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Learning and memory facilitators: experimental definition and current status
TIPS -June i 981
i 58
Reading list I Simon. E. J. and Hiller. J, t~r|.(1')78) Ann. Rev. Pharmacol. 18. 371-394
2 Bcaumom. A. and |tughcs, J. I ItJ79)Aan. Rev. PharmacoL 19.245-267 3 Martin, W. R., Eade,,. C. G., "rhomp~m. J. A.. Happier. R. E. and Gilbert. P. E. (1976)J. P/:arretacol. b+~p. Ther. 197, 517-532 4 Gilhcn. P. F.. and Marlin. W. R. 11976)J. Pharmacol. b+~p. Ther. 198 66-82 5 I_ord, J. A. 14., WateffHzld. A. A.. Hughes, J. and Koqcditz. 11 W. {1977) Nature (l,ondon) 267. 495-499 6 Smith. J. R. and Simon. E, .I. (1980) Proc. Nati Acad. Sci. U.S.A. 77, 281-284 7 Rob,am. L. E. :rod Koslerlitz. H. W. (1979) Proc. R. .%n'. l.ond. B. 205.425-432 g Simon E. J. BonneL A. Crain. S. M., Grolh. J., tlillcr. J M and :;mith. J. R. (19811) in Neural Peptide.~ and N'curoaal Communication (4~'osta. E. and Trabucchi. M.. eds). pp. 335-340. Raxen l'h'e~.,,.Ne~ York 9 ('hang. K. L. C(mper. B. R.. Hazurn. E. and ('uatreca,,as. P. (197'4) .~fol. PharmacoL 16. 91-lit4 I O Itiller. J M. and Simon, E. J. ( I tJg(|)J. Pharmat ol. Exp. Th+:r. 214. 51¢r+-~19 I I Herkenham. M. and Pert. C. B. (1980) Proc. +Nat/ +4cad.+%'i.U.S.A. 77. 5532-5536 12 I.in. H. KJ and Sirmm. E. J. (1978) ,%uure (london) 271.3g.L-394 13 Pastemak. G. W. (19~P) Pr~n'. Nati Acad. Sci. U.S.A. 77. 3691-3894 14 Simon. E. J.. ltiller. J. M. and Edelman. I. (1975) %'iencc I taL 389-39(I 15 Zukin. R. S. and Kream. R. M. (1979) Proc. Nati A=ad. Sci. U.S.,4. 76. 15tLa.- 1597 16 Rucgg. U. T., Hiller. ~1.M. and Simon, E. J. (19t(0) Ear. J, Pharmaod. 64. 367-368 17 Simonds. W. F. Ko',ki. G.. Streaty. R. A.. Hielmeland. L. M. and Kle,e, W. A. (1980) Proc. N'atl Aq'ad. Sct. ILXA, 77.462.L-4627 i 8 Bidlack. J. M, and Ah~'gl. L. G. (1980) Life Sci. 27.331-340
Learning and memory facilitators: experimental definition and current status GeorgeA. Heise Departmento1;Psyehology
Indiana Universety, Bloomington, IN 47401, U.S.A.
Learning facilitators, memory enhancers, intelligence boosters: are such compounds just around the corner? A major drug company informs stockholders that its "cognition activator" slated for clinical trials in 1980 is more efficacious than piracetam, the best-selling current agent. A recent popular article on 'mind food' proclaims that 'more than a dozen' different chemicals will promote learning or data processing abilities in animals and men. Viewed from the no-nonsense orientation of laboratory experiments, does the available evidence justify this enthusiasm? This review will critically examine the behavioral methodology and evidence for facilitation of learning and memory in animal experiments, where conditions can be rigorously controlled. Definitions, procedures, and controls will be emphasized because so many of the conflicting findings and interpretations in this difficult area of research caJ~ be attributed to inadequate methodology. The adage that the method underlies the meaning is nowhere more pertinent than here. Deffmifions and procedures Fig. 1 shows the essential features of
e x p e r i m e n t s o n facihtation of learning a n d m e m o , y by drugs. T h e animal receives o n e o r m o r e training trials beginning at time I"1 (see figure) a n d m a y be tested for acquisition during the training trials or very shortly thereafter. T h e a n i m a l m a y t h e n receive a retest for memory, at time TR, s u b s e q u e n t to a delay that m a y be o n l y a few seconds o r as long as 24 h o r m o r e . L e a r n i n g a n d m e m o r y will be defined here as inferred processes, derived f r o m the o b s e r v e d relationships b e t w e e n the e v e n t s of the training a n d testing trials and the resulting p e r f o r m a n c e . "Learning' is defined e x p e r i m e n t a l l y by the n o n transitory a c q u i s i t i o n of n e w o r different b e h a v i o r as a c o n s e q u e n c e of e x p o s u r e to o n e o r m o r e training trials. ' M e m o r y " is defined e x p e r i m e n t a l l y as the p r e s e r v a t i o n of the learned b e h a v i o r b e t w e e n the e n d of the training p e r i o d a n d the retest, and is m e a s u r e d by the difference in p e r f o r m a n c e at these, t w o times. P o o r e r p e r f o r m a n c e at 1"= t h a n at T= indicates forgetting, a n d is m e a s m ed by c o m p a r i n g the s a m e animal's p e r f o r m a n c e at different times o r by c o m paring p e r f o r m a n c e o f different animals. A s indicated in t h e figure, m e m o r y is divided into t w o inferred proo.~sses: a MEMORY
Inferred Processes ~
Dr Eric Z Simon recdved his Ph.D. in organic chemistry from the Unive~ity o f Chicago in 1951. He took p~t-doctoral training in biochemist~, at Columbia University College of Physiciarts and Surgeort~. From 1953-1959 he did research on vitamin E metabrdism and muwular dy~rophy at Corndl Medical Cgdlege. Since 1959 lie has been on the Facul~_,o f .%'ew York Unh,er~i~_"Med, cal Center where he is now Pcofey.~or o f Psychtatry aml Phar,macololo'. Dr Simon has reeeh'ed mmLaro~ts h=mors and awards for his laboratory~ pioneering work on the discovery, chayaaerization and isoL:tion oJ; opiate receptors. Among these are the Reseqrch PaeeseUer Award from the ,Vational Ins~ute on E'rug Abuse in 1977 and the l.oui~ and Ben Freedman ;:oundadon Award from the N'ew Yori[ Academy o1;Aciencej in 1980. i Ikbc'-m-trN=rrthHollandB.~r~lKal pI¢-.~I~1
