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Brain Research BuNefin Vol. 23, pp. 339-345. 0 Pergamon Press pk. 1989. Printed in the U.S.A 0361-9230189 3.00 + .oO

MEETING REPORT

Dissociating Learning and Performance:Drug and Hormone Enhancement

of Memory Storage

J AMES L. McGAUGH

Center for t he Neurobiol ogy of Learning and M emoryand Department of Psychobiol ogy Uni versity of Calif ornia Ir vi ne CA 92717

McGAUGH, J. L. Di ssociat ing learning andperform ance: Dr ug and hormone enhancement of memory torage. BRAIN RES BULL23(4/5) 339-345, 1989.-This paper reviews selected studies examining the enhancing effects of drugs and hormones on learning andmemory. Many strategies have been used in an effort to dissociate drug effects on learning from drug effects on other processesaffecting the performance of responses. These strategies include the use of tasks with various motivational and response requirements,the use of studies explicitly examining drug influences on performance, the use of posttraining drug administrat ion and the use ofvarious forms of latent learning tasks. I t seems clear from these studies that the dissociation of learning and performance effects ofdrugs cannot rest on one task or one experiment. Overall, the evidence summarized in this paper provides strong support for theconclusion that drugs can and do enhance retention and that the effects are due to influences on memory storage rather than to other

factors that influence performance.

Adrenergic antagonists CNS stimulants Drugs GABA antagonists Hormones Latent learningLatent extinction Latent inhibition Learning Memory Posttraining treatments Opiate antagonistsPerformance State-dependency

IS it possible to improve learning and memory with drugs? Thisquestion is the focus of much current research investigating theeffects, on learning and memory, of treatments affecting neuro-chemical systems. Much of the research stems from an interest,either explicit or implicit, in finding treatments for disorders oflearning and memory-particularly those associated with aging.Research addressing this question is also guided by a more general

interest in understanding the neurochemical systems involved inlearning and memory. Regardless of the basis of the interest, allstudies of drug influences on learning and memory face thedifficult task of determining how drugs act to improve perfor-mance on tasks that are used to measure learning and memory.

The distinction between learning and performance originallyoffered by Tolman (54) is accepted by most investigators asessential for understanding cognitive processes. Learning andmemory are inferred from experience-induced changes in behav-ior. The problem faced by the investigator is that of determiningthat the changes in performance are due to learning and memoryrather than to other influences. As performance is influenced bymany conditions, including arousal, sensitization, fatigue, illness,and so forth, distinguishing changes resulting from the acquisitionof information from those due to other influences is not a simpletask for any study of learning and memory. The difficulty ofdistinguishing between learning and performance becomes more

difficult in studies examining the effects of treatments that alterneurobiological systems. If a drug, for example, alters perfor-mance on a learning or memory task, it is, at the very least, riskyto conclude that the drug affects performance because it alters theneurobiological systems underlying learning and memory. In suchstudies controls are obviously needed to rule out the contributionof other influences of the drug that might affect performance on

the task.The problem of determining the basis or bases of drug

enhancement of performance on a learning task is illustrated by thefirst (to my knowledge) study reporting drug enhancement oflearning (31). In this study, Lashley injected rats with strychninesulphate each day before they were trained on a maze and foundthat they made fewer errors than control rats, as they acquired thetask. If one is only interested in concluding that acquisitionperformance can be improved on a cognitive task, then perhapsLashleys findings constitute acceptable evidence. But, the find-ings are clearly incomplete if one is, as most investigators are,interested in knowing the basis of the improvement. Manyadditional questions need to be asked. Does the drug alter sensory,motivational or motor processes in ways that would produceimproved maze performance? For example, the drug might in-crease hunger or alter taste (the rats were rewarded with food). Thedrug might also increase alertness or alter motor performance (44,

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53). If drugs are administered prior to training. controls are neededfor each of these possible influences on maze performance if oneis to be comfortable (as well as correct) concluding that the drugimproves performance by enhancing neural processes underlyinglearning.

CAN DRI G EFF ECTS ON LE ARNING AND MEMORY BE DISSOCIATED?

