36
Facilitating Effects of Pre- and Posttrial Amphetamine Administration on Discrimination Learning in Mice 1) by JARA A. KRIVANEK~) and JAMES L. MCGAUGH Department of Psychobiology, School of Biological Sciences, University of California, Irvine, California 92664
Abstract
Two experiments investigated the effects of d-amphetamine on food-rewarded visual discrimination learning in mice. The findings of Experiment 1 indicate that degree of facilitation learning obtained with posttrlal i.p. injections varied with dose: Facilitation was obtained with doses ranging from 0.25 to 2.0 mg/kg, but not with a higher dose (2.5 mg/kg). The findings of Experiment 2 indicate that degree of facilitation varies with time of administration. With two doses (0.5 and 2.0 mg/kg) facilitation was obtained with injections given up to 30 minutes before training or immediately after daily training. No significant effect was obtained with injection given 15 minutes after training. The findings are interpreted as providing further support for the view that amphetamine facilitates learning by affecting tLnne-dependent memory storage processes.
Numerous studies have shown that the performance of animals on learning tasks can be enhanced by CNS stimulants [18, 21, 24, 25, 30]. On the basis of these findings, it has been generally assumed that CNS stimulants influence learning by acting on neurobiological processes involved in memory storage. However, if animals are trained and tested while drugged, it is difficult to determine the bases of the drug's influence on behavior simply because there is no obvious way of distinguishing the drug's effects on memory from its effects on sensory, motor, and motivational processes. Consequently, strongest support for the view that drugs can facilitate learning by influencing CNS processes involved in memory storage has come from studies in which the drugs are administered shortly after training. The ral) This research was supported in part by Research Grant MH-12526 from the National Institute of Mental Health, United States Public Health Service. 8) Now at Department of Psychology, California State College, Fullerton, California.
tionale for this technique comes from the fact that there is increasing evidence [17, 19] that the formation of memory traces is a time-dependent process that is open to intervention for some time after the experience that initiated it. This means that a drug which has supposedly direct facilitative or disruptive effects on learning should be effective even if given after the experience provided that the onset of the drug's action after injection is short. At the same time, posttrial administration precludes, or at least minimizes most of the indirect performance effects the drug might have, since the animals are never tested while under the drug's direct influence. Evidence of facilitation of learning with posttrial drug administration has been obtained with a variety of drugs including strychnine, picrotoxin, bemigride, pentylenetetrazol, diazadamantanol, caffeine, and nicotine [2, 7, 8, 14, 23, 26, 31]. With posttrial drug injections, the degree of facilitation of learning has been found to decrease as the interval between training and drug administration is increased. Although the gradients of retrograde facilitation vary as a function of many factors including the strain of animals tested, drug and dose, they are roughly comparable to t h e gradients of retrograde amnesia obtained with ECS and other treatments which interfere with CNS functioning [I7]. The fact that the posttrial technique allows at least a partial separation of the effects a drug has on learning from other effects on performance makes it especially useful in the study of drugs that seem to affect both simultaneously, d-Amphetamine appears to be such a drug. The present study is a further investigation of its effects on learning in mice. Although the behavioral effects of amphetamine have been studied for several decades there is as yet no general agreement
Amphetamine and Discrimination Learning
concerning the effects o f a m p h e t a m i n e on learnfl)g. Most o f the early studies using pretrial injections reported impairment o f learning performance [21]. M o r e recent studies have generally reported facilitating effects o f a m p h e t a m i n e on learning [1, 1 I, 16]. These findings are difficult to interpret, however, since these studies used active avoidance tasks. It might be that the drug facilitated performance simply by increasing activity level [4], by decreasing the freezing behavior typically p r o d u c e d by footshock [10, 13] or by decreasing fatigue [3]. Further, there is some evidence to suggest that the performance enhancement obtained with amphetamine m a y be only temporary - that is, due directly to drug influences on performance rather than to influences on learning processes [27]. Some of the evidence f r o m these studies does suggest that amphetamine m a y enhance learning by affecting C N S processes involved in m e m o r y . F o r example, KELEMEN and BOVET (1961) found that low doses o f amphetamines (0.30 mg/kg), given pretrial, enhanced active avoidance learning without affecting the initial response latencies. These results are difficult to interpret in terms of activity effects. Nevertheless, the possibility that increased attention or motivation might be responsible cannot be ruled out. The m o s t convincing evidence o f facilitation o f learning with amphetamine was reported in a recent study by DOTY and D o r y [5] which used posttrial injection procedures. In their study, the degree o f facilitation obtained with amphetamine (2.0 mg/kg) varied with the task, the age o f the rats, and the time o f the posttrial drug injection. Facilitation was f o u n d with both simple and discriminated avoidance-learning tasks, provided that the drug was injected within 10 seconds after the training trials. These effects were obtained with both y o u n g and old rats. I f the injections . were delayed for 1 hour, only the oldest group showed facilitation with the simple avoidance tasks, although all groups showed facilitation with the m o r e complex discrimination tasks. W h e n the drug injection was delayed for 4 hours, facilitation was f o u n d only with the oldest group o f rats trained in the complex discrimination. This study strongly suggests that d-amphetamine facilitates learning by directly influencing some central process underlying learning; it also suggests that, given a specific task and type o f subject, the degree o f facilitation observed will depend on the time o f injection relative to the training trials.