Drug ~
I
I I kearmncl I
//
A
RETENTION
|
B
/
I Retrmvol I
/_h__ C
T, Periods
PRE TRAIN TRAINING :: (ond i test)
1-2 DELAY
PRE TE ST
RETEST
Fig. 1. Schematic representation oflime periods, times o1;pox~ible treatments, and duration o1;in1;erred processes in expetimen~ in effects o1;drugs on learning and memory. (Further description in text. j
TIPS -June 1981 time-dependent retention or storage process which occurs during the delay, and the retrieval process thai occurs at retest. Retrieval is the proces: by which whatever '.v,as learned during training and stored during the delay period is translated into behavior. Learning or memory facilitators might be tested by administering them either during the pretraining period (time A in Fig. 1), shortly after training (time B in Fig. 1), or shortly before the retest (time C in Fig. 1), A putative learning facilitator might be injected prior to training at A, and then compared with suitable control injections for effects on training trial performance. Possible drug effects on memory can also be asses,sed quite objectively. Drug effects on learning, memory, and the retention and retrieval components of memory can be distinguished by administering the test compound at appropriate times after the training period. A drug administered after the training trials are over obviously cannot affect learning. If the drug is given immediately post training (e.g. at time B in Fig. 1), effects on performance observed upon retest at time T= must be effects on memor},. Furthermore, if there is time for the drug to dissipate prior to the retest, then the effects produced by post training administration can be assigned to the retention component of memory rather than to retrieval processes. Effects on retrieval can be measured by giving the drug shortly before retest, always assuming appropriate controls for non-specific effects on retest performance.
drags given before training in passive avoidance must be regarded with scepticism. With respect to learning, specific effects on acquisition of a drug given before training may be confounded with non-specific effects on performance due to alterations in for example, general activity, alertness. motivation, or ~nsory capacity. The increased latency produced by a depressant or toxic drug could ~ construed as "facilitation'. With respect to memory,, specific effects on memory of a drug given before training will unavoidably be confounded by any specific or non-specific drug effects on acquisition. Typically, non-specific drug effects are measured in separate tests for motor activity, sensitivity to stimuli, etc. Thompson B has introduced a much more elegant procedure for evaluating non-specific effects on learning. Thompson compares pigeons" acquisition of new response sequences with their concurrent performance on similar but already well-learned control sequences. Non-specific drug effects which might affect acquisition of the new sequences are indicated by changes in behavior on the control sequences. However, Thompson's strategy for evaluating nonspecific effects is obviously not applicable to the passive avoidance procedure in which learning takes place in one trial. In contrast, facilitation of retest performance by drugs administered immediately after training in passive avoidance is good evidence that the drug improves retention. Evidence of facilitation by a stimulant drug is particularly impres~sive, since any nonspecific effects of the drug still operative at Passive a v o i d l t ~ : the standard procedure retest would probably decrease latency and The concepts just described apply thus subtract from measured memoD' perdirectly to the 'passive avoidance' proce- formance. dure, which is currently the predominant experimental situation used for studying Repeated measures The passive avoidance procedure probdrug effects on memory in animals. A rat or mouse is placed on a platform or small ably has been used so extensively because lighted compartment for a single training of its technical simplicity and because of trial at time "1"1.When (as it almost always tb~ ease of training animals. Furthermore. does) ~he animal steps down from the plat- ,'ince acquisition occurs on one trial, the torm or enters an adjacent dark compart- time when learning takes place can be prement, it is given a painful shock to the feet. cisely specified. On the other hand. the one-trial acquisiThe animal usually receives a second trial (the retest) 24 h or more after the first trial. tion in passive avoidance precludes multiIts departure latency on the second trial trial measures of acquisition and repeated will usually be considerably longer than on measures of learning or memory in the the first trial, indicating that 'memory' for same animaP. The use of repeated measthe learning on the first trial persists for at ures would permit parametric variations and systematic comparisons of treatment least 24 h. Facilitation of learning or memory of conditions in the same and different anipassive avoidance has been reported for mals, and could thus perhaps resolve or drugs injected prior to training, after train- reconcile many of the isolated or contradicing, and before retest. The reports of facili- tory findings that burden this area of tation of either learning or memory by research.