The questions raised by Lashleys study were addressed bymany subsequent studies of the effects of strychnine on learning(35.45). I will briefly review some of the major findings of theseearly experiments as the issues addressed by these studies, as wellas the experimental approaches used. remain relevant for currentstudies of drug influences on learning and memory.

Task Generali~

One approach to the problem of determining the basis of drugeffects on performance in learning tasks is that of examining theeffects of the drug in tasks that differ in motivational and responserequirements. If it is proposed, for example, that the performance

enhancement is due specifically to an increase in hunger or to areduction in locomotor activity then the drug would not beexpected to enhance performance learning tasks using shockmotivation or tasks in which learning requires increases in loco-motor activity. Thus, an examination of task generality of theeffect is essential for studies of drug influences on learning. Thefindings of studies examining the effects of strychnine adminis-tered prior to training indicate that strychnine enhances learningperformance n a wide variety of tasks including maze learning(43), aversively (46) as well as appetitively motivated (41,51)discrimination learning (both successive and simultaneous dis-crimination), as well as escape learning (29) and habituation (1).Such findings are consistent with the interpretation that strychnineimproves performance by enhancing learning. Or, more conser-

vatively. the findings argue against many. but perhaps not allalternative interpretations stressing specific motivational or per-formance effects. The problem facing the experimenter is thatlearning and memory are defined by exclusion. And it is difficult.at best, to determine whether all possible, or even reasonable.alternative interpretations have been excluded.

Drug hfluences on Performance

Another approach to the problem is that of examining the effectof drug and control injections on performance of the task duringand after acquisition. For example, after rats have learned a mazewhile under the influence of strychnine do they still perform wellwhen tested without the drug? And, is the performance of trainedcontrol animals influenced by administering the drug prior to being

tested n the maze? In his original study Lashley (3 1) reported thatwhen strychnine and a control solution were administered totrained rats on alternate days, maze performance was better ondays when the animals received strychnine. However, consideredalone, the finding that strychnine enhanced performance does notallow the conclusion that strychnine acts only through effects onperformance. Strychnine might affect both learning and perfor-mance. The critical question is whether the difference between theperformance of drug and control animals during training is dueentirely to drug influences on performance. That question could,of course, be addressed. Studies addressing the question wouldneed to include controls for state-dependency as differences inperformance might result simply from changes in drug state duringtraining and testing.

Latent Learning

The distinction between learning and performance was first

addressed experimentally in the well-known latent learningstudies conducted by Tolman and his students (55,55). In thesestudies. errors on a maze were significantly reduced when areward was introduced into the goal box following several nonre-warded trials. Clearly the animals were acquiring information

during the earlier trials. But the learning was latent until thereward was introduced. Latent learning tasks provide a powerfulmeans of distinguishing the effects of drugs on learning from theireffects on performance. As is discussed below, several varieties oflatent learning tasks have, in fact, been used. And, in each case,they have provided evidence that drugs can influence the storageof information independently of their direct effects on perfor-mance. For example, in one study (56) rats were injected with astrychnine-like drug each day for several days immediately aftereither a rewarded or nonrewarded training trial in a maze (seebelow for a discussion of the rationale underlying the use ofposttraining injections). The drug enhanced the learning of re-warded groups. However. the drug did not affect the performanceof the nonrewarded groups. Then, for several additional trials, thedrug injections were discontinued and all animals were rewarded.On these trials the errors of both groups that had received the drugimmediately after each of the earlier trials were lower than those ofboth control groups. Thus, the drug enhanced the latent learningthat occurred on the early nonrewarded trials. But. the fact that thedrug did not improve performance when administered after non-rewarded trials indicates that the drug injections were not reward-ing. These findings clearly argue that this drug improves ieamingby enhancing the storage of information. Of course. this drugmight also influence performance when administered prior totesting. But, by using latent learning procedures the effects onlearning and performance can be experimentally distinguished.