37 In an effort to explore this problem further, the present study investigated the effects o f posttrial injections o f d-amphetamine on foodmotivated discrimination learning in mice. Experiment 1 studied the dose-response effect with immediate posttrial injections. Experiment 2 studied the effects o f d-amphetamine on learning as a function o f the time o f drug administration. The task and training procedures were identical to those used in our previous studies o f the effects o f strychnine and pentylenetetrazol on discrimination learning in mice [15, 20].
Experiment 1: Effects of posttrial injections of d-amphetamine on discrimination learning The present study was designed to explore the range o f doses of d-amphetamine which, when given immediately after each training trial, would significantly facilitate the learning o f a simple brightness discrimination. Method Subjects: The subjects were 42 female Swiss-Webster mice, 50-60 days old at the beginning of the experiment. They were housed three to a cage, and were maintained on a 23-hour food and water deprivation scheduIe involving free access to dry food and water in their home cages for 1 hour each day. The mice were placed on the deprivation schedule for 10 days prior to the beginning of training. At the end of this time the weights of the animals fell to about 75-80% of their original values, and then remained reasonably constant during the experiment. Apparatus: The apparatus was a small visual discrimination Y-maze previously used in several similar experiments [15]. A medium grey starting alley, 25 cm long and 3.75 cm wide, was separated from the 'choice point' of the maze by a manually operated plastic gate. The maze consisted of a choice point, 6.5 cm long, and two alleys, each 22 cm long and 3.75 cm wide. One alley and its side of the choice point was painted black; the other alley and the corresponding side of the choice point was white. Two identical choice-point and alley units were mounted side by side with the colors in reverse order. This assembly could be shifted from side to side across the starting alley, allowing the black or white alley to be positioned on either the right or left. The whole apparatus was covered by a plexiglass lid, lightly sprayed black or white over the appropriate alleys. The floor consisted of metal plates wired to two SM-60 Standard Precision timers. These were automatically activated by a touchsensitive relay system as the mouse moved through the maze in such a way that the time spent in various sections could be recorded. Apart from raising the starting gate, no manual intervention was required. Two measures were taken: a decision time, the time taken to pass from the gate into one arm of the alley; and a running time, the time
38
Jara A. Krivanek and J. L. McGaugh
taken to move from the choice area to the goal section of an alley. An error was recorded when the animal entered about 6 cm into the incorrect alIey.
or better) f r o m all other dose groups. W i t h i n the dosage range f r o m 0.25 to 2.0 m g / k g n o n e o f the g r o u p s was significantly different f r o m any other group. I n s p e c t i o n o f F i g u r e 1 suggests t h a t the 2.0 m g / k g dose is the m o s t effective. I n an a t t e m p t to o b t a i n s o m e e s t i m a t e o f other effects o f the d r u g on p e r f o r m a n c e , the decision times o f the various g r o u p s on d a y 1 a n d d a y 3 o f t r a i n i n g are c o m p a r e d . T h e p e r f o r m a n c e on the three trials o f d a y 1 should reflect the ' n o r m a l ' p e r f o r m a n c e o f these groups, since n o n e h a d yet received the drug. O n d a y 3, all a n i m a l s except the c o n t r o l s h a d received two injections o f the drug. These d a t a are shown in F i g u r e 2. The D u n c a n M u l t i p l e R a n g e test was again used in their analysis.
