REVIEW

Drug enhancement of memory consolidation: historicalperspective and neurobiological implications

James L. McGaugh & Benno Roozendaal

Received: 28 May 2008 /Accepted: 29 July 2008 / Published online: 15 August 2008# Springer-Verlag 2008

AbstractIntroduction Studies of drug enhancement of cognitionbegan with Lashley’s (Psychobiology 1:141–170, 1917)report that strychnine administered before daily trainingtrials enhanced rats’ maze learning. Many subsequentstudies confirmed that finding and found that stimulantdrugs also enhance the learning of a wide range of tasks.Discussion A central problem in interpreting such findingsis that of distinguishing the drug effects on brain processesunderlying memory formation from many other possibleeffects of the drugs on the behavior used to assess learning.The subsequent finding that comparable learning enhance-ment can be obtained by posttraining drug administrationprovided compelling evidence that drugs can enhancememory by acting on memory consolidation processes.Such evidence stimulated the investigation of endogenousregulation of memory consolidation by arousal-releasedadrenal stress hormones.Conclusion Considerable evidence now indicates that suchhormones regulate memory consolidation via activation ofthe basolateral amygdala and subsequent influences onmany efferent brain regions involved in processing recentexperiences. The implications of these findings for thedevelopment of cognitive enhancing drugs are discussed.

Keywords Memory . Consolidation . Amygdala . Learning .

Drug enhancement . Strychnine . Stress hormones

Introduction

There is abundant evidence that drugs can enhancecognitive performance. Drug-induced improvement ofcognitive performance might be due to effects on manyfunctions, including perception, attention, arousal, motiva-tion, and motor performance as well as influences onneurobiological processes directly involved in learning andmemory. If it is proposed that the enhanced performanceinduced by a drug is due to influences on neurobiologicalprocesses involved in learning and memory, it is essentialthat the bases of the influences on performance effects bedetermined. Thus, in research on drug-induced cognitiveenhancement, a major conceptual task is that of distin-guishing the effects of drugs on learning and memoryprocesses from the many other processes that may enhanceperformance. This paper reviews the findings of animalstudies of drug enhancement of learning and memory thathave addressed the bases of the enhancement. More spe-cifically, major emphasis is given to studies investigatingthe effects of drugs on memory consolidation.

Early studies of drug enhancement of learning

In the first published study of the effect of a drug onlearning, Lashley (1917) reported that low doses ofstrychnine administered to rats each day prior to trainingon a maze enhanced their performance, as evidenced byreduced errors, compared to controls, on subsequent days.Lashley (1917) also reported that when strychnine and a

Psychopharmacology (2009) 202:3–14DOI 10.1007/s00213-008-1285-6

Supported by NIMH Research Grant MH 12526 (JLM) and NSFGrant IOB-618211 (BR).

J. L. McGaugh (*) : B. RoozendaalCenter for the Neurobiology of Learning and Memory,University of California,Irvine, CA 92697-3800, USAe-mail: JLMCGAUG@UCI.EDU

J. L. McGaugh :B. RoozendaalDepartment of Neurobiology and Behavior,University of California,Irvine, CA 92697-3800, USA

control solution were administered on alternate days,performance was better on days in which strychnine wasadministered. Thus, it could well be that strychnine affectedthe behavior used to assess learning by influencing someprocesses that directly affect performance, rather than byinfluencing learning and memory. However, that findingdoes not allow the conclusion that strychnine affected onlyperformance; both learning and performance may havebeen affected. Importantly, however, Miles (1929) subse-quently reported that strychnine did not affect rats’performance of very well-learned maze habits.