[ 5t,I
It might seem impo,sil, le to te~,t an animal repeatedly for learning or remembering the same or similar thing,~ because later tests will be distorted by carr~-o~er from previous testing. The dilemma ce,n be r e , d y e d by first training the animal on a series of different learning or memory 'problems'. all of ,~'hich eml~Mv the same general "concept' or strategy. When the animal's rate of learning ne~ problems has stabilized, it.,, performance of further prob-
lems can be svstematicaliy compared under various treatment conditions. Fxample*, of series of learning or memory "problems" are the pr¢'~iously cited response ~equences that Thomp,~m u~s in ,,tudying acquisition R, and the tariow, series of delayed matching and dela)ed rewon~c problems used to study memory. Drugs that facilitate learning and memory There is little e~idcnce taat an.~ compounds can specifically facilitate learning. Many of the older rel~rts of learning" facilitation by drugs failed to control for possible stimulant or depressant etfects. Furthermore, all of the compounds tested (including d-amphetamine, cocaine, imipramine, diazepam, haloperidol, and phcnc}ciidine) in the unusuall)well-con;rolled studies by Thompson and collaborator~ cited above ~ disrupted rather than improved acquisition performance. There is good evidence that the drugs in each of the t'ollo~sing classes **ill facilitate retention*:
!. choline r~ics-mu~ca rinic~: ph} ~,~stigmine and nicotine 2. central stimulants: anlphctanline. caffeine, etc. 3. convulsants: st~'chnine, picrotoxin. bemegridc, an¢/pent.vFenetetrazol 4. pituitary hormones: ACTH and related peptide~, and vasopressin a~. Several of the corlicosteroids ha~e al~.o [~en sho~A n to e n h a n c e retemion 5. Miscellaneous. There arc ~attered reports of facilitation of retention b} a variety of other compounds, including eth:mol, morphine, and dictarx choline. A final decision on the efficacy of these compound.,, nlu~,t a~ nit replication and thorough analysis of possible stimulant or dcpressam, reinforcing, or other effects not specific to memor3.. In general, enhancement of retention by the substances listed abo~e varies inver~ly with the time elapsed between training and drug administration: the shorter this interval the greater the facilitation of m e m o ~ ob~rved upon retest 24 h later. Facilitation of retention by post training adminis-
TIPS - J u n e 1981
160
tration is often interpreted as an effect on a hypothetical consolidation process that is maximally labile immediately after training but with time becomes progressively less modifiable by pharmacological or other treatments. T,L,c wide variety of drugs that affect retention has been noted by several autho:s. These drugs may directly or indirectly affect all of the major neurotransmittcr sy.~tems, but they need not affect any particular system in order to be effective. The predominance of drugs with central stimulant action ~uggests that memory facilitation may be more a matter of general 'arousal' than of action on any specific neural system. The inverted-U-shaped dose response function typically observed for facilitation of retention by stimulatd and convulsant drugs supports this interpretation. Thus. although many drugs have been found that specifically stimulate m e m o r y , it appears unlikely that drugs will be found that stimulate specific memories or only particular functional neural memory systems t°. Three substances which facilitate retteval are strychnine, ACTH, and vasopressim ~hese substances also facilitate retention. Conversely. m_'m~ c,f the drugs that facil;tate retention :~, now being found to ~;acilitate retriev~i S~ch findings as these support the increa.~ngly popular notion that many otthe effects on retemion previousl~ attributed to consolidation proeesses should rather be assigned to pl~ces,ses likt attention or arousal that cot.ld also affect retrieval. Piracetam {2-~,rrolidone acetamide) deserves special mention because of iLs apparently mdque pattern of pV,armacological activity=. Although piracetam is inactive even at very high doses in most pharmacological tests, it apparently improves maze learning and may also facilitate retrieval. Condmions: substantiated and otherwise in a still-timely review written over 12 years ago, W¢issman" argued that research on learning and memory facilitators was handicapped by, lack of a "comparison standard'. Such a compound - one that clearly facilitated learning or memory would be invaluable for validation of measures and for implementation of screening ~trategies in which actions of test c o m p o u n ~ are compared with those oftbe comparison standard. Although there ha,:e been many advances in the physiology of learning and memory {which cannm be covered in this review), and facilitation of m e m o r y by drugs is now well established,
