml x 120 rain) when com~su~ed to D~tI alone (29188 :h 2761 ~/UIml x 120 rain). Similar results were observed for C0R release following D~LI ,nich was not affected by clenbuterol pretrealnent (1988:hi05 ~gllOO ml x 120 rain) in ccn~parison to E~tl aior~ (1966~i05 ~gIl00 n~ x 120 m/n). These results cor~irm that noradrenergic betareceptors play an ir~nibit0ry role with regard to (~stimulation and are not involved in C0R stimulation after E~[[ . The lack of influence of clenbuterol on [~LIinduced PRL secretion is unexpected and in opposite to the suggestion that noradrenergic beta-receptors are in~libitory to PRL release. Psychiatrische K1 ~_~k der Universi t~t t,i~chen, NuBbaumstr. 7, D-8000 Mt~chen 2

NEUROENDOCRINE

34.06.04 STIMULATION BY DMI SOLVERUM IN TWELVE HEALTHY

M. Ortner, A. Hinz, G. L a a k m a n n , W. S c h 6 n An i n v e s t i g a t i o n by L a a k m a n n et al. (1985) showed that Desipramine i.v. stimulated GH, P R L and Cortisol. D o u b t s a r o s e c o n c e r n i n g the methodology in r e g a r d to if DMI c a u s e d the s t i m u l a t i o n or if it was the r e s u l t of the i n v a s i v e i n t e r v e n t i o n b a s e d on the a c t i o n of the s o l v e n t in the substrate. Therefore we i n v e s t i g a t e d GH, PRL and c o r t i s o l s t i m u l a t i o n by DMI s o l v e n t in c o m p a r i s o n to DMI. Twelve healthy age-matched male subjects r e c e i v e d DMI 50 mg i.v. or DMI s o l v e n t 50 mg i.v. the e x a m i n a t i o n was carried out u n d e r basal m e t a b o l i c c o n d i t i o n s , b e g i n n i n g at 8.00 h • 30 min (t = 0 min) at t = 60 min the trial s u b s t a n c e s w e r e a d m i n i s t e r e d . The GH, PRL ~ c o r t i s o l p l a s m a levels w e r e d e t e r m i n e d at the b e g i n n i n g of the e x a m i n a t i o n and t h e n e v e r y 30 min up to t = 120 min. The results are d e p i c t e d in the f o l l o w i n g table: (120 min)

Solvent Mean value SD

DMI Mean value SD

OF B U S P I R O N

H. N e u h a u s e r , G. L a a k m a n n , A. K n o s s a l l a B u s p i r o n is a ,novel a n x i o l y t i c s u b s t a n c e w i t h m o d e r a t e a f f i n i t y to d o p a m i n e and 5 - H T - r e c e p tots (Am. J. Med. 80,1, 1986; J. Clin. P s y c h i atry 43, Ii, 1982). E n d o c r i n o l o g i c a l l y , a stim u l a t i o n of p r o l a c t i n and g r o w t h h o r m o n e has been described (J. Clin. Psychiatry 43, 76, 1982). We e x a m i n e d the e f f e c t of b u s p i r o n 60 mg p.o. on p l a s m a levels of p r o l a c t i n , growth hormone and cortisol in 6 h e a l t h y m a l e s u b j e c t s a g e d 18-35 years. We a l s o e x a m i n e d the e f f e c t of the s e r o t o n i n a n t a g o n i s t m e t h y s e r g i d e on b u s p i r o n i n d u c e d r e l e a s e of p r o l a c t i n . We found that b u s p i r o n leads to a m a r k e d rise of p l a s m a p r o l a c t i n (peak v a l u e x • SE 8 0 2 . 1 7 • 205,75 ~g/ml; a r e a u n d e r the c u r v e A U C • S E 90512.50 • 1 8 3 2 2 . 7 8 ~g/ml x 180 min). After pretreatment with methysergide prolactin stim u l a t i o n was m a r k e d l y r e d u c e d (x • SE 326.50 • 110.70 ~g/ml; A U C • SE 4 6 0 7 5 . 0 0 • 7 6 6 8 . 3 5 ~g/ml x 180 min). The d i f f e r e n c e is s t a t i s t i c a l l y s i g n f i c i c a n t (p S 0.05). - B u s p i r o n a l s o leads to a m o d e r a t e stimulation of p l a s m a growth h o r m o n e (AUC • SE 601.80 • 2 6 8 ~ ~g/ml x 180 min) and to a m o d e r a t e rise of p l a s m a c o r t i s o l (AUC • SE 2 2 3 2 . 8 2 • 1 3 6 . 0 5 ~ g / 1 O 0 ml x 180 min). Our results i n d i c a t e t h a t the s t i m u l a t i o n of p r o l a c t i n by b u s p i r o n is m e d i a t e d t h r o u g h c e n tral n e r v o u s s e r o t o n i n r e c e p t o r s . The s t i m u l a tion of g r o w t h h o r m o n e and c o r t i s o l is an indic a t i o n that b u s p i r o n a l s o e f f e c t s c e n t r a l nervous r e c e p t o r s o t h e r than those of the s e r o t o nergic system. P s y c h i a t r i s c h e K l i n i k der U n i v e r s i t A t M ~ n c h e n , N u B b a u m s t r a B e 7, 8000 M ~ n c h e n 2

34.06.05

GH- PRL- AND CORTISOL VENT IN COMPARISON TO SUBJECTS.