Posttraining Administrution

The experiment discussed above combined two techniques thatare used to distinguish learning and performance in studies of drugeffects on learning: latent learning and posttraining drug adminis-tration. The use of posttraining administration in studies of drugenhancement of learning and memory is based on the generalassumption that the processes underlying the storage of informa-tion are initiated by training and continue for some periodfollowing the completion of a training experience (39.50). Thus,according to this assumption it should be possible to modulatememory storage by administering treatments shortly after training.Further, treatments administered several hours following trainingshould be ineffective even though they are closer in time to thesubsequent retention test. The first studies examining the effects ofposttraining injections on memory used strychnine and other

central nervous system stimulants (2. 3. 47, 48). There isextensive evidence indicating that such treatments enhance mem-ory in a time-dependent manner-that is, delayed injections areineffective (41). Furthermore, posttraining injections of suchtreatments have been found to enhance retention of a wide varietyof training tasks (36, 39, 45).

The findings of studies using posttraining injections providestrong evidence that drugs can affect memory without directlyaffecting performance during acquisition and retention testing.Drug effects on performance are excluded as possible contribu-tions to the enhanced retention. The use of posttraining injectionstogether with latent learning tasks has provided the clearestevidence that drugs can enhance the storage of information(22.56). The central feature of a latent learning task is that a firstphase of training provides an opportunity for learning without theinfluence of reinforcement on performance followed by a test todetermine the degree of learning. In a sensory preconditioning

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task, for example, two stimuli (e.g., a light and sound) arepresented together on several trials. Then, one of the stimuli (e.g.,the tone) is paired with a reinforcing stimulus (e.g., a shock) usingclassical conditioning procedures. Finally, the other stimulus(e.g., the light) is presented to see if it will elicit the conditioned

response. Using such procedures, Humphrey (22) found thatstrychnine administered immediately after the initial pairing of thetwo stimuli enhanced the association (sensory preconditioning)between the two stimuli as indicated by the effectiveness of thelight in eliciting the conditioned response on the final test. Thesefindings are highly comparable to those obtained in the latentlearning maze study summarized above. Clearly, drug enhance-ment of memory does not require the presence of the drug duringeither training or retention testing.

The use of posttraining drug administration does not, however,eliminate all possible nonassociative effects of drugs on retentionperformance. As I noted above, it is possible that a drug mighthave rewarding or punishing effects independently of its effects oninformation storage. The findings of the latent learning studydiscussed above clearly indicated that the drug enhanced learningbut was not rewarding. But, the issue must be addressed with eachdrug examined. Thus, studies using posttraining injections typi-cally include nomeinforced controls to assess possible rewardingand punishing effects. It has also been suggested that posttraininginjections may affect performance by altering perceptual statesfollowing training (6). Furthermore, it has been argued thatrecently acquired information may be stored in a brain stateinduced by the posttraining injection (28). These issues arediscussed further below.

INVOLVE MENT OF NEUROMODULATORY SYSTEMS IN MEMORY

STORAGE

The early experiments examining the effects of strychnine andother CNS stimulants on learning provided essential evidencearguing that it is possible to distinguish between learning andperformance effects of drugs. Studies using different tasks, post-training injections, and various forms of latent learning haveprovided rather convincing evidence in support of the conclusionthat drugs can enhance memory storage. More importantly,however, the findings of these early experiments encouraged theuse of drugs and other posttraining treatments in the investigationof the involvement of neuromodulatory systems in memorystorage. There is now extensive evidence indicating that retentioncan be enhanced by drugs affecting a number of neurochemicalsystems, including catecholaminergic, opioid peptidergic, cholin-ergic and GABAergic systems (38). The general assumptionmotivating this research is that drugs can be used to understand theinvolvement of these systems in learning and memory. Thus, inthis research dissociation of learning and performance effects isabsolutely critical to the interpretation of the findings.