progress has nevertheless been slow. We still lack our comparison standard. What are directions for research that would most further our understanding of drug effects on learning and memory and might, perhaps, even produce the elusive comparison standard? More research with repeated measures procedures. Statements concerning drug effects on learning or m e m o r y depend on
a context of definitions, methods, and interpretation rules. The context of the passive avoklance procedure underlies our present knowledge of learning and memory facilitators. We have seen that with the passive avoidance procedure, drugs that facilitate memory have been identified, their effects on m e m o r y have been separated from their effects on learning, and their effects on memory have been separated into effects on retention and retrieval. However. rather than further demonstrations that miscellaneous compounds will facilitate passive avoidance performance, what we need now are systematic analyses of drug effects on learning and m e m o r y components and more sophisticated experimental separation of specific drug effects on learning and memory from non-specific effects. As previously diseus.~ed, multi-triaL repeated measures procetures are more suitable tha~ passive avoidance procedures tbr these latter purposes. M o t e research on retrieval. Recent experiments have shown how otherwise "forgotten" memories can be restored at retest by presenting reminder stimuli or by restoring the context of the training~''. Effect,~ of drugs on these retrieval phenomena should be extensively investigated. More research with deficient subjects.
terns or functions than memory. That is, learning ;nay be too generalized a .set of behaviors to be specifically sensitive to facilitatory drugs. Perhaps an indirect strategy would be more likely to lead to drugs that will improve learning. 'Memory' (defined more broadly than in this review) is necessarily involved in any learning behavior. Rather than searching for learning facilitators directly, a better strategy might be to search for and systematically examine the mode of action of drugs that facilitate memory. Reading list I Alpem. H.P. and Jackson. S.J. (i978) in Psyehophannaeology: A Generaiton of Progrexv, 1967-1977 {Lipton, M.A., DiMa~cio, A. and
Killam. K. F.. cds). pp. 663-675. Raven Pres~, New York 2 DeWied. D. and Versteeg, D. H. G. {1979)Fed. Proc. Fed. Am. Soc. Exp. Biol. 38, 2348--2354 3 Giurgea. C. {1976) in Current Developments in Psychopharmacology, Vol. 3, pp. 22.%272,Spectrum. New York 4 Hunter. B.. Zornetzer. S. F., Jarvik, M. E. and McGaugh, J.L. (1977) in Handbook of Psychopharmacology (Iversen, L.L.. Iversen, S. D. and Snyder,S. H., e&s),Vol. 8, pp. 531-577. PlenumPress, New York 5 Miller, R. R. (1978) in Aspects of .l#emo~. (Gruenberg, M. M. and Morris, P.. eds). pp. 104-131. London. Methuen 6 Rigter. H. and VanRiezen. H. (!g78) in Psychopharmacology: A Generation of Progress, 1967-1977 (Lipton, M. A.4DiMa~io, A. and Kil-
lain. K F., eds). pp. 677-689. Raven Press. New York 7 Spear. N. E. (1978) The Procesving of Memories: Forgetting and Retention. Erlbaum {Wiley),Hillside, New Jersey 8 Thompson. D.M. and Moerschbaeehei'.J.H. (1979) in Advances in Behavioral Pharmacology {Thompson. T. and Dews, P., eds), Vol. 2, pp. 229-259, AcademicPress. New York 9 Weissman, A. {1967) Annu. Rep..~led. Chem. 279-289 10 Zometzer, S. F. (1978) in Psychopharmacology: A Generation of Progress, 1967-1977 (Lipton, M. A., DiMascio, A. and Killam. K. F., eds), pp. 637-649. Raven Press,New York
Old, poorly trained, or otherwise deficient subjects seem especially sensitive to the action of facilitatory drugs. For example, a very recent report claims that aging mice maintained on diets enriched with choline, a cholinergic precursor, have significantly better retention of passive avoidance than aging mice h'.d diets deficient in choline. Focus on m e m o r y . As previously noted, a number of substanoes may specifically facilitate retention, but none has been found so far that specifically improves GeorgeA. Heiseis a professor ofpsychology at Indiana learning. The relatively greater success University, where he does research on the behavioral with m e m o r y might merely reflect better pharmacology of teaming and memory. He received means of measurement of memory and the his Ph.D. in experimental psychology from Harvard greater technical difficulties in identifying University in 1952. He was a senior scientist in the Department of Pharmacology at Hoffinann La Roche specific effects on learning. However, it and held faculty appointments at Oberlin and Hayercould indicate that learning requires the ,ford Collegesbefore coming to Indiana University in collaboration of a greater n u m b e r of sys- 1964.