AUC

EFFECTS

GH (ng/ml)

PRL (~U/ml)

Cortisol (~g/100 ml)

64.3 21.4

20013 1539

1133.4 73.0

1704.4 334.4

31044 3712

2322.4 160.6

In c o n t r a s t to the s t i m u l a t i o n e l i c i t e d by DMI no s i g n i f i c a n t h o r m o n e s t i m u l a t i o n was f o u n d a f t e r the a d m i n i s t r a t i o n of DMI s o l v e n t alone. Nervenklinik der Ludwig-MaximiliansUniversit~t M~nchen, Nuflbaumstra~e 7, 8000 M ~ n c h e n 2.

EFFECTS OF TRIMIPRAi41NE ON SLEEP-EEG, NOCTURNAL PENILE TUMESCENCE (NPT) AND NOCTURNALHORMONAL SECRETION IN NORMAL CONTROLS S. W~hrmann A. Steiger, O. Benkert and F. Holsboer She antidepressive p r o p e r t i e s of trimipramine (TR) are w e l l documented. P r e v i o u s s t u d i e s showed t h a t , in contrary to most other antidepressants, t h i s substance does not suppress rapid-eye-movement-(REM-)sleep. To f u r t h e r e l u c i d a t e the way of action of TR, a long-termstudy was performed in 3 normal c o n t r o l s (23-26 years o l d ) . They were i n v e s t i g a t e d during 21 consecutive nights with sleep-EEG and nocturnal penile tumescence (NPT) and received: ( I ) placebo f o r 3 days; (2) then increasing dosages of TR up to 200 mg f o r I0 days; and (3) p l a c e b o again a f t e r withdrawal f o r 8 days. During the l a s t n i g h t of each of the 3 parts of the study a hormone s e c r e t o r y p r o f i l e was c o l l e c t e d simultaneously with sleep between I0 pm and 7 am to measure the course of the plasma concentration of c o r t i s o l , growth hormone, p r o l a c t i n (PRL), testosterone, LH and FSH. Under TR sleep s t r u c t u r e did not change; e s p e c i a l l y REM sleep was not affected. i~PT a c t i v i t y was not d i s t u r b e d , in one subject NPT increased. PRL was enhanced under TR and normalized a f t e r drug c e s s a t i o n . Under 200 mg TR the c o r t i s o l concent r a t i o n decreased and the c o r t i s o l increase occurred markedly delayed. A f t e r withdrawal of TR the c o r t i s o l c o n c e n t r a t i o n exceeded b a s e l i n e v a l u e s , w h i l e t h e nocturnal cortisol i n c r e a s e was found advanced. No systematic e f f e c t on the other endocrine v a r i a b l e s was observed. The r e s u l t s suggest: ( I ) there is a low r i s k of e r e c t i l e dysfunction under TR; and (2) the way of action of TR is different from the m a j o r i t y of antidepressants, which suppress REM sleep, while TR acts by a suppression of cortisol, which is known to be i n c r e a s e d in a c u t e depression. Department of Psychiatry, U n i v e r s i t y of Freiburg, Hauptstrasse 5, D-7800 Freiburg, West-Germany

393

34.06.07 BLUNTED

RESPONSE OF TSH IN pANIC DISORDER 1

=

i

2

~

I

R.Martfn-San~os+~ , C.Udin~ , J.Rodrfguez , _.Alvarez , R. Guillamat , M.Torrens-.

34.06.06

Withdrawn

In the last years it has been reported that ~ne TRH test has abnormal results in some psychiatric disorders and there is so~e evidence suggesting that the hipothalamicpituitary-t~yroidaxis play a role in their ethiopathogenesis. Between 30-4C% of panic disorders show ablmnted thyroidestimulating hormone (TSH) response to thyrotropin-rele• sing hormone (TRH) (Roy Borne et al., Psychopha.~nacol. Bull., 21,546-60, 1985). The interpretations of the results of the TRH test de-pends on I) the thecnique use to measure the TSH, 2) the criterion of ! max TSH used, and 3) the ade~aa%e control. Twenty-seven outpatients with panic disorder (DSM-III) participated in the TRH test study (i0 male and 18 female rangering in age from 21-59, with a mean age of 37). All patients had normal plasma levels of T and FT and 9 4 were not taking any medication for two wee{s prlor to testing and they were free of medical and others psychia tric illnesses. The TRH test was measured by inmunoradio metric assay (IRMA), using a criterion of ~Eax TSH<5mU/u from the normal controls (sex-age-matched wi~_/nout psychiatric and endoerinologic personal and family history). Seven of twenty-seven (26%) had

ablunted TSE response.

This findings and their significance in order to predict treatment response in considered. Departments of P s y c h i a t r y I and Biochemistry 2. Hospital de la Santa Creu i Sant Pau (Medical Szhool). Avda. S.A.M. Claret 167. 08025 BARCELONA. SPAIN.