Procedure (I) Training: All animals were trained to a criterion of 9 correct choices out of 10. Half the animals in each group were rewarded in the white alley, the other half were rewarded in the black alley. The position of the rewarded alley was varied systematically over trials. The reward consisted of access to wet mash for 30 seconds on each trial. The mouse was placed in the starting section and the gate was raised. As the mouse entered the choice point, the gate was lowered behind it to prevent retracing. If a correct choice was made, the animal was allowed to feed for 30 seconds, and was then given a second trial. If an error was made, it was given a second trial immediately. The length of the intertrial interval therefore depended on whether an error was made. Three trials were given each day. Immediately after the third daily trial, the animal was injected and returned to its home cage. The mice were given additional food after all mice had been run. (II) Injection: Following the third daily trial, the mice received 10 yJ/gm intraperitoneal injections of either 0.9% saline or d-amphetamine solution. The doses of d-amphetamine were 0.25, 0.5, 1.0, 1.5, 2.0 and 2.5 mg/kg. All solutions were coded so that the experiment was run 'blind'. Six animals were trained at each dose level. Results The m e a n errors a n d trials to criterion for g r o u p s receiving various doses o f d - a m p h e t a m i n e are p l o t t e d in F i g u r e 1. T h r o u g h o u t this study, all d a t a were a n a l y z e d using the D u n c a n M u l t i p l e R a n g e test [6]. Since the results o f b o t h trials a n d 5O
2O
5O
9 5trials day ;
r751rials ~ day 3
20
j
e~
saline G25
(35
IO
1.5
20
25
O-/~,mphet ~mine (mq/kg)
Figure 2 Mean running times (in seconds) on day 1 and day 3 of mice in Experiment 1.
Standard error
40 o 50
2o i0
sa~ine o.25 o.5 Lo 15 2D Z5 D- Arnphelamine (mg/kg)
saline 0.25 05 1.0 Le ~.0 2.5 D-Amphetamine (mg/kg)
Figure ] Mean trials and errors to criterion (9 out of 10 error trials) for mice given saline or d-amphetamine immediately after daily training trials. Six mice per group. errors were essentially the same, only the analysis o f m e a n errors are r e p o r t e d in detail. T h e g r o u p receiving the highest dose used (2.5 mg/kg) d i d n o t differ significantly f r o m the saline g r o u p ( m e a n difference = 4.63, difference r e q u i r e d for 0.01 level o f significance = 6.16); b o t h these groups, however, differed significantly (P < 0.01
As F i g u r e 2 indicates, there is no significant difference in the first d a y p e r f o r m a n c e o f the various groups. By d a y 3, the speed o f all g r o u p s d e c r e a s e d c o n s i d e r a b l y . This effect, t h o u g h n o t previously r e p o r t e d by us, is one we characteristically observe in this t y p e o f learning task. The t h i r d d a y p e r f o r m a n c e o f the saline g r o u p does n o t differ significantly f r o m those o f the 0.25, 0.5 a n d 1.0 m g / k g g r o u p s (mean differences = 0.62 [0.25 mg/kg], 1.68 [0.5 mg/kg] a n d 1.42 [1.0 m g / k g ] ; difference required for 0.01 level o f significance = 3.9). All these groups, however, differ significantly f r o m t h e 1.5, 2.0 a n d 2.5 m g / k g g r o u p s (P < 0 . 1 ) . I n a d d i t i o n the 1.5 a n d 2.0 mg/ kg groups, t h o u g h n o t differing significantly f r o m each other ( m e a n difference = 0.2; difference r e q u i r e d for 0.01 level o f significance = 4.1), differ significantly f r o m the 2.5 m g / k g g r o u p (P < 0.001).