Many studies reported finding additional evidence thatstrychnine administered to rats or mice prior to training onvarious tasks that employed different motivation (e.g., foodreward or footshock) and different responses (e.g., activeapproach or avoidance or inhibitory avoidance) enhanceslearning. The findings of these studies excluded any simpleinterpretation suggesting that the effects were due tononspecific influences on performance such as slowedresponding (leading to more accurate choices) or increasedmotivation (i.e., increased hunger or fear; Thiessen et al.1961; McGaugh and Petrinovich 1963; Whishaw andCooper 1970). Some nonspecific performance effect of thedrug might account for the findings of Lashley (1917) aswell as the replication of his effects (McGaugh andPetrinovich 1959) and the findings of other maze-learningstudies in which the animals received daily injections ofstrychnine prior to food-rewarded training trials (e.g.,McGaugh 1961; McGaugh et al. 1962a; Prien et al. 1963;Greenough and McGaugh 1965). However, strychnine alsoenhances the learning of many other kinds of tasks,including a hot-plate escape task (Kelemen and Bovet1961), appetitively and aversively motivated visual discrim-ination tasks (Petrinovich 1963; McGaugh and Thomson1962), and habituation (Andry and Luttges 1971). Clearly,any hypothesis suggesting that the enhanced learninginduced by strychnine is due solely to nonspecific perfor-mance effects would have difficulty accounting for theenhanced performance obtained with different motivationalconditions and with such a wide variety of behaviors used toassess learning.

Enhancement of memory consolidation: posttrainingdrug administration

Learning and memory are, of course, inferred fromexperience-induced changes in behavior. The distinctionbetween learning and performance originally proposed byTolman (1932) is essential for understanding any influenceon cognition. Drug studies of “cognitive enhancers” thatuse pretraining drug administration must, of course,explicitly confront the critical and complicated issue of

determining the basis (or bases) of the enhanced perfor-mance that is used to make inferences about cognition.Enhanced cognition is but one possibility (McGaugh1989a). Excluding all possible or reasonable alternativeinterpretations is, at best, a difficult task.

In the late 1940s, studies of retrograde amnesia inducedby electroconvulsive shock and drugs (Duncan 1949;McGaugh 1966; McGaugh and Herz 1972) provided thefirst compelling evidence supporting the consolidationhypothesis proposed by Müller and Pilzecker (1900) a halfcentury earlier (McGaugh 1999). Hebb (1949) incorporatedthe idea that memory traces are initially fragile and becomestable over time into his “dual-trace” hypothesis ofmemory. These findings and ideas suggested an alternativeapproach to investigating drug effects on learning andmemory. If memories are susceptible to disruption bytreatments applied shortly after learning, then they mightalso be susceptible to enhancement by treatment adminis-tered after learning. That is, according to the memoryconsolidation hypothesis, it should be possible to enhancememory by administering drugs shortly after training.

Posttraining drug administration thus provided a possiblemeans of distinguishing drug effects on memory from drugeffects on performance, as with this procedure, theexperimental subjects are drug-free during acquisition aswell as during retention testing (McGaugh and Petrinovich1965; McGaugh 1966, 1973; McGaugh and Herz 1972).The latter assumes, of course, that the drugs are metabo-lized or excreted prior to the retention test. Additionally, itis essential, of course, to investigate the time-dependenteffects of drugs administered posttraining. If drugs act bymodulating memory consolidation, drug administrationmany hours posttraining should be less effective thanimmediate posttrial administration in influencing retention.Also, as delayed treatments are closer in time to retentiontesting, typically after a delay of 1 or 2 days, lack of effectson retention provides strong evidence that the enhancedretention is not due to any direct effect of the drug onretention performance.

The first study reporting that strychnine administeredafter each of a series of daily training trials enhanced rats’maze learning (McGaugh 1959) was followed by a series ofexperiments investigating the effects of posttraining admin-istration of strychnine and many other CNS stimulant drugson memory of rats and mice trained in a wide variety oflearning tasks (McGaugh and Petrinovich 1965; McGaughand Herz 1972; McGaugh 1973). The first published study(Breen and McGaugh 1961) reported that daily posttraininginjections of the GABAergic antagonist picrotoxin en-hanced rats’ maze learning. These findings were subse-quently confirmed in many studies (cf. McGaugh et al.1982; Brioni and McGaugh 1988; Castellano and McGaugh1989; McGaugh 1989b; Izquierdo and Medina 1991).

4 Psychopharmacology (2009) 202:3–14

Additionally, as discussed below, many subsequent studiesfound that several stimulant drugs enhance retention of avariety of training tasks when administered posttraining.