Involvement of GABAergic Systems

An early study from my laboratory (3) was the first to suggestthe possible involvement of the GABAergic system in memory. Inthat study we found that posttraining injections of the GABAergicantagonist picrotoxin enhanced rats maze learning. This basicfinding was confirmed and extended by findings from otherlaboratories (4, 10, 13, 18, 36, 57) as well as by more recentfindings from my laboratory. Briefly, the findings of studies of theeffects of GABAergic antagonists indicate that: 1) time-dependentmemory enhancement is produced by posttraining injections (12);2) enhancement is obtained in several types of tasks (24); 3) thememory-enhancing effects are not due to rewarding or punishingeffects (4); 4) the posttraining memory-enhancing effects are seen

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Picrotoxin mglkg)

PIG. 1. Dose-dependent and time-dependent effects of p&training injec-tions of picrotoxin (II) on retention, by mice, of a one-trial inhibitoryavoidance task. Each bar indicates median response latency ( 2 interquartilerange) on the retention test trial. From (12).

in a type of latent learning task as well as in conventional learningtasks (unpublished findings); and 5) the effects are not due toinduction of posttraining state-dependency (12). Thus, by exclu-sion, the findings provide strong support for the view thatGABAergic antagonists enhance memory storage. As a peripher-ally acting GABAergic antagonist is ineffective (4), while directinjections into a region of the brain (amygdaloid complex) areeffective (5) the findings also argue that the drugs enhancememory by directly modulating brain systems.

Figure 1 shows the findings of a study, using mice, of theeffects of posttraining injections of picrotoxin on retention of aone-trial inhibitory avoidance task. The effects are both dosedependent and time dependent. And posttraining injections do notaffect the retention performance of animals unless they receivedfootshock on the training trial (12). Similar results have beenobtained with the GABAergic antagonist bicuculline (4). And,while it is not the focus of this paper, retention is impaired byposttraining administration of the GABAergic agonists baclofenand muscimol (9,lO). Figure 2 shows the effects of posttraininginjections of bicuculline on retention of a Y-maze discriminationtask (4). In this task mice were trained on several trials to escapefrom footshock by entering one arm of the Y-maze. On theretention test the position of the safe arm was reversed andretention was assessed by the number of errors made on 8 reversaltraining trials. The experiment was based on other evidence

indicating that errors on the discrimination reversal test increaseddirectly with the amount of original training. Thus, if posttrainingadministration enhances learning of the discrimination, the effectsshould be comparable to those produced by additional training.Clearly, the posttraining injections produced dose-dependent en-hancement of retention of the original training, as indicated byerrors on the retention test. With this task, as well as with theinhibitory avoidance task, retention was not affected by posttrain-ing intraperitoneal injections of bicuculline methiodide, a GABAer-gic antagonist that does not pass the blood-brain barrier (4).

Izquierdo (27,28) has reported evidence suggesting that theinformation acquired on training may be stored in the brain stateinduced by the posttraining treatment. Under some conditions, theretrograde amnesia induced by posttraining treatments can beattenuated by administration of the same treatments prior to theretention test (27,28). While state-dependency is not seen with allposttraining treatments that produce amnesia (11,42) the finding of

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ElCUCULLlNEY MAZE

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FIG. 2. Effects of posttraining injections of bicuculline (IP) on retention,by mice, of the Y-maze ~sc~~nation task. Each bar indicates the medianerrors ( A interquartile range) on the disc~mination reversat retention test.*p

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DRUG EFFECTS ON PERFORMANCE AND MEMORY

antagonists into the amygdaloid complex (5). These latter findingsare consistent with evidence from other recent experiments sum-marized below suggesting that neuromodulatory systems withinthe amygdaloid complex are involved in the regulation of memorystorage.

Involvement of Adrenergic Systems

The evidence of time-dependency in memory storage hassuggested that memory storage may normally be regulated byendogenous systems activated by learning experiences (19.30).Extensive evidence suggests that hormones released in response tostimulation and stress modulate memory storage. Experimentsexamining the effects of hormones on learning and memory haveexamined a number of hormones, including epinephrine, ACTH,vasopressin, opioid peptides, CCK, substance P as well as otherpeptide hormones (37,38). Most of the work in my laboratory hasfocussed on adrenergic and opioid peptide systems. In this sectionand the following section I will briefly review some of the recent

findings concerning the involvement of these systems in learningand memory.Gold and van Buskirks report (20) that posttraining injections

of epinephrine produced dose-dependent and time-dependent en-hancement of memory in an inhibitory avoidance task stimulatedextensive research examining the involvement of adrenergic sys-tems in memory (37). Such a quest assumes, of course, that theeffects of epinephrine seen in such studies are due to influences onlearning rather than to other nonassociative processes that affectretention performance. In general, the findings of studies that haveaddressed this issue have provided strong evidence that epineph-rine influences memory storage. The findings indicate that: 1)posttraining injections of epinephrine produce dose-dependent andtime-dependent enhancement of retention (20); 2) retention en-hancement is seen in a variety of aversively motivated trainingtasks, including inhibitory avoidance, active avoidance, discrim-ination learning, as well as appetitively motivated tasks (20, 21,24, 32, 52); 3) epinephrine injections alone are neither rewardingor punishing (34); 4) the memory-enhancing effects are long-lasting (24).