Amphetamine and Discrimination Learning
39
Experiment 2: Effects of time of drug injection The results of Experiment 1 indicate that a fairly wide range of doses of d-amphetamine will facilitate brightness discrimination learning when given immediately after the training trials. Two +facilitating doses were chosen from the extremes of this range for further investigation: 0.5 and 2.0 mg/kg. Experiment 2 studied the degree of facilitation obtained with these doses when the drug was given at various intervals either before or after the daily training sessions. Method Subjects. The subjects were 36 female Swiss-Webster mice, comparable in age and weight to those used in Experiment 1. Housing and deprivation schedules were those used in Experiment 1. Apparatus and Procedure. The apparatus was that described in Experiment 1, and the general training procedure was identical. Injection. The mice were divided into two groups of 18 animals each. One of these received daily intraperitoneal injections of 10 /~l/gm body weight of d-amphetamine; the other received 2.0 mg/kg injections. Each of these groups was further divided into 3 subgroups of six animals. These received the appropriate dose of damphetamine 30 minutes pretrial, 15 minutes pretrial, and 15 minutes posttrial respectively. The intervals between injection and training were kept as constant as possible throughout the experiment. Results The mean errors and trims to criterion for the various dose and injection time groups are shown in Figure 3. The data for the groups receiving immediate posttrial injections of saline, 0.5 and 2.0 mg/kg d-amphetamine in Experiment 1 are also included in this figure. The Duncan [ ] saline [ ] 0.Smg/kg
5O
Multiple Range test was used in the analysis, and the data for the saline, 0.5 and 2.0 mg/kg groups from Experiment 1 were included for comparative purposes. Again, since the results based on mean errors and trims to criterion were virtually identical, only the mean errors are discussed in detail. As may be seen from Figure 3, mice given pretrial injections of either dose made significantly fewer errors than did the saline controls (P < 0.001). The two doses are equally effective at either pretrial injection time (mean differences from the 2.0 mg/kg, 15 minutes pretrial group = 1.34 [0.5 and 2.0 mg/kg, 30 minutes pretrial] and 2.34 [0.5 mg/kg, 15 minutes pretrial]; difference required for 0.01 level of significance = 5.14). The findings shown in Figure 3 suggest that the 0.5 mg/kg dose in particular may be more effective when given pretrial than immediately posttrial. This effect, however, is not statistically significant (mean differences from the 0.5 mg/kg, 30 minutes pretrial group = 1.0 [0.5 mg/kg, 15 minutes pretrial] and 4.16 [0.5 immediately posttrial]; difference required for 0.01 level of significance = 5.40). Groups given either dose 15 minutes after training did not differ significantly from the saline controls (mean differences from the 2.0, 15 minutes posttrial group -- 0.34 [0.5, 15 minutes posttrial] and 5.13 [saline, immediately posttrial]; difference required for 0.01 level of significance = 6.09). Again, mean decision times for the various groups on days 1 and 3 of training were compared in an attempt to estimate the effect of the drug on performance. These data, together with those for the saline, 0.5 and 2.0 mg/kg groups from Experiment 1, are shown in Figure 4. It should
9 2.0mg/kg ~ Standard error 2 0
30
l=+trio,+,~o+, ~+3+i+i I
g 0~ 3=
40
b
b
o
o
o
20
50
w 20 I0
~Onm
~min
bnmed 15rain
p~tl-trio] pre-triolpo~-tdal pc~t*ttkll Time of injection
~Ofl~n 1,5~11
Lmrl~d 15min
pre-tfiot pre-~l po'~-tt~olpo~l-trial Time of injection
Figure 3 Mean trials and errors to criterion (9 out of 10 errorless trials) for mice given either saline or d-amphetamine before or after daily training trials at the times indicated. Six mice per group.
05 2.0 50min pre-trial
] 0.5 2.0 15min pre-trial
i saline 05 20 I imrnediole post-trial
i 0.5 2.0 15rain post-trial
Dose (rng/kg) and time of injection
Figure 4 Mean running times (in seconds) on day 1 and day 3 of mice in Experiment 2.