i 58
Reading list I Simon. E. J. and Hiller. J, t~r|.(1')78) Ann. Rev. Pharmacol. 18. 371-394
2 Bcaumom. A. and |tughcs, J. I ItJ79)Aan. Rev. PharmacoL 19.245-267 3 Martin, W. R., Eade,,. C. G., "rhomp~m. J. A.. Happier. R. E. and Gilbert. P. E. (1976)J. P/:arretacol. b+~p. Ther. 197, 517-532 4 Gilhcn. P. F.. and Marlin. W. R. 11976)J. Pharmacol. b+~p. Ther. 198 66-82 5 I_ord, J. A. 14., WateffHzld. A. A.. Hughes, J. and Koqcditz. 11 W. {1977) Nature (l,ondon) 267. 495-499 6 Smith. J. R. and Simon. E, .I. (1980) Proc. Nati Acad. Sci. U.S.A. 77, 281-284 7 Rob,am. L. E. :rod Koslerlitz. H. W. (1979) Proc. R. .%n'. l.ond. B. 205.425-432 g Simon E. J. BonneL A. Crain. S. M., Grolh. J., tlillcr. J M and :;mith. J. R. (19811) in Neural Peptide.~ and N'curoaal Communication (4~'osta. E. and Trabucchi. M.. eds). pp. 335-340. Raxen l'h'e~.,,.Ne~ York 9 ('hang. K. L. C(mper. B. R.. Hazurn. E. and ('uatreca,,as. P. (197'4) .~fol. PharmacoL 16. 91-lit4 I O Itiller. J M. and Simon, E. J. ( I tJg(|)J. Pharmat ol. Exp. Th+:r. 214. 51¢r+-~19 I I Herkenham. M. and Pert. C. B. (1980) Proc. +Nat/ +4cad.+%'i.U.S.A. 77. 5532-5536 12 I.in. H. KJ and Sirmm. E. J. (1978) ,%uure (london) 271.3g.L-394 13 Pastemak. G. W. (19~P) Pr~n'. Nati Acad. Sci. U.S.A. 77. 3691-3894 14 Simon. E. J.. ltiller. J. M. and Edelman. I. (1975) %'iencc I taL 389-39(I 15 Zukin. R. S. and Kream. R. M. (1979) Proc. Nati A=ad. Sci. U.S.,4. 76. 15tLa.- 1597 16 Rucgg. U. T., Hiller. ~1.M. and Simon, E. J. (19t(0) Ear. J, Pharmaod. 64. 367-368 17 Simonds. W. F. Ko',ki. G.. Streaty. R. A.. Hielmeland. L. M. and Kle,e, W. A. (1980) Proc. N'atl Aq'ad. Sct. ILXA, 77.462.L-4627 i 8 Bidlack. J. M, and Ah~'gl. L. G. (1980) Life Sci. 27.331-340
Learning and memory facilitators: experimental definition and current status GeorgeA. Heise Departmento1;Psyehology
Indiana Universety, Bloomington, IN 47401, U.S.A.
Learning facilitators, memory enhancers, intelligence boosters: are such compounds just around the corner? A major drug company informs stockholders that its "cognition activator" slated for clinical trials in 1980 is more efficacious than piracetam, the best-selling current agent. A recent popular article on 'mind food' proclaims that 'more than a dozen' different chemicals will promote learning or data processing abilities in animals and men. Viewed from the no-nonsense orientation of laboratory experiments, does the available evidence justify this enthusiasm? This review will critically examine the behavioral methodology and evidence for facilitation of learning and memory in animal experiments, where conditions can be rigorously controlled. Definitions, procedures, and controls will be emphasized because so many of the conflicting findings and interpretations in this difficult area of research caJ~ be attributed to inadequate methodology. The adage that the method underlies the meaning is nowhere more pertinent than here. Deffmifions and procedures Fig. 1 shows the essential features of
e x p e r i m e n t s o n facihtation of learning a n d m e m o , y by drugs. T h e animal receives o n e o r m o r e training trials beginning at time I"1 (see figure) a n d m a y be tested for acquisition during the training trials or very shortly thereafter. T h e a n i m a l m a y t h e n receive a retest for memory, at time TR, s u b s e q u e n t to a delay that m a y be o n l y a few seconds o r as long as 24 h o r m o r e . L e a r n i n g a n d m e m o r y will be defined here as inferred processes, derived f r o m the o b s e r v e d relationships b e t w e e n the e v e n t s of the training a n d testing trials and the resulting p e r f o r m a n c e . "Learning' is defined e x p e r i m e n t a l l y by the n o n transitory a c q u i s i t i o n of n e w o r different b e h a v i o r as a c o n s e q u e n c e of e x p o s u r e to o n e o r m o r e training trials. ' M e m o r y " is defined e x p e r i m e n t a l l y as the p r e s e r v a t i o n of the learned b e h a v i o r b e t w e e n the e n d of the training p e r i o d a n d the retest, and is m e a s u r e d by the difference in p e r f o r m a n c e at these, t w o times. P o o r e r p e r f o r m a n c e at 1"= t h a n at T= indicates forgetting, a n d is m e a s m ed by c o m p a r i n g the s a m e animal's p e r f o r m a n c e at different times o r by c o m paring p e r f o r m a n c e o f different animals. A s indicated in t h e figure, m e m o r y is divided into t w o inferred proo.~sses: a MEMORY
Inferred Processes ~
Dr Eric Z Simon recdved his Ph.D. in organic chemistry from the Unive~ity o f Chicago in 1951. He took p~t-doctoral training in biochemist~, at Columbia University College of Physiciarts and Surgeort~. From 1953-1959 he did research on vitamin E metabrdism and muwular dy~rophy at Corndl Medical Cgdlege. Since 1959 lie has been on the Facul~_,o f .%'ew York Unh,er~i~_"Med, cal Center where he is now Pcofey.~or o f Psychtatry aml Phar,macololo'. Dr Simon has reeeh'ed mmLaro~ts h=mors and awards for his laboratory~ pioneering work on the discovery, chayaaerization and isoL:tion oJ; opiate receptors. Among these are the Reseqrch PaeeseUer Award from the ,Vational Ins~ute on E'rug Abuse in 1977 and the l.oui~ and Ben Freedman ;:oundadon Award from the N'ew Yori[ Academy o1;Aciencej in 1980. i Ikbc'-m-trN=rrthHollandB.~r~lKal pI¢-.~I~1
