Psychopharmacologia (Bed.) 42, 235-242 (1975) 9 by Springer-Verlag 1975
Effects of Morphine and Heroin on Discrimination Learning and Consolidation in Mice CLAUDIO CASTELLANO Laboratorio di Psicobiologia e Psicofarmacologia, C.N.R., Roma, Italy Received June 28, 1974; Final Version December 9, 1974
Abstract. Morphine and heroin were administered to mice learning to swim toward a light source (L procedure) or toward the dark (D procedure), in a Y water maze, under preand post-trial drug treatment conditions. In the pre-trial experiments a clear disrupting effect on performance with the two procedures followed administration of both drugs, but for the L procedure, performance never fell below the 50 ~ level of correct choices.
Analysis of the performance within each session demonstrated a disruption in the long term memory consolidation mechanism. The administration of naloxone, or alternatively, discontinuation of the treatment, was followed by a gradual improvement, in performance by the treated animals. In both procedures, a performance disruption also followed the administration of the drugs immediately after each experimental session.
Key words: Morphine - Heroin - Learning - Consolidation - Mice.
A review of the literature reveals varying behavioural effects of morphine, which is used therapeutically as an analgesic. Behavioural depression following morphine administration has been demonstrated using various experimental measures (running, lever press, discrimination) by Holten and Sonne (1955), C o o k and Weidley (1957), Verhave et al. (1959), Clark and Samuel (1969) and Castellano (1973). Other studies however have reported behavioural stimulation (Djahanguiri etal., 1966; McMillan and Morse, 1967; Woods, 1969). C o o k and Weidley (1957), Verhave et al. (1959) and Banerjee (1971) have demonstrated disruption to the avoidance response both with learned behaviour and with learning due to a reduction of the alarm reaction following morphine administration, whilst others (Domino et al., 1958) disclaim such a selective depressant effect of morphine on the CAR. Perhaps some of the contradictory evidence can be explained by the work of T h o m p s o n and Shuster (1968), who demonstrated that behavioural depression or stimulation which follow drug treatment is dependent upon drug dose and experimental conditions. This series of experiments investigates the effects of morphine and heroin on learning and consolidation in mice using a discrimination task. F o r this purpose
a Y water maze was used, in which, under conditions of high motivation, the animals had to learn to swim towards the light or the dark. Two experimental procedures, were e m p l o y e d - the first involved orientation towards a light source (L procedure) corresponding to innate behaviour; the latter involved orientation toward the dark (n procedure) investigating the acquisition of a new pattern of behaviour. The nature of this task eliminates the influence of analgesia (which follows opiate administration) on the sensitivity to shock.
Methods The apparatus consisted of automated Y water mazes, with walls of black plexiglas. At the end of each alley there was a platform above which a 3 W lamp was placed, behind an opalescent screen. In this apparatus two procedures were carried out: L procedure, in which the mice must swim toward the light, i.e. toward a platform raised in the only lighted alley; and n procedure, in which the platform is raised only in the dark alley, while the other two alleys are lighted. During the experiments the platforms were raised in randomized order manipulated by a programmer who also controlled the lighting in the alleys. The mazes were covered with a black cloth, to isolate them from the external environ-
236
Psychopharmacologia (Berl.), Vol. 42, Fasc. 3 (1975)
ment and the temperature of the water was maintained between 18 and 20~ All animals before beginning the learning trials, underwent 5 pre-training sessions, consisting of 5 trials in a straight alley, with a platform placed at each end. During each trial the time taken to cover the distance (70 cm) between the two platforms was recorded. The few animals which did not succeed in covering this distance in a mean time of 3 - 5 sec were excluded. a) Pre-Trial D r u g Treatment These experiments were carried out in order to study the effects of morphine and heroin on learning. Three doses of each drug were used: 5, 10 or 30 mg/kg of morphine and 25, 5 or 10 mg/kg of heroin. Each dose was administered to two different groups of 8 animals, one group being trained to go towards the light, the other towards the dark. Opiate + saline treated control groups were all trained for 10 sessions held daily over 10 consecutive days. Each session consisted of 5 trials at 1 min intervals. After the 10th session the administration of the drugs was discontinued, and the animals were tested. In a further series of experiments morphine (30 mg/kg) or heroin (10 mg/kg) was administered to 4 groups of mice-two experimental learning conditions, I~ and D, for each drug. Beginning with the 6th session, administration of Naloxone HC1 (4 mg/kg) was carried out 5 rain before injection of opiate. The performance of these animals was compared with animals were withdrawal was not precipitated. The third of the pretrial treatment experiments involves administration of Naloxone HC1 (4 mg/kg) to two groups of 8 mice-one group trained under L procedure and one group under D conditions. In all the pretrial experiments morphine HC1 4- heroin HC1 were injected 15 rain before testing. b) Post-Trial D r u g Treatment The effects of 30 mg/kg of morphine and 10 mg/kg of heroin on the long term memory consolidation process were investigated, using animals learning to swim towards the light or the dark. Two series of experiments were carried out. In the first series, 16 animals were treated with each drug (two groups of 8 mice assigned to i~ or L procedures). These were injected immediately after the last trial of each of the ten consecutive daily training sessions. In the second series, drug treatments were carried out 2 hrs after the last trial of each experimental session. In both series performance was compared with that of saline controls. All drugs were dissolved in saline and injected intraperitoneally. DBA/2J mice (Jackson Lab.) weighing about 25 g at the beginning of the experiments were used throughout.