40 be noted that on day 1 the pretrial injection groups were trained while under the influence of the drug; also, on day 3 these had received three injections of d-amphetamine, while all other groups had only two. Several points emerge from Figure 4. First, d-amphetamine in either of the two doses and pretrial injection times studied does not affect running times on the first day. The performance of these groups on day 1 does not differ significantly from the day 1 performance of non-drugged groups. Third day performance, however, is significantly affected. The animals given pretrial d-amphetamine do n o t show the decrease in speed characteristic of animals not under the immediate influence of the drug. The third day running times of the pretrial injection groups do not differ from those of day 1, but do differ significantly from those of the saline group on day 3 (P < 0.01). Further, the 15-minute delay in injection produces effects essentially identical to those observed with immediate posttrial injections: the 0.5mg/kg, 15-minute posttrial group shows a third day performance comparable to that of the 0.5, immediate posttrial group; neither of these differ significantly from third day saline group performance (mean difference = 4.43; difference required for 0.01 level of significance = 8.60). Both groups, however, differ significantly from the third day saline group performance (P < 0.01).
Jara A. Krivanek and J. L. McGaugh
tration. Significant facilitation was found with injection given either 30 or 15 minutes pretrial (and as the results of Experiment 1 showed, immediately posttrial) but not with injections given 15 minutes posttrial. Thus, the posttrial retrograde facilitation gradient is steeper than that obtained with 'optimal' doses of strychnine and pentylenetetrazol in experiments using the same task and procedures. With pentylenetetrazol facilitation was obtained with injections given 15 minutes (but not 30 minutes) posttrial [15]. With strychnine, facilitation was obtained with injections given 1 hour (but not 2 hours) posttrial [20]. These results are, however, somewhat consistent with those of the younger animals in the study of DoTY and D}3TYwhere it was found that for all tasks studied the retrograde facilitation gradient was steeper for young animals than for older animals. All of the animals in the present study were young (50-60 days old). These findings provide further support for the hypotheses that drugs can influence drugs by acting on time-dependent processes involved in memory storage. A potential problem is the fact that d-amphetamine is rather stable and is excreted slowly, the process requiring as much as 48 hours [12]. It is possible, therefore, that a dose injected after training on one day may remain in the animal long enough to exert 'pretrial' performance effects on the following day. The present experiment, however, suggests that such an effect is unlikely: were this the case, greater facilitation would be predicted with the delayed postDiscussion These findings provide further evidence that trial injections than with those given immediately learning is facilitated by d-amphetamine. Al- posttrial. Moreover, metabolic studies of brain though facilitation was obtained with a wide tissue (as opposed to whole body assays) show range of doses (0.25-2.0 mg/kg) the optimal dose that following i.p. administration of amphetafor the mice and task used was 2.0 mg/kg. No mine levels in the brain increase sharply with facilitation was obtained with the highest dose 30 minutes and decrease to preinjection levels (2.5 mg/kg). These results are consistent with within 3-5 hours [9]. Thus, the amount of unthose of earlier studies which used rats. KELEMEN metabolized or unexcreted amphetamine remainand BOVET [11] found facilitating effects of am- ing in the brain 24 hours following i.p. injections phetamine on learning with doses as low as would not appear to be sufficient to produce the 0.30 mg/kg and DOTYand DOTY [5] found facilita- observed behavioral effects. The evidence that amphetamine levels in the tion with 2.0 mg/kg. The findings also provide additional support for the interpretation that the brain remain high for over 1 hour following i.p. effects of amphetamine on learning cannot be injections is consistent with our behavioral explained simply on the basis of the drug's effects evidence that highly significant facilitation of on the activity level. In Experiment 1, the injec- learning is obtained with injections given 30 mintions were administered immediately after train- utes prior to training. In all probability, the effects of the pretrial injections reflect a posttrial action ing. Further, the findings of Experiment 2 in- of the drug on the central processes underlying dicate that for both doses used (0.5 and 2.0 mg/kg) learning. However, the design of the present exthe drug effect depends upon the time of adminis- periment does not eliminate the possibility of an
Amphetamine and Discrimination Learning