34.06.08

34.06.09

CH~gNIC D E X ~ N E A N D CSF MONfI~MINE M E T A B O ~ . G. Santagostino, S. Schinelli, P. Frattini, M.L. O/cchi, G.L. Corona and G. Spanu There is strong reason to suspect an interaction between glucocorticoids and biogenic amines (B.S. M c E ~ n , Biochem. Phanmacol., 36,1755,1987). Recently, various authors have re~orted modifications of the concentrations of monoamines and their metabolites in plasma and cerebrospinal fluid (CSF) of subjects acutely treated %ith de_xanethasone (O.M. Wolkowitz et al., Arch.Gen.Psychiatry, 44,782,1987; C.M. Banki et al., Phazn~copsychiatry, 16,77,1983). In order to examine the effect of a chronic treatment with gluoocorticoids on catecholanir~ and serotenin metaholisa, we measured levels of 3 n m e ~ - 4 - h y d r o x y phenylglycol C-IYLPG), homovanillic acid (HVA~ and 5-hydroxy indolacetic acid (5HIAA), the main metabolites of noradrenaline, dopamine and seroten/_n, in ventricular CSF of hydrocephalic patients either untreated (n=21) or treated with d e x a m e t ~ s o n e (n= 21, 4 mg twice daily, i.m.) for at least 15 days: in sc~e patients pla~na ~ was also determined. Metabolite analyses were carried cut by liquid chranatography with electrochemical detection (G.M. Anderson et al., J. Cb~samatogn 142,501,1979; S. Schinelli et al., J.Chromatogr.Bic~aed. Appl., 338,396,1985). No significant differences were noted in metabolite concentrations of untreated and treated subjects: only slightly lower MHPG levels (alx~t 8%) were found in CSF and plamma of dexarrethasone treated patients. These results indicate that effects of a chronic treatment with d e x a m e ~ on monoamine metabolism may be quite different frQm those observed after administration of a single dose of the drug. Institute of Phazmacology, University of Pavia, Via Taramelli 14, 27100 PAVIA (Italy)

LEVELS OF PRL POST-DOM IN SCHIZOPHRENICS: DIFFERENT RESPONSES AS A FUNCTION OF THE TIME-SPAN OF THE ILLNESS AND CLINICAL RESPONSETO HALOPERIDOL. J.., A. Cabranes, I. Almoguera, C. V~zquez, J. A. Ramos, and & L. Santos. The response of PRL to 4 rag. of DOM l.v. was determined. Subjects were-35 schizophrenics (DSM-III) and 15 normal controls. 9 patients were classified as subchronic (SS) and did not receive any neuroleptic (NL) treatment ever before. 26 patients were classified as chronic (SC) and were free of NL at least 10 days before the study began. The analyses of data (ANOVA) showed that the response of PRL to DOM (area under the curve) was nigher in SC than in SS patients [/-(2,47) -- 3.25, p < 0.048). Furthermore, non-repondent patients (N-23) did show, after 21 days of treatment, a higher response than respondent patients did [F(2,47) = 3127, p < 0.047]. Thus, the two following conclusions may be drawn: I) Normal response to DOM is associated to both a good clinical response and the absence of previous NL treatment9 2) The higher response of PRL to DOM observed in the SC and the non-respondent subgroups suggests a dysfunction of the dopaminergic post-synaptic receptor (TIDA) as a likely result of either the illness itself or the effects of previous NL treatments.

394

Hospital Unlversltario San Carlos. 28040-Madrid.

34.06.10

34.06.11

EL-rf AND THE h~LFHO~NDOCRINE W I N D O W M. Steiner,J.R.PeILettier,R.N.Gupta and E , S . W e r s t i u k Preclinical data irdicate that repeated ECS in anirmls indtre in central mmcsmirergic system.. 2he purpose of the present study was to further ewaluate ~ e t h e r ~ f prcduces similar changes in man. ~%is was ck~e indire~ztly by determining the effects of ~ i r e challef~es to prc~dde infozmation about ~ a t e d central e v ~ t s (the "neurseodocrire w i r 6 ~ v ' ) .

CHANGES IN NOCTURNAL SECEETION OF ANTERIOR PITUITARY HORMOhYS FOLLOWING A SERIES OF SIX ECTs J.D.Bergiannaki, C.R.Soldatos, P.N.Sakkas,C.Christodoulou, A.Botsis,C.N.Stefanis. Previous studies have reported on changes of anterior pituitary hormonal secretion as an immediate effect of electroconvulsive treatment (ECT).They included only daytime plasma samples of pituitary hormones although the secretory peaks of these hormones occur during nocturnal sleep. Therefore,we studied the effects of ECT on nocturnal plasm~ concentrations of prolactin (PRL),growth hormone(GH), thyroid stimulating hormone (TSH) and cortisol(F). In six male drug free schizophrenics blood samples were hourly (S.00p.m. to 8.00a.m.) collected through a continuous withdrawal pump,the n i g h t b e f o r e the first and the nights after the first and the sixth of a series of ECTs. Hormonal l e v e l s w e r e determined using radioimmunoassay methods. O u r r e s u l t s show that nocturnal PRL secretion did not significantly change following the first ECT (NS),while there was a trend towards a decrease following the sixth (p~0.1) Total amount of GH secretion was not markedly affected by either the first or the sixth ECT (both NS),although the latter caused a 2-hour phase advance of GH p e a k . T S H secretion increased after the first ECT and even more after the sixth (both p~O.001),whereas T3 and T4 secretion was not significantly affected. Finally,secretion of F did not show any sZatistically significant change either after the first or the sixth ECT(boZh NS). The findings regarding the effects of ECT on pituitarythyroid axis suggests that ECT may cause a degree of hyporesponsiveness of the thyroid gland.Our results will be further discussed in terms of their relation to clinical characteristics of our patients as well as their tzeatment outcome. Sleep Research Unit of the Department of Psychiatry,Univ. of Athens,74,Vas. Sophias Ave. Athens 115 28,Greece.