Results Controls In accordance with previous results (Sansone et al., 1969), the animals trained under the L procedure achieve high levels of performance from the first
session. At this stage the mean number of correct choices exceeded the 50 ~ level (which represents the normal chance level). A low percentage of simple errors (when mice make a wrong followed immediately by the right choice) and multiple errors (when mice make a wrong choice and return into the start alley at least once during each trial) is observed in the first sessions. Conversely, the animals trained under the I) procedure (Fig. 1) start with a very low level of correct choices, and multiple errors are high, decreasing steadily until the fifth session. Pre-Trial Experiments (Tables 1 - 4) The lowest dose of both drugs (5 mg/kg for morphine and 2.5 mg/kg for heroin) did not significantly affect the performance of the injected animals during training in both procedures, compared with the saline injected controls. Following the administration of 10 mg/kg of morphine and of 5 mg/kg of heroin, performances under both procedures were impaired, gradually improving over the sessions, and no significant difference was evident at the 10th session, between treated animals and the controls. The performance impairment became more evident after the administration of 30 mg/kg of morphine (Fig. 2) and 20 mg/kg of heroin. At these dose levels a lower rate of improvement in the number of correct choices was observed from the first to the last treatment session. However, it should be noted that, for the I~ procedure, performance of the animals, at all the doses tested, never fell below the 50 ~ level of correct choice. Cessation of drug treatment, in both procedures, as well as the administration of Naloxone to the drugged animals (Fig. 3) was followed by a gradual improvement in performance. Pre-trial administration of Naloxone alone (4 mg/kg) to the animals had no significant effect on performance. F o r both procedures, the percentage of correct choices for every trial of each training session was considered. F r o m this analysis clear evidence of improvement in performance fi'om the first to the fifth trial of each session in both control and treated mice can be observed. Further, in animals injected with the effective doses of opiate, a clear performance impairment was evident between the last trial of a session and the first of the following one. This contrasts with marked improvements by the controls as well as other experimental groups. A gradual improvement in performance replaces this impairment after the cessation of drug treatment, or after the administration of Naloxone.
C. Castellano: Morphine and Heroin on Learning and Consolidation
237
I00-
100-
%50.
[]
mean%of correct choices
m
%50.
I~]mean%of simple errors 9 mean%of multiple errors
J O III
IV
V
Vl
VII
II
VIII
Ill
IV
V
Vl
Vii
VIII
iX
X
Xl
Xll
SESSIONS
SESSIONS
Fig. 3. b procedure, Sessions I - VI : Performance of 8 animals following treatment with morphine HC1 (30 mg/kg). Sessions V I I - XII: Performance following administration of Naloxone (4 mg/kg) to the morphine injected animals. Student's test (correct choices) : Sessions I - VIII: ns; Session IX: P < 0.05 ; Sessions X - X I I : P < 0.01
Fig. 1. D procedure: Each column represents the mean number of correct choices, simple errors + multiple errors made by 30 control mice. Each of the five point inside the columns represents the mean number of correct choices made by the 30 animals corresponding to each of the five trials of a training session. (All values are expressed as percentages)
100.