indirect effect on learning resulting from the peripheral actions of the drug. The locomotor activation produced by d-amphetamine is well known, and has been clearly demonstrated in this study by the effects of pretrial injections on run" ning speed. In the learning task used in these experiments, this might be expected to facilitate acquisition simply by exposing the animal more quickly to the various relevant features of the situation. Further, there is some evidence that [22] the anti-depressant effects of this drug are due to activation of the ascending reticular formation. Such an action might be expected to lower the thresholds for peripheral stimulation, and thus tend to facilitate learning. In addition, T~ITELBAUMand DERKS [29] report that d-amphetamine produces a narrowing of the attentional focus: the subjects' ability to use peripheral cues decreased, but they were more responsive to the central aspects of the situation. In sum, the facilitative effects observed in the present study with pretrial injections of d-amphetamine may equally be due to actions on posttrial consolidation processes, or to increased motility and increased attentiveness to a narrow range of sensory stimuli. A decision cannot be made on the basis of this study - further research is needed to determine the relative contribution of these factors to the observed effects. It might be that the posttrial injections facilitate learning by acting in some way to enhance the rewarding effects of food. STEIN [28] has proposed, for example, that amphetamine acts on brain structures involved in reward through reducing reward thresholds; evidence from studies using an avoidance response support this hypothesis. If this explanation were to apply to the present results, it would be expected that amphetamine given posttrial would increase running speeds on subsequent trials. The results of ~Experiment 2 clearly do not support this interpretation. As Figure 2 shows, high doses (1.5 to 2.5 mg/kg) result in highly significant decreases in performance. Since lower doses (0.25 - - 1.0 mg/kg) affect performance no more than do injections of saline, this effect is evidently something more than a simple "injection effect'. Apparently, the positive effects of the food reward are considerably attenuated by the drug. It is clear from Figure 4 that in the case of high doses, such an effect can still affect performance when the drug is given 15 minutes after the food reward. Received 25 June 1969.
41 References [1] D. BovEr and L. GATTI,Pharmacology of lnstrumental Avoidance Conditioning, in Pharmacology of Conditioning, Learning and Retention (M. Y. Michelson and V.G. Longo; Permagon, New York 1965), 75-89. [2] D. BOVET,J. L. MCGAtI~a and A. OLIV~RIO,Effects of Posttrial Administration of Drugs on Avoidance Learning, Life Sci. 5, 1309-1315 (1966). [3] D. BOVETand A. OLIVERrO,Decrement of Avoidance Conditioning Performance in lnbred Mice Subjected to Prolonged Se~Csion; Performance Recovery After Rest and Amphetamine, J. Psychol. 65, 45-55 (1967). [4] P.B. DEWS, Measurement of the lnfluence of Drugs on Voluntary Activity in Mice, Br. J. Pharmac. 8, 46--48 (1953). [5] B.A. DOTY and L.A. DorY, Facilitating Effects of Amphetamine on Avoidance Conditioning in Relation to Age and Problem Difficulty, Psychopharmacology 9, 234-241 (1966). [6] A.L. EDWARDS, Experimental Designs in Psychological Research (Rinehart, New York 1960). [7] J.L. FRANC~NA and M.H. MOORE, Strychnine and the Inhibition of Previous Pelformance, Science 160, 903-904 (1968). [8] M. GARGandH.C.HOLLAND, ConsolidationandMaze Learning: The Effects of Posttrial Injections of a Stimulant Drug (Picrotoxin) , Psychopharmacologia 12, 96-103 (1968). [9] S. GARATrINr, Importance of a Knowledge of Drug Metabolism for the Assessment of Drug Interactions, in Importance of Fundamental Principles in Drug Evaluation (D. H. Tedeschi and R. E. Tedeschi; Raven, New York 1968), p. 129-139. [lO] E. HEARSTand R.E. WaALEN, Facilitating Effects of d-Amphetamine on Discriminated Avoidance Performance, J. Comp. Physiol. Psychol. 56, 124-128 (1963). [111 K. KELEMENand D. BOVET,Effect of Drugs Upon the Defensive Behavior of Rats, Acta Physiol. Acad. Sci. Hung. 19, 143-154 (1961). [12] J.C. KRANTZ and C.J. CARR, Pharniacologic Principles of Medical Practice, 6th ed. (Williams and Wilkins 1965). [131 E.E. KRIECKHAUS,N.E. MILLERand P. ZIMMERMAN, Reduction of Freezing Behavior and Improvement of Shock Avoidance by d-Amphetamine, J. Comp. Physiol. Psychol. 60, 36-40 (1965). [14] J.A. KRIVANErZand E.B. HuNt, The Effects of Posttrial Injections of Pentylenetetrazol, Strychnine, and Mephenesin on Discrimination Learning, Psychopharmacologia 10, 189-195 (1967). [i5l J. KRIVANEKand J.L. McGAuG~I, Effects of PentyIenetetrazol on Memory Storage in Mice, Psychopharmacologia 12, 303-321 (1968). [16] A.S. KULKARNt, Facilitation of Instrumental Avoidanee Learning by Amphetamine: An Analysis, Psychopharmacologia 13, 418-425 (1968). [17] J. L. McGAUGH, Time-DependentProcesses in Memory Storage, Science 153, 1351-1358 (1966).