Strychnine administered immediately or 15 min aftereach daily training trial enhanced food-rewarded mazelearning; injections administered 30 or 90 min posttrainingwere ineffective (McGaugh et al. 1962a). The strychnine-like drug diazadamantanol induced memory enhancementlike that seen with strychnine: Diazadamantanol enhancedlearning when administered either before (McGaugh et al.1961) or after training (McGaugh et al. 1962b). Petrinovichet al. (1965) found that strychnine administered afterrewarded trials in a T-maze enhanced memory as assessedby responding to alternate goal boxes on each subsequenttrial. As the intervals between trials were increased,controls responded correctly only at intervals up to 3.5 h.In contrast, rats given strychnine posttraining respondedcorrectly (i.e., alternated) for intervals up to 8 h. As theonly cue to the correct choice on each trial was memory ofthe choice on the immediately preceding trial, the findingsclearly indicated that strychnine increased the interval oftime over which the animals remembered each priorresponse. Hudspeth (1964) found that posttraining strych-nine administration enhanced rats’ learning of an aversivelymotivated oddity discrimination task. Posttraining strych-nine administration also enhanced learning of a food-rewarded brightness discrimination task (McGaugh andKrivanek 1970). Administration each day either before orafter mice received three rewarded trials produced dose-dependent and time-dependent enhancement of learning.Significant enhancement was obtained by administration ofstrychnine up to 1 h before daily training trials or 1 h aftertraining. Injections administered 2 or 4 h after training wereineffective.

Similar results were obtained with other stimulant drugsand with other training tasks. Ott and Matthies (1971)reported that pretraining administration of pentylenetetrazol(metrazol) enhanced aversively motivated discriminationlearning. As with strychnine, pentylenetetrazol adminis-tered posttraining produced dose- and time-dependentenhancement of food-rewarded discrimination learning;enhancement was found with administration up to 15 minbefore or after daily training trials (Hunt and Krivanek1966; Krivanek and McGaugh 1968; Hunt and Bauer1969). In that same task, amphetamine enhanced learningwhen administered 30 min prior to training or up to 15 minposttraining (Krivanek and McGaugh 1969). Previously,Kelemen and Bovet (1961) reported that amphetamineadministered before training enhanced active avoidance bymice. Doty and Doty (1966) were the first to report thatposttraining administration of amphetamine enhancedavoidance learning. In old, but not young, rats, memoryenhancement was produced by injections administered up

to 4 h after training. Avoidance learning is enhanced byposttraining administration of several other stimulant drugs,including strychnine (Bovet et al. 1966), picrotoxin(Zerbolio 1967) pentylenetetrazol (Krivanek 1971), andbemegride (Luttges and McGaugh 1971a, b). Posttrainingadministration of picrotoxin enhances extinction as well asoriginal learning. In one study (McGaugh et al. 1990), micewere first given tones paired with footshock in onecompartment of a Y-maze. On the following day, they wereplaced again in the compartment and given 20 tonepresentations without any shock, followed by injections ofpicrotoxin or a control solution. Locomotor activity in themaze tested the next day was substantially reduced in micegiven only the tone-footshock training; that is, withoutextinction. Administration of picrotoxin after the tone-alonepresentations enhanced extinction. On the locomotoractivity retention test, the performance of mice givenpicrotoxin post-extinction was comparable to that ofcontrols that had not received footshock training.

As noted above, all of the stimulant drugs studiedinduced dose- and time-dependent memory enhancement.Additionally, and importantly, the enhancement found insuch studies does not vary directly with the drug dose.Rather, the dose–response effect is typically in the form ofan inverted-U. Furthermore, the optimal dose, i.e., the dosethat produces maximal enhancement, varies with thespecific experimental conditions used. Thus, when admin-istered either before training or posttraining, a specific drugdose may induce either memory enhancement or memoryimpairment, depending on the experimental conditions usedin training.

Further analysis of learning-performance effectsin posttraining drug administration studies

As discussed above, the critical importance of the post-training drug administration procedure in experimentsinvestigating drug enhancement of learning and memoryis that the subjects are drug-free during both training andtesting. Thus, by inference, the drugs can affect thesubsequent behavior used to assess retention only byactions occurring shortly after training. Again, time-dependency controls (i.e., delayed injections) excludepossible direct effects of the drugs on behavior during theretention tests. As summarized briefly above, many studieshave provided compelling evidence that drugs administeredposttraining can improve retention by enhancing posttrain-ing memory consolidation. Of course, in order to acceptthat interpretation, it is essential to exclude the possibilitythat enhancement of retention performance is due torewarding properties of the drugs. Several studies haveaddressed this issue. In a study of sensory preconditioning