1004
%so.
%50.
1 II
0 11]
IV
Vl
Vii
~
IX
~1~
X]
Xll
Xlll
~
SESSIONS
XV
III
IV
il
VII
VIII
IX
SESSIONS
Fig. 2. D procedure, Sessions I - X : Mean number of correct choices, simple errors + multiple errors made by 8 animals, following treatment with morphine HC1 (30 mg/kg). All values are expressed as percentages. Session X I - X V : Withdrawal of the drug. Sessions I - I I : ns; Sessions I I I - V and XIII: P < 0.01; Sessions V I - X I I : P < 0.001; Sessions X I V - XV: ns
Fig.4. D procedure: Performances of 8 animals following administration of morphine HC1 (30 mg/kg) immediately after each training session. Student's test (correct choices): Sessions I - I I : ns; Sessions I I I - I V : P < 0.01; Sessions V - X : P < 0.001
Post-Trial Experiments (Tables 1 - 4)
of drug treatment, or alternatively the administration of naloxone to the treated animals, was followed by a gradual performance improvement. The analysis of performance within each session provided similar results to those obtained in the pretrial experiments. However, no significant difference was observed under both procedures, between the performances of the controls and mice injected with morphine or heroin 2 hrs after each experimental session.
The administration of morphine (30mg/kg) (Fig.4) and heroin (10 mg/kg) during training immediately after each experimental session, resulted in greater disruption of performance under both L and D conditions compared with the saline injected controls. The performances of the mice trained under the L procedure never fell below the 50 ~o level of correct choices. As for the pre-trial experiments, the cessation
238
Psychopharmacologia (Berl.), Vol. 42, Fasc. 3 (1975) Table 1.
Sessions
I
Controls (pre trial)
II
III
a
b
a
b
a
b
46
61.3 • 3.2
76
90.7 • 3.7
86
94
• 3.2
75 50 50
85 • 3.2 70 • 7.5** 62.5 • 8.8**
75 50 50
90 70 60
• 3.7 • 8.2** • 8.1"**
Morphine ( I - V I I )
5 10 30
50 50 50
60 60 55
• 3.2 • 3.7 • 5.6
Heroin ( I - V I I )
2.5 5 10
50 50 37.5
62.5 • 5.9 62.5 • 4.5 52.5 • 5.7
75 50 37.5
85 • 3.2 67.5 • 6.2** 55 __+6.8***
75 50 37.5
90 60 60
• 3.7 • 4.5*** • 6.5***
Naloxone 4
50
60
• 3.2
75
95
• 3.2
87.5
99
• 3.2
Morphine 30 ( I - VI) Morph30 + Nalox4 (VII)
37.5
55
• 3.2
37.5
55
_ 3.2
50
60
• 3.7
Heroin 10 ( I - V I ) H e r o l 0 + Nalox4 (VII)
37.5
55
• 6.2
37.5
60
_ 3.7
37.5
60
• 3.7
Controls (post trial)
50
60
• 3.7
75
85
• 3.2
87.5
95
• 3.2
Morphine 30 (post trial) 1
50
60
• 0
50
60
• 3.7**
50
62.5 • 4.5***
Heroin 10 (post trial) 1
50
60
• 3.7
50
60
• 3.7**
50
60
• 0"*
Morphine 30 (post trial) 2
50
65
• 3.2
75
90
• 3.7
87.5
95
• 3.2
Heroin 10 (post trial) z
50
60
___3.7
75
85
• 3.2
87.5
92.5 • 3.6
a Mean percent of the correct choices corresponding to the first of the five trials of each session. b Mean percent ( • S.E.) of the correct choices corresponding to the whole session. 1 Immediately after each session.