To date t~e~ty acutely depressed i~patie~ts were studied, htieats ~_re given a structured inte~rie~ (S~:~C) and were imh~led only if they qualified for the diagnosis of M~jor Depressive Disorder. Following a se~m day m.=dicatic~t free period the q]~flX~q, 13st and clonidiee/~ ~ challenge t e s t s were ;w~-mnlstrered in succession over a period of 3 days. Patients ~P_re then treated with ~ . No other m-~dications ~ used through~t the study, qhe ~ of ECTs v~re detezrained by c l i n i c a l s t a t u s v.hich was assessed ~ee/dy using the Hamilton Depression Scale. 2he challenge t e s t s ~ - r e repeated 11-14 days a f t e r the last ECT treammnt. T~4, cortisol and Od~m_rerm_as~ed using RIA. ~ a a m M - l ~ a s mel~ured by }~_C-~D. Besu]ts: ~ ~ e s s i o n r e f l e c t e d s e v e r i t y of depression and "nozrrelizatioa" of DST cccured in all EITs responders. The Erowth homxre, level of sedation and blc~d pressure r ~ to clonidine did not c h a n ~ with treatment v~ereas the M - ~ G . r ~ to clc~idine decreased following treatment in ECT r ~ s . A anrl~d increase in T~t resporu~ to 3~-Ivas:also noted in ]~Yr r ~ s .

Cur data suggest that ECT might cause c _ ~ in central noradrenergic s e n s i t i v i t y . Tse p o s s i b i l i t y that ~ of the observed changes in neuroendocrine responses are attrib,-table to the effects of a course of ECT itself rather than to clinical recover7 ~41] be discussed. Stpportcd by a 8rant frcm The Chtario Mental Pealth Fotr~ation. E.S.W. is also the recipient of an ~ career a~ard. Clinical Studi~ Program, IvhVester Psychiatric Unit, St. Jaseph's }bspital, and D ~ t s of Psychiatry and N~urosciences, M/Vaster Lhi~.rsity, }~iltan, Chtarin, Canada.

34.07.01

POSTER PRESENTATION 34.07

Miscellaneous

SEASONAL VARIATION OF DEPRESSION:DIAGNOSTIC ASPECTS A.J.H.T. de Bie~A.L.van Ben~nel and R.van D i e s t The seasonal v a r i a t i o n of a f f e c t i v e disorders has been deduced from both case- and p o p u l a t i o n - s t u d i e s . Elaborate c r i t e r i a to define seasonal a f f e c t i v e d i s o r d e r s (SAD) have been put forward by Rosenthal et a l . ( * ) . The aim of t h i s study is twofold. F i r s t l y : what is the occurrence of seasonal v a r i a t i o n of depression in a p s y c h i a t r i c outp a t i e n t population. Secondly: how well do Rosenthal's c r i t e r i a apply to these p a t i e n t s . 362 Outpatients were screened f o r seasonal v a r i a t i o n of depression by means of a questionnaire. Of the 112 patients who f i l l e d out t h i s questionnaire 54 reported seasonal v a r i a t i o n of depression. Subsequently, 32 of these 54 p a t i e n t s were interviewed to f u r t h e r i n v e s t i g a t e the a p p l i c a b i l i t y of the c r i t e r i a for SAD. Only 13 p a t i e n t s met a l l c r i t e r i a f o r SAD. 9 out of these 13 SAD p a t i e n t s reported a l i f e event characterized by loss j u s t preceding t h e i r f i r s t depressive episode. Rosenthal's d e f i n i t i o n f o r SAD excludes p a t i e n t s with c l e a r - c u t seasonally changing psychosocial circumstances t h a t would account f o r the seasonal v a r i a b i l i t y in t h e i r mood and behavior. Such circumstances, however, can be i n t e r p r e t e d as o r i g i n a t i n g from environmental and/or psychological sources. We wonder, t h e r e f o r e , the necessity of the psychosocial exclusion c r i t e r i u m f o r any d e f i n i t i o n f o r SAD. More knowledge, e . g . , about the influence of s i n g l e l i f e events j u s t preceding the f i r s t episode of SAD i s needed. (*)Rosenthal et el ,Arch.Gen.Psychiat.,41, 72-80, 1984 Department of C l i n i c a l Psychiatry, State U n i v e r s i t y of Limburg, PO Box 616, 6200 MD Maastricht, The Netherlands.