Drug ~
I
I I kearmncl I
//
A
RETENTION
|
B
/
I Retrmvol I
/_h__ C
T, Periods
PRE TRAIN TRAINING :: (ond i test)
1-2 DELAY
PRE TE ST
RETEST
Fig. 1. Schematic representation oflime periods, times o1;pox~ible treatments, and duration o1;in1;erred processes in expetimen~ in effects o1;drugs on learning and memory. (Further description in text. j
TIPS -June 1981 time-dependent retention or storage process which occurs during the delay, and the retrieval process thai occurs at retest. Retrieval is the proces: by which whatever '.v,as learned during training and stored during the delay period is translated into behavior. Learning or memory facilitators might be tested by administering them either during the pretraining period (time A in Fig. 1), shortly after training (time B in Fig. 1), or shortly before the retest (time C in Fig. 1), A putative learning facilitator might be injected prior to training at A, and then compared with suitable control injections for effects on training trial performance. Possible drug effects on memory can also be asses,sed quite objectively. Drug effects on learning, memory, and the retention and retrieval components of memory can be distinguished by administering the test compound at appropriate times after the training period. A drug administered after the training trials are over obviously cannot affect learning. If the drug is given immediately post training (e.g. at time B in Fig. 1), effects on performance observed upon retest at time T= must be effects on memor},. Furthermore, if there is time for the drug to dissipate prior to the retest, then the effects produced by post training administration can be assigned to the retention component of memory rather than to retrieval processes. Effects on retrieval can be measured by giving the drug shortly before retest, always assuming appropriate controls for non-specific effects on retest performance.
drags given before training in passive avoidance must be regarded with scepticism. With respect to learning, specific effects on acquisition of a drug given before training may be confounded with non-specific effects on performance due to alterations in for example, general activity, alertness. motivation, or ~nsory capacity. The increased latency produced by a depressant or toxic drug could ~ construed as "facilitation'. With respect to memory,, specific effects on memory of a drug given before training will unavoidably be confounded by any specific or non-specific drug effects on acquisition. Typically, non-specific drug effects are measured in separate tests for motor activity, sensitivity to stimuli, etc. Thompson B has introduced a much more elegant procedure for evaluating non-specific effects on learning. Thompson compares pigeons" acquisition of new response sequences with their concurrent performance on similar but already well-learned control sequences. Non-specific drug effects which might affect acquisition of the new sequences are indicated by changes in behavior on the control sequences. However, Thompson's strategy for evaluating nonspecific effects is obviously not applicable to the passive avoidance procedure in which learning takes place in one trial. In contrast, facilitation of retest performance by drugs administered immediately after training in passive avoidance is good evidence that the drug improves retention. Evidence of facilitation by a stimulant drug is particularly impres~sive, since any nonspecific effects of the drug still operative at Passive a v o i d l t ~ : the standard procedure retest would probably decrease latency and The concepts just described apply thus subtract from measured memoD' perdirectly to the 'passive avoidance' proce- formance. dure, which is currently the predominant experimental situation used for studying Repeated measures The passive avoidance procedure probdrug effects on memory in animals. A rat or mouse is placed on a platform or small ably has been used so extensively because lighted compartment for a single training of its technical simplicity and because of trial at time "1"1.When (as it almost always tb~ ease of training animals. Furthermore. does) ~he animal steps down from the plat- ,'ince acquisition occurs on one trial, the torm or enters an adjacent dark compart- time when learning takes place can be prement, it is given a painful shock to the feet. cisely specified. On the other hand. the one-trial acquisiThe animal usually receives a second trial (the retest) 24 h or more after the first trial. tion in passive avoidance precludes multiIts departure latency on the second trial trial measures of acquisition and repeated will usually be considerably longer than on measures of learning or memory in the the first trial, indicating that 'memory' for same animaP. The use of repeated measthe learning on the first trial persists for at ures would permit parametric variations and systematic comparisons of treatment least 24 h. Facilitation of learning or memory of conditions in the same and different anipassive avoidance has been reported for mals, and could thus perhaps resolve or drugs injected prior to training, after train- reconcile many of the isolated or contradicing, and before retest. The reports of facili- tory findings that burden this area of tation of either learning or memory by research.