Table 2. Sessions
VIII a
Controls (pre trial)
b
100
Morphine 10 (VIII-X) Saline 30 (VIII-X) Heroin 5 (XI-XIII) Saline 10 (XI-XIII) Morph 30 § Nalox 4 (VIII-X) Hero i0 + Nalox 4 (VIII-X) Morphine 30 (post trial) 1 Heroin 10 (post trial) 1
IX
X
a
b
a
b
62.5
82.5 • 4.5*
75
88.5 • 3.2
50
62.5 • 3.2***
100
62.5
80
• 3.2**
50.5
62.5 • 3.7***
50
65
62.5
85.0 _ 5.0
62.5
87.5 • 5.2
75
95
• 5.2
50
65
_ 3.7***
50
70
• 5.3***
50
65
• 3.2***
62.5
80
• 3.7**
87.5
95
• 3.2***
100
100"**
62.5 50 50
80 65 60
• 3.7** • 3.2*** • 3.7***
70 50 50
90 65 65
• 3.7** • 3.2*** • 3.2***
100 50 50
100"** 65 • 3.2*** 65 • 3.2***
• 6.3***
For legends see Table 1.
Discussion T h e m a i n p o i n t w h i c h e m e r g e s f r o m these e x p e r i m e n t s seems to be the d i s r u p t i v e effect o n l o n g t e r m m e m o r y consolidation processes following opiate administra-
tion. T h e d e v e l o p m e n t o f t o l e r a n c e with c o n t i n u e d d r u g t r e a t m e n t is d e m o n s t r a t e d m a i n l y at the lowest effective doses, b y the g r a d u a l i m p r o v e m e n t in perf o r m a n c e . Even if t o l e r a n c e m a y have influenced
C. Castellano : Morphine and Heroin on Learning and Consolidation
239
L Procedure (a) IV
V
a
b
96
99
87.5 50 37.5 87.5 50 37.5
a
b
• 1.8
100
i00
95 • 3.2 67.5 • 3.7*** 62.5 • 5.0***
100 50 50
100 75 • 5.9*** 72.5 • 5.2***
50 50
95 • 3.7 60 • 4.5*** 57.5 • 6.1"**
100 50 37.5
100 72.5 • 5.9*** 62.5 • 5.9***
100
100
50
60
37.5
62.5 • 2.5
87.5
95
• 3.7
50
65
• 3.7***
37.5
VI
• 3.7
60.0 • 3.7***
100
100
100
100
50
VIII
a
b
a
b
62.5 • 5.3*** 65 • 5.8***
62.5 50
80 • 5.3** 62.5 • 9.6***
62.5 37.5
75 65
62.5 50
75 65
• 3.7**
• 5.4***
• 7.5**
• 5.4***
65
• 3.2
50
62.5 • 3.2
50
62.5 • 2.5
• 5.0
37.5
62.5 • 2.5
50
65
• 3.2
50
65
100
100
50
65
• 3.2***
37.5
62.5 • 3.7***
50
65
• 5.0***
37.5
57.5 • 5.9***
37.5
60
50
65
• 3.2***
• 3.2***
2 2 hrs after each session. * P < 0.05. - ** P < 0.01. - *** P < 0.001.
L Procedure (b) XI
XII
a
b
75
90
• 3.2
50
65
• 6.3***
87.5
95
• 3.2
50
70
• 5.3***
XIII
a
b
100
100
75
82.5 • 3.7
100
100
75
85
• 3.7
p e r f o r m a n c e to some degree, over a testing session, ' the hypothesis that long term m e m o r y c o n s o l i d a t i o n i m p a i r m e n t occurs in a n i m a l s l e a r n i n g to go t o w a r d the d a r k can be investigated.