395

34.07.02

34.07.03

A NON-24-HOUR SLEEP-WAKE CYCLE: FREE-RUNNING RHYTHMS AND THEIR RESPONSIVeneSS TO BRIGHT LIGHT PULSES K__ t. Honma~ S__~.Honma~ *M___~.Kosaka~ *N__~.Fukuda~ and *Y. Asano A non-24-hour sleep-wake cycle is characterized by a failure of stable entrainment of the circadian sleep-wake rhythm to environmental time cues in persons with normal vision, and by a unique pattern of the rhythm known as a relative coordination. This state is thought to be caused by an altered function of the underlying circadian clock; either the endogenous period or the sensitivity to environmental time cues. We examined this hypothesis in a student who has been suffering from a periodic insomnia since his childhood. His illness was diagnosed as a non24-hour sleep-wake cycle from a three month record of his sleep-wake cycle in a normal environment and the medical examinations such as sleep EEG and ophthalmological tests. The free-running period of the rectal temperature and sleep-wake rhythms, and the responsiveness of the circadian rhythms to a bright light pulse were studied in this subject under temporal isolation. The latter attempt was based on our recent observations that the free-running circadian rhythms in these variables phase-advanced in response to a bright light pulse given at the early subjective morning, which is thought to be the basis of the light entrainment. The subject (22 yr old) spent alone in an isolation unit for 3 weeks without knowledge of time. After one week in the unit, a light pulse (5,000 ix) of 3 hr duration was applied one hr after he awoke spontaneously. One week later, a light pulse was given at the s a m e circadian phase with extending the duration to 6 hr. His free-running period ~as 25.9 hr, which was longer than the average of healthy Japanese subjects (25.2 hr). Noteworthy was the absence of phase-advance shift of the circadian rhythms after the bright light pulses. From these results, it is surmized that a non-24-hour sleep-wake cycle in this particular subject is mainly due to the lack of response of the circadian clock to the environmental light. Department of Physiology, ~Department of Psychiatry, Hokkaido University School of Medicine, Sapporo, Japan.

SEASONAL VARIATIONS IN HOSPITAL ADMISSIONS (~ Voll, $ Kasper. Th Nicdermeyer. Circannual rhythms in biochemical, endocrine, and physiological activity have been reported for various psychiatric diseases. In order to determine if these changes are also reflected in the pattern of circannual hospital utilization, we studied the seasonal variation of admission rate.s to the Psychiatric Department of the University Hospital of Heidelberg (FRG). We obtained the date of contact and further variables for 4371 patients with different diagnoses who requested psychiatric inpatient care during a five year period from 1980-1985. This total population consisted of schizophrenic disorders (40%), affective disorders (28%), neuroses (17%), and other disorders (15%). Seasonal patterns in the frequency of contacts were compared for these patient groups. Affective disorders as a group and uhipolar depressions did not show a clear pattern, but admissions for bipolar depression and also for mania occurred significantly (p < 0.01) more in spring and summer. Psychosomatic syndromes were significantly (p < 0.01) more diagnosed in winter and there was also a fall/winter peak for depressive neuroses and schizoaffecfive psychoses. Higher adunission rates in summer could be detected for acute schizophrenia whereas chronic schizophrenic patients were s i ~ c a n t l y (p < 0.01) more likely to be admitted in winter. These reported changes could be seen more clearly in patients with first admissions compared to the group with repeated admissions. The finding of an interaction between seasons of the year and the prevalence of selected psychiawic disorders suggests a role for climatological factors, such as temperature and photoperiod. This might contribute to our understanding of the etioIogy and course of psychiatric disorders. In groups of patients with a seasonal occurance of the symptomatolog3, it seems worthwhile to study the effects of treatments which include principles of the physicai environment which might trigger the illness episodes, like phototherapy or temperature manipulations. Psychiatric Department of the University of Heidelberg D-6900 HEIDELBERG, Vogstr.4, FRG

34.07.04

34.07.05

THE F/FECT OF BRIGHT LIGHT ON DEPRESSIVE SYMPTC61@ AND ST,FrRP DISTORBANCES Y.ASANO, K. HoD/ra*and S. Honma* Th~ effect of bright artificial light on depressive symptoms and sleep disturbances was examined in this study. In the first experiment, an entrainment of human Circadian rhythms by a bright light pulse was examined in the temporal isolation unit. Bright light of 5000 Lux was emitted by a metal reflex fixture in the u~tit, where a subject lived for three weeks without kno~5.ng the time of day. To avoide the behavioral effect of the complete darkness, he %~s allowed to use another light ( 500 Lux ). When bright light was introduced at the early subjective day(n=8), the circadian rhythm in body temperature phase-advanced almost immediately, but the rhyth~ of sleep-wakefulness shifted sometimes one day later. On the other hand, when the light pulse was applied to the late subjective day(n=2) and early subjective night(n=8), the circadian rhythms did not show a distinct phase shift. There was a transcient internal desynchronization between the circadian rhythm in body temperature and in sleep-wakefulness. This phase-r phase s~lltt ot the circadian rhythm indicates that bright light is an effective zeitgeber of the hlanan circadian pacemaker. Based on these findings,patients with major affective disorders or seasonal affective disorders were exposed to +~he bright light pulse during the morning hours frc~n 6 to 9 a.m., in order to phase-advance their circadian rhy~hn~. The light therapy was done during winter time.~e bright light was dramatically effective to a case of seasonal affective disorder and 4 major affective disorders out of 6 examined judging from HRS and Sleep Observation Inventory. The bright light th=_rapy was effective to depressive symptoms and sleep disturbance on affective disorders. T~e bright light may also be helpful to anither circadian disorders.

BRIGHT LIGHT DEPRESSION

Shukuzu Mental Hospita~ , Shukuzu 3-16-i0, Muroran 051, JAPAN. * Department of Physiology, Hokkaido Univ=_rsity School of Medicine, Sapporo 060, JAPAN.