Psychopharmacology (2009) 202:3–14 5

in rats, Humphrey (1968) gave rats paired presentations of asound and a light, followed by administration of strychnine.Then, the sound was paired with a footshock. Subsequently,the animals displayed emotional responsiveness whenpresented with the light stimulus alone. The findingsstrongly suggest that strychnine enhanced the nonrewardedlearning of the association between sound and light. In aconceptually similar study, Oliverio (1968) trained mice inan active avoidance task using a buzzer as a conditionedstimulus. They then received additional training with both abuzzer and a light-conditioned stimulus and were givenstrychnine (or a control solution) either before or immedi-ately after this training session. On a subsequent test, thestrychnine-treated mice displayed more active avoidances,in comparison with those of controls, when light alone wasused as the conditioned stimulus.

A study of the effects of posttraining drug administrationon “latent learning” in a maze provided a more directexamination of the hypothesis that posttraining drugs mightaffect retention by acting as a reward (Westbrook andMcGaugh 1964). Rats received injections of the strychnine-like drug diazadamantanol after several food-rewarded ornonrewarded trials in a maze. Learning, compared tocontrols, was enhanced in the rewarded group but not inthe nonrewarded group. This provided the first explicitevidence that the drug did not act as a reward. Then, forseveral additional trials, rewards were administered aftereach trial, and no further posttraining injections wereadministered. On these trials, the performance of bothgroups, i.e., the rewarded and the nonrewarded groups thathad received posttraining diazadamantanol on the previoustraining, was superior to that of comparable groups given acontrol solution. The findings clearly indicated that the drugenhanced the “latent learning” occurring on nonrewardedtrials as well as the learning occurring on rewarded trials.Thus, by revealing that the posttraining drug administrationenhanced learning but did not do so by serving as a reward,the findings provided strong evidence supporting thehypothesis that the drug improved memory by enhancingposttraining memory consolidation.

Another important issue concerning the memory en-hancement induced by drugs administered either before orafter training is that of determining whether the effect is“state-dependent.” According to a state-dependent interpre-tation of posttraining drug enhancement retention, perfor-mance reflects the degree to which the brain state at thetime of retention testing is congruent with the state thatoccurs normally or is induced after training. Thus a state-dependent interpretation of drug-induced posttrainingmemory enhancement would require the additional assump-tion that the “state” during drug-free retention testing withwhich memory enhancement is found is congruent with thestate induced by the posttraining treatment. Accordingly,

administration of the treatment again, just prior to the reten-tion test would be expected to decrease the congruence andprevent or attenuate the memory enhancement. An experi-ment investigating this implication obtained clear evidencethat failed to support the state-dependent hypothesis(Castellano and McGaugh 1989). Posttraining administra-tion of picrotoxin enhanced rats’ retention of inhibitoryavoidance, and picrotoxin administered to either picrotoxin-treated or control rats prior to the retention test did not alterthe retention performance. Thus, these findings provideadditional evidence consistent with the hypothesis thatposttraining picrotoxin influences memory by modulatingmemory consolidation (McGaugh 1989b).

Conclusions concerning pre- and posttraining drugenhancement of learning and memory

Many drugs, in addition to those discussed above, have beenreported to enhance learning in animals when administeredeither before or after training. Some studies have focused onspecific neurochemical hypotheses. For example, an earlystudy by Stratton and Petrinovich (1963) found thatposttraining administration of the acetylcholinesteraseinhibitor physostigmine enhanced rats’ maze learning. Itwas decades later that acetylcholinesterase inhibitors werefirst used for the treatment of Alzheimer’s disease. Otherdrugs emerged from pharmaceutical research laboratoriesthat screened for drug enhancement (e.g., Hock andMcGaugh 1985) or developed new drugs (e.g., Decker etal. 1994a, b) based on drugs, such as nicotine, which werepreviously found to enhance memory (Oliverio 1968;Battig 1970; Evangelista et al. 1970; Orsingher andFulginiti 1971), and of course, both approaches continuein current efforts to develop memory-enhancing drugs.