a
b
100
100
87.5
95
+ 3.2
Analysis, in the pre-trial experiments, of the perf o r m a n c e s w i t h i n each session, a n d between two consecutive sessions was carried out. This shows that, as with the controls, a g r a d u a l i m p r o v e m e n t is evident
240
Psychopharmacologia (Berl.), Vol. 42, Fasc. 3 (1975) Table 3,
Sessions
I
II
III
b
a
b
a
b
Morphine (I-VIII) 5 10
12.5 12.5
30 • 3.7 22.5 • 3.2
25 0
45 • 3.2 37.5 • 7.0
37.5 12.5
60 • 3.7 42.5 • 6.2*
Heroin ( I - VIII)
12.5 12.5 0
27.5 • 5.2 35 • 3.2 22.5 -I- 5.9
25 25 0
40 • 5.3 42.5 • 5.2 25 • 3.2*
37.5 25 0
55 50 25
Morphine 30 (I-VIII)
12.5
27.5 • 4.5
0
27.5 • 6.2
12.5
32.5 • 3.6**
Heroin 10 (I-VIII)
12.5
25
• 3.2
12.5
27.5 • 3.7
12.5
30
• 3.7**
Naloxone 4
12.5
35
_+ 3.7
37.5
45
• 3.2
50
65
• 3.7
Heroin 10 ( I - V I ) Hero 10 + Nalox 4 (VII-- VIII)
12.5
25
• 3.2
12.5
25
• 3.2
12.5
30
•
Controls (post trial)
12.5
30
_ 3.7
25
40
• 8.2
37.5
50
• 3.7
Heroin 10 (post trial)
0
25
_+ 5.2
0
30
• 3.7
0
30
• 3.7**
Morphine 30 (post trial) 2
12.5
30
• 3.7
25
45
• 5.2
37.5
55
• 6.2
Heroin (post trial) 2
12.5
25
• 5.2
25
37.5 • 5.2
25
50
• 3.2
2.5 5 10
• 3.2 • 3.6 • 5.0**
For legends see Table 1. Table 4. Sessions
IX
X
XI
a
b
62.5
82.5 • 4.5*
62.5
82.5 • 4.5*
62.5 12.5
90 40
• 3.2 • 5.3***
87.5 12.5
95 40
• 3.7***
12.5
45
• 3.2***
12.5
47.5 • 3.2***
45
• 5.3***
25
45
• 3.2***
75
85
• 3.2***
a
b
Saline ( X I - XIII) Heroin 5 10 Saline ( X I - XV)
50
75
50 0
77.5 • 7.9* 37.5 • 7.0***
Morphine 30 ( I X - X I I )
12.5
45
a
b
Morphine 10 ( I X - X ) • 5.0**
Heroin 10 (IX-XII)
12.5
42.5 • 3.7***
12.5
Hero 10 + Nalox 4
37.5
60
50
70
• 3.7**
Heroin 10 (post trial)
12.5
42.5 • 4.5***
12.5
45
• 5.0***
• 3.7*
• 3.2 • 5.3***
For legends see Table 1.
in the opiate injected animals, within each session, demonstrating that short term memory processes were unaffected by drug treatment. A clear performance decrement compared to saline injected animals (more evident, probably due to the lack of tolerance in the early sessions) appears in these animals, between the last trial of one session and the first of the following one. As far as the h procedure is concerned the innate tendency of the animals to go toward the light seems to be less affected by opiate treatment: N o difference was observed for each dose level in the first session,
between the performance of the control and treated animals. However, in later sessions, performance is impaired, even though it never falls below the initial chance level (50 ~). Further under the h procedure, marked performance improvement during each session, and impairment between two consecutive sessions, were recorded. It should be stressed that, in our experiments, no clear disruption of response or symptoms obviously interpretable as "withdrawal syndrome", were observed, either following withdrawal of narcotic, or
241
C. Castellano : Morphine and Heroin on Learning and Consolidation I) Procedure (a) IV
V
VI
VII
a
b
87.5 95 • 3.2 37.5 62.5 • 6.5***
100 50
100 65 • 3.7***
80 k 3.5 57.5 • 5.6** 42.5 • 6.5***
87.5 90 • 3.2 37.5 57.5 • 8.4*** 12.5 37.5 • 5.9***
100 37.5 12.5
100 77.5 • 5.0** 40 • 6.5***
12.5
42.5 • 2.5***
12.5
40
• 7.9***
12.5
40
• 5.0***
12.5 42.5 • 3.2***
12.5
45
• 3.7***
12.5
40
• 3.7***
12.5
45
• 3.2***
• 3.2
62.5
80
• 3.5
75
85
• 3.7
87.5
95
• 3.2
100
100
30
• 3.7
12.5
35
• 3.2
12.5
35
• 3.2
12.5
35
• 3.2
25
45
50
60
• 3.7
62.5
75
• 3.2
75
85
• 3.2
87.5
95
• 3.2
100
100
12.5
35
• 3.2**
12.5
40
• 0"**
12.5
45
• 5.6***
12.5
40
• 3.7***
37.5
55
•
50
65
•
75
85
• 3.7
87.5
95
• 3.2
100
100
37.5
60
• 3.6
50
70
• 3.7
75
80
• 3.2
87.5
95
• 3.2
100
100
a
b
a
b
50 65 • 3.2 12.5 52.5 • 5.3
50 25
75 50
50 25 0
62.5 • 3.6 57.5 • 6.6 30 • 3.7***
50 25 12.5
0
a
b
62.5 37.5
85 60
75 • 3.2 57.5 • 7.5* 35 • 7.3***
62.5 25 12.5
42.5 • 7.5**
12.5 42.5 • 2.5***
0
35
• 3.2***
50
75