396

TREATMENT

OF P R E M E N S T R U A L

B.L. Parry, S.L. Berga, D.F. Kripke, J.C. G i l l i n Bright light has been used to treat Seasonal A f f e c t i v e Disorder, Seasonal P r e m e n s t r u a l Syndrome and Major Depression. In this study, we tested the e f f i c a c y of m o r n i n g vs. e v e n i n g bright light (> 2500 lux) in p a t i e n t s w i t h n o n s e a s o n a l PMS. B a s e d on some of our p r e v i o u s work, we h y p o t h e s i z e d that some p a t i e n t s w i t h PMS, like some p a t i e n t s w i t h a f f e c t i v e disorders, have an abnormal p h a s e - a d v a n c e of certain c i r c a d i a n rhythms w i t h respect to the sleep/wake cycle. This model w o u l d p r e d i c t that patients w o u l d respond more to e v e n i n g light (which d e l a y s c i r c a d i a n rhythms) than to m o r n i n g light (which a d v a n c e s these rhythms). Subjects u n d e r w e n t a 2-3 m o n t h initial d i a g n o s t i c evaluation. P a t i e n t s then were p h a s e - t y p e d by o b t a i n i n g o v e r n i g h t c i r c a d i a n profiles of m e l a t o n i n at four s p e c i f i c e n d o c r i n e phases of the m e n s t r u a l cycle. In the t r e a t m e n t studies p a t i e n t s were r a n d o m i z e d to m o r n i n g vs. evening b r i g h t light for 7 days d u r i n g the p r e m e n s t u r a l period. After each intervention, raters blind to the t r e a t m e n t c o n d i t i o n a s s e s s e d the patients' m o o d u s i n g the Ham-D, and p a t i e n t s c o m p l e t e d the Beck Inventory. Initial results showed a s i g n i f i c a n t reduction in H a m i l t o n ( p < . 0 0 0 3 ) and Beck (p<.01) d e p r e s s i o n ratings after evening, but not morning light treatment. Futher trials w i t h a d i m red light control c o n d i t i o n are b e i n g conducted and will be p r e s e n t e d in c o n j u n c t i o n with the m e l a t o n i n data. D e p a r t m e n t of Psychiatry, U n i v e r s i t y of california, San Diego, T-004, La Jolla, C a l i f o r n i a 92093 USA.

34.07.06

34.07.07

BIOLOGICAL CORRELATES OF SOME DRUG I k O l E ~ CAL CHANGES.

PSYCHOLOGI-

~.Sim~es da Fonseca, M. Puri~icaq~o Horta, Isabel Barah2na da Fonseca~ N.F~!ix da Costa. The problem of ~he choice os biological indicators for normal psychological as well as psychopathological pr~ cesses as well as For their changes u~der the actioS of psychopharmaca is iiscussed taking as a reference some advances in the methodo!ogy which was used and in one case developed by the Lisbon group. Drug effects in Normal Volunteers as well as in Paranoid Schizophrenics are reported and their signi.micance is reconsidered, taking into account the approach which are proposed both at the b i o l o ~ c a l and at the psychopathological levels. Dept. os Medical Psychology, Faculty os Medicine os Lisbon, Hospi=al de Sta, Maria, 1600 Lisbon, Portugal.

SOME RESULTS CON~ERhqN~ INDICATORS OF SCI~CJLUS- FREB PSYCHOLOGICAL EVEh~ S Isabel Barahona da Fonseca r Jos~ Ba2ahona da Fonseca, M. Purifica~o Horta As most of the psychophysioiogical indiza~ors which are used in the domain in which we are interested co~ cern stimuli-bound responses, and their biological i',,n-dicators, such as E~Fs of the Brain, we have tried to overcome the limitation of having to use a stimulus. For this purpose we have developed an a.~e. n a ~-i v e~' ~tech nique in which subjects are required to fency, with closed eyes, some agreable or else disagreable situation, or to perform some mental task, as a control, and to signal the beginning of the state whizh is required to them. Conventional bipolar EEG recording was m~de during those states. Periodic waveForms extraction was perFo~ med through cross-correlation and afuerwards took place an averaging procedure. In the final comparisons between different subjective states, were used the amplitudes of some components of the Power Spectrum, (concerning each wave~orm charact~ ristic for a given _~requency). In normal volunteers a significant difference was found in the amplitudes of components 3, 6, 9, 12 and 15, of waveforms of frequency 3 c/s, when agreable states were compared "~_th another state. Data concerning paranoid and depressive subjects under or not under therapy are reported. Dept. of Medical Psychology, Faculty of Y~iicine of Lisbon, Hospital Sta. N~ria, 1600, Lisbon, Portugal.

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34.07.09

~ H E C H O L I N E R G I C S Y S T E M /CH/ A N D T H E E P I L E P S Y M . ~ v e j d o v l , I. R e k t o r

THE P O S S I B L E CIIOLINERGIC S Y S T E M / C E / D I S T U R B A N C E IN EARLY M E N T A L I M P A I R ~ E N T I.Rektor,M.~vejdov~,C.Silva Barrat,C.M4nini