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It might seem impo,sil, le to te~,t an animal repeatedly for learning or remembering the same or similar thing,~ because later tests will be distorted by carr~-o~er from previous testing. The dilemma ce,n be r e , d y e d by first training the animal on a series of different learning or memory 'problems'. all of ,~'hich eml~Mv the same general "concept' or strategy. When the animal's rate of learning ne~ problems has stabilized, it.,, performance of further prob-
lems can be svstematicaliy compared under various treatment conditions. Fxample*, of series of learning or memory "problems" are the pr¢'~iously cited response ~equences that Thomp,~m u~s in ,,tudying acquisition R, and the tariow, series of delayed matching and dela)ed rewon~c problems used to study memory. Drugs that facilitate learning and memory There is little e~idcnce taat an.~ compounds can specifically facilitate learning. Many of the older rel~rts of learning" facilitation by drugs failed to control for possible stimulant or depressant etfects. Furthermore, all of the compounds tested (including d-amphetamine, cocaine, imipramine, diazepam, haloperidol, and phcnc}ciidine) in the unusuall)well-con;rolled studies by Thompson and collaborator~ cited above ~ disrupted rather than improved acquisition performance. There is good evidence that the drugs in each of the t'ollo~sing classes **ill facilitate retention*:
!. choline r~ics-mu~ca rinic~: ph} ~,~stigmine and nicotine 2. central stimulants: anlphctanline. caffeine, etc. 3. convulsants: st~'chnine, picrotoxin. bemegridc, an¢/pent.vFenetetrazol 4. pituitary hormones: ACTH and related peptide~, and vasopressin a~. Several of the corlicosteroids ha~e al~.o [~en sho~A n to e n h a n c e retemion 5. Miscellaneous. There arc ~attered reports of facilitation of retention b} a variety of other compounds, including eth:mol, morphine, and dictarx choline. A final decision on the efficacy of these compound.,, nlu~,t a~ nit replication and thorough analysis of possible stimulant or dcpressam, reinforcing, or other effects not specific to memor3.. In general, enhancement of retention by the substances listed abo~e varies inver~ly with the time elapsed between training and drug administration: the shorter this interval the greater the facilitation of m e m o ~ ob~rved upon retest 24 h later. Facilitation of retention by post training adminis-
TIPS - J u n e 1981
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tration is often interpreted as an effect on a hypothetical consolidation process that is maximally labile immediately after training but with time becomes progressively less modifiable by pharmacological or other treatments. T,L,c wide variety of drugs that affect retention has been noted by several autho:s. These drugs may directly or indirectly affect all of the major neurotransmittcr sy.~tems, but they need not affect any particular system in order to be effective. The predominance of drugs with central stimulant action ~uggests that memory facilitation may be more a matter of general 'arousal' than of action on any specific neural system. The inverted-U-shaped dose response function typically observed for facilitation of retention by stimulatd and convulsant drugs supports this interpretation. Thus. although many drugs have been found that specifically stimulate m e m o r y , it appears unlikely that drugs will be found that stimulate specific memories or only particular functional neural memory systems t°. Three substances which facilitate retteval are strychnine, ACTH, and vasopressim ~hese substances also facilitate retention. Conversely. m_'m~ c,f the drugs that facil;tate retention :~, now being found to ~;acilitate retriev~i S~ch findings as these support the increa.~ngly popular notion that many otthe effects on retemion previousl~ attributed to consolidation proeesses should rather be assigned to pl~ces,ses likt attention or arousal that cot.ld also affect retrieval. Piracetam {2-~,rrolidone acetamide) deserves special mention because of iLs apparently mdque pattern of pV,armacological activity=. Although piracetam is inactive even at very high doses in most pharmacological tests, it apparently improves maze learning and may also facilitate retrieval. Condmions: substantiated and otherwise in a still-timely review written over 12 years ago, W¢issman" argued that research on learning and memory facilitators was handicapped by, lack of a "comparison standard'. Such a compound - one that clearly facilitated learning or memory would be invaluable for validation of measures and for implementation of screening ~trategies in which actions of test c o m p o u n ~ are compared with those oftbe comparison standard. Although there ha,:e been many advances in the physiology of learning and memory {which cannm be covered in this review), and facilitation of m e m o r y by drugs is now well established,