12.5
XII a
• 3.2 • 4.5**
XIII b
75
90
100 37.5
100 50
• 3.2 • 7.0***
25
47.5 • 3.7***
25
47.5 + 3.2***
87.5
95
• 3.2***
• 3.2 • 6.5**
b
XIV
a
b
100
100
50
75
25
47.5 • 3.2***
100
a
VIII
• 3.2**
12.5
45
• 3.2
• 5.0***
XV
a
b
75
85
• 3.7
a
b
87.5
95
• 3.2
100"**
after antagonist administration. It should be noted regarding this point, that Heifetz and McMillan (1971) report that the lack of a pronounced withdrawal syndrome depends on many factors, such as animal species, dose levels, frequency of administration and schedule parameters. Banerjee (1971), whose results, obtained in a discrimination conditioned avoidance situation (pool climbing) agree extensively with our results, has shown, for example, that morphine withdrawal improved performance in rats injected for as long as 12 con-
secutive sessions. Woods and Schuster (1971), on the other hand, found that morphine deprivation in rhesus monkeys, following 15 days of treatment with morphine, produced a decrease in behavioural outputs, maintained by food or water reinforcers, which, however, lasted for only 24 hrs. They interpreted this short lasting effect as the consequence of the relatively brief exposure to the drug. It is of interest to note that the DBA/2J mice, which under different experimental conditions (Oliverio and Castellano, 1974) did not show the typical
242
Psychopharmacologia (Berl.), Vol. 42, Fasc. 3 (1975)
"running fit" following morphine of heroin administration, did not demonstrate avoidance of behavioural stimulation following opiate treatment after the first sessions. The hypothesis of an impairing effect of morphine and heroin on consolidation mechanisms would appear to gain further support f r o m the results of the posttrial experiments. It is widely known (McGaugh, 1966) that the post-trial administration of a drug m a y modify the consolidation p r o c e s s - a n improvement in performance corresponding to m e m o r y enhancing; an impairment corresponding to the m e m o r y disrupting effects of the drug tested. We found that the administration of both drugs immediately after the fifth trial of each experimental session was invariably followed by a clear disruption of performance. The lack of any impairment when opiate administration occurred 2 hrs after conclusion of the experimental sessions, confirms that this disruption can be attributed to post-trial effects of the drugs. It would appear of interest to note that investigations carried out in man (Kay etal., 1969), cats (Echols and Jewett, 1972), and rats (Colasanti and Khazan, 1973) have shown that opiate administration is followed, in these species, by R E M deprivation, and that a recovery in the normal sleeping cycle follows naloxone administration. It is, moreover, well known that R E M deprivation impairs the consolidation processes in rats (Pearlman, 1969), and mice (Sagales and Domino, (1973). The finding that naloxone administration to morphine or heroin treated mice was followed, in our experiments, by improvement in long term m e m o r y consolidation suggests that neurophysiological investigations of the relationship between R E M sleep and opiate adminstration in the mouse, too, might be useful. Acknowledgements. Thanks are given to Mr. Giuseppe Olimpieri and Mrs Rita Gasbarra for their technical assistance. Naloxone HC1 was kindly supplied by ENDO Lab.
References Banerjee, U. : Acquisition of a conditioned avoidance response in rats under the influence of addicting drugs. Psychopharmacologia (Berl.) 22, 133-143 (1971) Castellano, C. : Morphine, Mescaline and Cocaine on water maze discrimination in mice. Psychopharmacologia (Berl.) 28, 147-153 (1973)
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C. Castellano, Laboratorio di Psicobiologia e Psicofarmacologia C.N.R., Via Reno 1, 1-00198 Roma, Italy