A r e v i e w is p r e s e n t e d and c o n f r o n t e d w i t h o w n results. The c h o l i n e r g i c a c t i v a t i o n is g e n e r a l l y a c c e p t e d to be p r o c o n v u l s i v e . F o r e x a m p l e it has b e e n p r o p o s e d t h a t the c h o l i n e r g i c m o d u l a t i o n may be i n v o l v e d in the i n i t i a t i o n of the focal d i s c h a r g e s and in the t r a n s i t i o n f r o m the interictal to ictal stage. T h e r e are m o r e e x o e r i m e n t al m o d e l s using the p r o e p i l e p t i c e f f e c t s of the CH a c t i v a t i o n /e.g. T u r s k i et a l . , F a r i e l l o e t a ! . S o o e et al./. E s p e c i a l l y in the t e m p o r a l e p i l e p sies the CII a c t i v a t i o n may be p r o c o n v u l s a n t . The r o l e of CH in the c h e m i c a l l y i n d u c e d " c h o l i n e r gic" k i n d l i n g seems to be i m n o r t a n t / W a s t e r l a i n / . In humans i s o l a t e d i n f o r m a t i o n a b o u t a n t i e ~ i l e p tic p r o p e r t i e s of a n t i c h o l i n e s t e r a s e s are d o u b t = ful / i k o n o m o f f / l a z a r s / . On the c o n t r a r y , the a n t i e p i l e p t i c e f f e c t s of a n t i c h o l i n e r g i c s w e r e more o r o b a b l e / M i l l i c h a p / . Our r e s u l t s in a d u l t s w i t h p a r t i a l and s e c o n d a r y g e n e r a l i z e d e p i l e p s i e s c o n f o r m w i t h other literature data. P h y s o s t i g m i n e acts m a i n l y as a nroconvulsant. H o w e v e r , t h e r e is also a r e c e n t l y d e s c r i b e d group of i n f a n t i l e e D i l e n t i c e n c e n h a l o paties w i t h c o m o l e t e l y o p p o s i t e CH a c t i o n p h y s o s t i g n i n e acts as an a n t i e o i l e p t i c and a t r o n i n e as p r o e p i l e p t i c a g e n t / R e k t o r et al./. It seems that CH plays a s p e c i f i c role in the e p i l e n t i c e n c e n h a l o o a t h i e s due to early c e r e b r a l damage. t~eurclogical 656 91 Brno,

C l i n i c KUI~Z and P u r k y n j e U n i v e r s i t y , P e k a ~ s k ~ 53, C z e c h o s l o v a h i a

The role of CH d i s t u r b a n c e in A l z h e i m e r ' s d e m e n tia is k n o w n . A u t h o r e s h y p o t h e t i s e that CH d i s t u r b a n c e is i n v o l v e d also in g e n e s i s of m e n t a l i m p a i r m e n t due to an e a r l y c e r e b r a l lesion. CH was p h a r m a c o l o g i c a l l y tested in acute tests in 30 p a t i e n t s w i t h and after i n f a n t i l e e o i l e p tic e n c e p h a l o o a t h y . A l l w e r e m e n t a l l y s e v e r l y impaired. A s i g n i f i c a n t r e d u c t i o n of CEG p a r o x y smal a c t i v i t y after i.v. Dhysostigrnine and its increase after a t r o p i n e was d i s n ! a y e d . P e r s i s ~ tent s t a r t l e r e s n o n s e was also b l o c k e d by p h y sostigmine.The results were similar regardless of the actual type of E E G , c l i n i c a l seizures or actual a g e . T h e CH d i s t u r b a n c e seems to be t y o i cal for i n f a n t i l e e p i l e p t i c e n c e o h a l o p a t h i e s because in the cases of e D i l e o s i e s a p p e a r i n g later the e f f e c t s of both of the t e s t e d d r u g s are ~ rather o p p o s i t e . H o w e v e r , t h i s e f f e c t of CH a c t i v a t i o n seems to be linked w i t h the m e n t a l d e f e cts b e c a u s e the r e s p o n s e of p a r o x y s m a l a c t i v i t y was d i f e r e n t in the i n f a n t i l e e p i l e p t i c s w i t h normal m e n t a l d e v e l o n m e n t . A d i r e c t r e l a t i o n between EEG p a r o x y s m a l a c t i v i t y and o t h e r e p i l e p tic f e a t u r e s on the one hand and the d e g r e e of mental i m p a i r m e n t on the other, is not p r o b a b l e . More p r o b a b l e is the s i t u a t i o n w h e n the CH d i s turbance i n f l u e n c e s b o t h f a c t o r s - E E G and a l s o the o c c u r e n c e of m e n t a l d e f e c t . T h e p r e s u m e d t h e r a p e u t i c effect of CH A C T I V A T I O N is d i s c u s s e d N e u r o l o g i c a l Clinic, P u r k y n j e U n i v e r s i t y , P e k a F s k l 53, 656 91 Brno, C z e c h o s l o v a k i a

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34.07.11

CYTOGENETIC INJURY IN SCHIZOPHRENIC PATIENTS JoKo~i~ov~, Go~iriBan, R.Jo~r~m Psychiatric Research Institute, 181 03 Prague, Czechoslovakia

Enhanced Pressor Sensitivity to Oral TyramineChallenge Following High DoseSelegiline Treatment A. PRASAD, V. GLOVER, B.O. GOODWIN, M. SANDLER,M. SIGNY,