The long-lasting effects of a single posttraining injection ofepinephrine are shown in Fig. 5. Mice in this study (24) weretrained on the Y-maze discrimination task described above andinjected immediately following training with either saline or a lowdose or high dose of epinephrine. Independent groups were thentested for retention, using performance on discrimination reversalas the index of retention, one day, one week, or one month later.Comparable results were obtained at all retention intervals: Thelow dose of epinephrine enhanced learning while the high dose

impaired retention. The findings obtained on the one day and oneweek tests are highly comparable to those obtained with othertypes of training tasks. This is the only experiment, to date, whichhas examined the retention-modulating effects of epinephrine at aretention interval of greater than one week. The finding ofcomparable effects at all retention intervals provides additionalsupport for the view that epinephrine affects retention performanceby strengthening processes underlying the long-term storage ofinformation.

As I indicated earlier, studies of the effects of epinephrine onlearning are guided by an interest in understanding how thisadrenal medullary hormone acts to influence memory storage.While this issue is not the focus of the present discussion, somerecent findings are relevant to the issues raised here, The effects ofperipherally administered epinephrine are blocked by intra-amygdalainjections of the adrenergic antagonist propranolol. Further, reten-tion of an inhibitory avoidance task is enhanced by intra-amygdala

24 HR

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Legend0 SALINErZa EP I 0.3 mg/kg

iZZ EPI 1.0 mg/kg

RETENTION INTERVAL

FIG 5 Effects of posttraining epinepbrine (IP) on retention, in mice, ofthe Y-maze discrimination task one day, one week, and one monthfollowing original training. Each bar indicates mean errors ( 2 SEM) on thediscrimination reversal retention test. From (24).

injections of norepinephrine in a dose-dependent and time-depen-dent manner (33). These findings, considered together with otherfindings suggest that epinephrine effects on memory involve therelease of central norepinephrine (25, 33,40). More generally, thefindings are consistent with evidence that GABAergic influenceson memory, as discussed above, as well as opioid peptidergicinfluences, as discussed below, involve activation of systemswithin the amygdaloid complex.

Involvement of Opioid Peptidergic Systems

Studies of the memory-modulating effects of posttraininginjections of opioid peptide agonists and antagonists have providedadditional evidence that memory storage is regulated by endoge-nous neuromodulatory systems (7, 8, 14, 26, 49). In general,posttraining administration of opioid agonists such as morphineand P-endorphin impair retention while opioid antagonists such asnaloxone and naltrexone enhance memory. The effects of opiateantagonists are generally comparable to those seen with strych-nine, picrotoxin and epinephrine: 1) the memory-enhancing effects

of posttraining injections are dose dependent and time dependent(23); 2) Evidence of retention enhancement with posttrainingtreatments has been obtained with a wide variety of tasks,including inhibitory avoidance, active avoidance, discriminationlearning, habituation and spatial learning (17, 26, 40); 3) In dosesthat enhance retention, opiate antagonists are neither rewardingnor punishing when administered alone (23); 4) Retention en-hancement is obtained with a form of latent learning as well asexplicit learning tasks. This latter effect was shown in a study byGallagher and her colleagues (14) using a latent inhibition proce-dure. The term latent inhibition refers to the decreased effective-ness of a stimulus in conditioning if the stimulus has previouslybeen presented without the unconditioned stimulus. That is, theprevious learning that the stimulus lacks significance lessens itseffectiveness as a CS. In the Gallagher et al. study naloxone orsaline was administered to rabbits immediately following thepreexposure of a tone which was later to be used as a CS in a

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