42
Jara A. Krivanek and J. L. McGaugh
[18] J.L. McGAUGI% Drug Facilitation of Memory and Learning, in Psychopharmacology : A Review of Progress (D. Efron et al.; U.S. Government Printing Ofrice, Washington D. C. 1968a), PHS Publ. No. 1836 p. 891-904: [19] J.L. McGAUGH, A Multi-Trace View of Memory Storage Processes, in Recent Advances on Learning and Retention (D. Bovet, F. Bovet-Nitti and A. Oliverio; Roma Accademia Nazionale dei Lincei, Quaderno N. 109 Anno CCCLXV, 1968b), p. 13-24. [20] J.L. McGAUGH and J. KRIVANEK,Strychnine Effects on Discrimination in Mice: Effects of Dose and Time of Administration, in preparation. [21] J.L. MCGAUGH and L. PETRINOVICrI,Effects of Drugs on Learning and Memory, Int. Rev. Neurobiol. 8, 139-196 (1965). [22] J. MoRuzzi and H.W. MAaOUN, The Brain Stem Reticular Formation and Activation of the EEG, Electroencephalog. Clin. NeurophysioL 1 (1949). [23] A. OLIVERIO, Effects of Nicotine and Strychnine on Transfer of Avoidance Learning in the Mouse, Life Sci. 7, 1163-1167 (1968a). [24] A. OLIVERIO, Inhibitory and Facilitating Factors in Learning, in Recent Advances on Learning and Retention (D. Borer, F. Bovet-Nitti and A. Oliverio; Roma Ac-
cademia Nazionale dei Lincei, Quaderno N. 109 Anno CCCLXV, 1968b), p. 220-230. [25] A. OLIVERIO,Neurohumoral Systems and Learning, in Psychopharrnacology: A Review of Progress (D. H. Efron; U.S. Government Printing Office, Washington D.C. 1968c), PHS Publ. No. 1836, p. 867-878. [261 W. PARE, The Effect of Caffeine and Seconal on a VisualDiscrimination Task, J. Comp. Physiol. Psychol. 54, 506-509 (1961). [27] R.H. RECH, Amphetamine Effects on Poor Performance of Rats in a Shuttle Box, Psychopharmacologia 9, 110-117 (1966). [28] L. STEIN, Chemistry of Reward and Punishment, in Ps'ychopharmacology: A Review of Progress (D. H. ' Efron, U.S. Government Printing Office, Washington D.C. 1968), PHS Publ. No. 1836, p. 105-123. [29] P. TEITELBAUMand P. DERKS, The Effect of Amphetamine on Forced Drinking in the Rat, J. Comp. Physiol. Psychol. 51, 801-810 (1958). [30] A. WEISSMAN, Drugs and Retrograde Amnesia, Int. Rev. Neurobiol. 10, 167-198 (1967). [31] D.J. ZERBOLIO, Within-Strain Facilitation and Disruption of Avoidance Learning by Picrotoxin, Psychon. Sci. 9, 411-412 (1967).