progress has nevertheless been slow. We still lack our comparison standard. What are directions for research that would most further our understanding of drug effects on learning and memory and might, perhaps, even produce the elusive comparison standard? More research with repeated measures procedures. Statements concerning drug effects on learning or m e m o r y depend on
a context of definitions, methods, and interpretation rules. The context of the passive avoklance procedure underlies our present knowledge of learning and memory facilitators. We have seen that with the passive avoidance procedure, drugs that facilitate memory have been identified, their effects on m e m o r y have been separated from their effects on learning, and their effects on memory have been separated into effects on retention and retrieval. However. rather than further demonstrations that miscellaneous compounds will facilitate passive avoidance performance, what we need now are systematic analyses of drug effects on learning and m e m o r y components and more sophisticated experimental separation of specific drug effects on learning and memory from non-specific effects. As previously diseus.~ed, multi-triaL repeated measures procetures are more suitable tha~ passive avoidance procedures tbr these latter purposes. M o t e research on retrieval. Recent experiments have shown how otherwise "forgotten" memories can be restored at retest by presenting reminder stimuli or by restoring the context of the training~''. Effect,~ of drugs on these retrieval phenomena should be extensively investigated. More research with deficient subjects.
terns or functions than memory. That is, learning ;nay be too generalized a .set of behaviors to be specifically sensitive to facilitatory drugs. Perhaps an indirect strategy would be more likely to lead to drugs that will improve learning. 'Memory' (defined more broadly than in this review) is necessarily involved in any learning behavior. Rather than searching for learning facilitators directly, a better strategy might be to search for and systematically examine the mode of action of drugs that facilitate memory. Reading list I Alpem. H.P. and Jackson. S.J. (i978) in Psyehophannaeology: A Generaiton of Progrexv, 1967-1977 {Lipton, M.A., DiMa~cio, A. and
Killam. K. F.. cds). pp. 663-675. Raven Pres~, New York 2 DeWied. D. and Versteeg, D. H. G. {1979)Fed. Proc. Fed. Am. Soc. Exp. Biol. 38, 2348--2354 3 Giurgea. C. {1976) in Current Developments in Psychopharmacology, Vol. 3, pp. 22.%272,Spectrum. New York 4 Hunter. B.. Zornetzer. S. F., Jarvik, M. E. and McGaugh, J.L. (1977) in Handbook of Psychopharmacology (Iversen, L.L.. Iversen, S. D. and Snyder,S. H., e&s),Vol. 8, pp. 531-577. PlenumPress, New York 5 Miller, R. R. (1978) in Aspects of .l#emo~. (Gruenberg, M. M. and Morris, P.. eds). pp. 104-131. London. Methuen 6 Rigter. H. and VanRiezen. H. (!g78) in Psychopharmacology: A Generation of Progress, 1967-1977 (Lipton, M. A.4DiMa~io, A. and Kil-
lain. K F., eds). pp. 677-689. Raven Press. New York 7 Spear. N. E. (1978) The Procesving of Memories: Forgetting and Retention. Erlbaum {Wiley),Hillside, New Jersey 8 Thompson. D.M. and Moerschbaeehei'.J.H. (1979) in Advances in Behavioral Pharmacology {Thompson. T. and Dews, P., eds), Vol. 2, pp. 229-259, AcademicPress. New York 9 Weissman, A. {1967) Annu. Rep..~led. Chem. 279-289 10 Zometzer, S. F. (1978) in Psychopharmacology: A Generation of Progress, 1967-1977 (Lipton, M. A., DiMascio, A. and Killam. K. F., eds), pp. 637-649. Raven Press,New York
Old, poorly trained, or otherwise deficient subjects seem especially sensitive to the action of facilitatory drugs. For example, a very recent report claims that aging mice maintained on diets enriched with choline, a cholinergic precursor, have significantly better retention of passive avoidance than aging mice h'.d diets deficient in choline. Focus on m e m o r y . As previously noted, a number of substanoes may specifically facilitate retention, but none has been found so far that specifically improves GeorgeA. Heiseis a professor ofpsychology at Indiana learning. The relatively greater success University, where he does research on the behavioral with m e m o r y might merely reflect better pharmacology of teaming and memory. He received means of measurement of memory and the his Ph.D. in experimental psychology from Harvard greater technical difficulties in identifying University in 1952. He was a senior scientist in the Department of Pharmacology at Hoffinann La Roche specific effects on learning. However, it and held faculty appointments at Oberlin and Hayercould indicate that learning requires the ,ford Collegesbefore coming to Indiana University in collaboration of a greater n u m b e r of sys- 1964.