S.E. SMITH Some recent hzpotheses expect the injury of cell and nucleus membrane due to the long-term therapy with neuroleptics and by the disease itself in schizophrenics~ Therefore,we analysed the cytogenetic injury in a group of schizophrenics (n=Yl) and in group of patients with other psychiatric diagnoses (oligophrenics and personality disorders, n=8)o The cytogenetic analysis of chromosome aberrations in peripheral lymphocytes and the determination of micronuclei in buccal epithelium cells were used for the detection. The samples were collected on day O, on day 28 and on day 56o In the s e c o n d period the basic therapy was supplemented with antioxidants - v i t a m i n E (400mg per day) and vitamin C (IO00mg per day)~ The frequency of aberrant cells in peripheral lymphocytes did not differ in both of these groups, but was higher than the frequency of aberrant cells in healthy population~ The frequency of micronuclei in buccal epithelium cells in both of these groups was higher than the f r e q u e n c y of m i c r o n u c l e a t e d c e l l s in healthy volunteers~ After 4 weeks a d m i n i s t r a t i o n of vitamins E and C we did not find any significant decrease either in micronucleated cellap or in aberrant cells in peripheral lymphocyteso

34.07.12 METHYL FOLATE ENHANCES RECOVERY PSYCHIATRIC I L L N E S S

A. Prasad, Consultant Psychiatrist, Claybury Hospital, Woodford Bridge, Essex, England

34.07.13 FROM

Toone B,K., P. Godfrey, M.W.P. Carney, T. Flynn, T. Bottiglieri, M. Laundy, E.H. Reynolds We'bave reported that approximately one quarter of acute psychiatric inpatients have low red cell folate levels (less than 200 ng/ml). We have undertaken a double b l i n d placebo controlled trial of methyl folate, the transport f o r m of folate in the nervous system, as add on therapy to psychiatric patients with low red cell folate levels. Patients were stratified according to psychiatric diagnosis, i.e. affective illness or schizophrenia. The methyl folate 15 mg daily or p l a c e b o was added to standard psychiatric medication a n d the 23 patients were followed for 6 months. At 3 and 6 months of follow up the clinical and social recovery of the patients on vitamin replacement were significantly better than those on placebo.

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Blood pressure and heart rate responses to oral tyramine have been measuredin healthy volunteers before and after administration of the selective monoamineoxidase B-inhibitor, selegiline, at high dosage {30 mg/day). Treatment brought about a two- to four-fold increase in tyramine sensitivity and a concomitant small, but significant reduction in plasma 4-hydroxy-3-methoxyphinylconcentration, pointing to the emergenceof somedegree of monoamineoxidase A-inhibition. I t is suggested that the patients treated with selegiline, 30 mg/day or more, should be placed on a tyramine-free diet.

The acceleration of antidepressants's effects by using photoherapy in endogenous depression 3. Pras~o, Czechoslovakia The combined therapy composed of antidepressants and light exposure was carried out, covering three groups of depressive patients. All patients were treated with the antidepressants and the light exposure (5000 tux for 1 hour daily), the first group ~11 patients) at 5 a.m., the second group (9 patients) at 9 p.m.. The control group consisted of 9 patients was only treated with tricyklic antidepressants. The best improvement, according to the Montgomery and Asberg Depression Rating Scale, was recorded in the First group, Lhough there was a tendency of mood worsening at the end of phototherapy. In the second group there was not so good improvement comparing with the results achieved in the first one, but still significantly better than in the control group. The worst results were ascertained in the third group (evening phototheray). However, all three groups by combined therapy showed better results than control group.

34.07.14 DOTHIEPIN VERSUSTRAZODONE~N MAYORDEPRESSION INELDERLY C. Cocconcelli, R. Caso]i and G. Turrini A double-blind s-tudy in 40 old depressives (12 M and 28 F, mean age 68,5 + I SEM) has been performed in order to evaluate the effectiveness and safety of dothiepin compared to trazodone in elderly. Patients were selected according to DSM-III diagnostic c r i t e r i a for Major Depression and evaluated by means of the Hamilton Psychiatric Rating Scale for Depression (~HRSD), the Cassano-Castrogiovanni SelfEvaluation Scale for Depression (SAD) and a visual analogue scale of the severity of the depressiv e symptomatology (VAS). All the patients were randomly treated with dothiepin (D) 75 mg or trazodone (T) lO0 mg p.o. at night for 4 weeks. The HRSD scores significantly decreased at the 2rid (-43% with D and --31,8% with T) and at the 4th (-60,7% with D and -49,4% with T) week. So did the SAD scores (-24,7% with D and -18% with T at the 2nd week; -32,1% with D and -25,3% with T at the 4th week) and the VAS (-38,3% with D and ~ with T at the 2nd week; -63% with D and -54,9% with T at the 4th week). The ANOVAdifference between treatments within times showed a significant trend for dothiepin compared to trazodone (p~-.O,Ol) on all the Depression Scales used. Side effects were foreseeable and mild; two patients on dothiepin dropped out for dizziness. Dothiepin showed a more quick and incisive action than trazodone in old patients affected by Mayor Depression. S. Maria Nuova Hospital - 42100 Reggio Emilia - I t a l y

34.07.15 Subtypes of Neurometric Profiles in Schizophrenia and Relationship to Drug Response L.S. prichep 1,2, E.R. John 1,2, J. Volavka 1,2, R. Chabot l, T. Essig-Peppard t , K. Alper1 E g g recordings were obtained from schizophrenic patients during a drug free period, and a period whih on medication. Neurometric features were extracted from these recordings and subjected to cluster analysis. PreLiminary results suggest at least three major subgroups in this sample of patients, with markedly different profiles of pathophyslology.

Members of these sub-

groups appear to display different responses to drugs.

IDep~tment of Psyc.hlatry, New York University Msdlcal Center, New York, NY 2N~th~n S. ICllneIr~titute for Psychlstrle Research, Ora~geburg, NY

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