Several conclusions can be drawn from the extensivefindings of the early studies of drug-induced enhancementof learning and memory in animals. First, many drugsenhance learning when administered prior to training. Asdiscussed above, it is difficult, however, to interpret thebasis of the enhancement because influences on sensory,motor, and motivational processes cannot be readily ex-cluded. Second, there is very extensive evidence that drugscan produce dose- and time-dependent enhancement ofmemory when administered posttraining. Such findingsprovide strong evidence that the memory enhancement isdue to influences on memory consolidation. Control studieshave excluded interpretations suggesting that the effects aredue to reward, state-dependency, and other possible post-training influences. Third, a few studies have reported thatpre- or posttraining drug administration produce comparablememory-enhancing effects. Such findings strongly suggestthat, as suggested above, apart from any performance effects,

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pretraining drug administration may also enhance memoryby influencing memory consolidation. Fourth, drugs en-hance learning/memory in a very wide variety of learningtasks that differ in motivational requirements as well as typesof responses assessed. The common feature assessed is thebehavior in each task that allows the inference that theimproved behavior reflects enhanced memory of the trainingexperience. The many studies summarized above have used awide variety of experimental approaches, and their findingsprovide compelling evidence that drugs can enhance reten-tion via influences on posttraining memory consolidationprocesses.

Neurobiological implications of drug enhancementof learning/memory

The aim of many, if not most, studies of drug enhancement oflearning and memory is to understand the neurobiologicalmechanisms underlying the enhancement. Such under-standing may, it is hoped, provide insights into the brainprocesses underlying memory. The many hypothesesconcerning receptor systems and intracellular mechanismshave guided the use of drugs with known mechanisms ofaction as well as the development of new drugs that targetspecific cellular mechanisms. There is now abundantevidence that memory can be enhanced by drugs affectinga variety of receptor systems, including cholinergic, adren-ergic, serotonergic, GABAergic, and opioid peptidergic,among others (Hunter et al. 1977; McGaugh 1989a, b).Many other studies have investigated memory enhancement(and impairment) induced by drugs affecting intracellularmechanisms (Silva et al. 1998; McGaugh and Izquierdo2000; Izquierdo and McGaugh 2000; Barco et al. 2003;Routtenberg and Rekart 2005; Sweatt 2007).

Memory modulation hypothesis From a broader perspec-tive, however, it is of interest and importance to considerwhy our memories are susceptible to posttraining modula-tion by any kind of drugs—or other treatments. One mightargue that a better designed brain would consolidatememories instantly, or at least quickly, rather than slowly.So, why do our memories, and those of all animals studied,consolidate slowly? One possibility is that slow consolida-tion provides the opportunity for postlearning modulationof consolidation (Gold and McGaugh 1975). The findingsof drug studies clearly indicate that such modulation canoccur. Additionally, there is now extensive evidence thatendogenous stress hormone systems activated by emo-tionally arousing learning experiences serve to regulateconsolidation (Gold and McGaugh 1975; McGaugh 1989b,2000; McGaugh et al. 2000; McGaugh and Cahill 2002;McGaugh and Roozendaal 2002). Such endogenous regu-

lation of consolidation provides an opportunity for thesignificance of experiences to modulate the strength of thememories of the experiences (Gold and McGaugh 1975;McGaugh 1990).

It is now well established that stress hormones, includingepinephrine and cortisol (corticosterone in the rat) normallyreleased from the adrenal medulla and cortex, respectively,by emotional arousal enhance memory when administered torats or mice posttraining (McGaugh and Roozendaal 2002).The initial findings of Gold and van Buskirk (1975) thatepinephrine produces dose- and time-dependent enhance-ment of inhibitory avoidance long-term memory have beenextensively replicated and also found with a wide variety ofother types of training tasks, including active avoidance,discrimination learning, and appetitive learning (e.g., Lianget al. 1985; Sternberg et al. 1985; Introini-Collison andMcGaugh 1986). Highly comparable results are obtained instudies of the effects of posttraining administration ofcorticosterone and drugs that activate glucocorticoid recep-tors (GRs; Sandi and Rose 1994; Roozendaal 2000;Zorawski and Killcross 2002; Okuda et al. 2004).

Findings of several studies indicate that epinephrineaffects brain functioning via activation of β-adrenoceptorson the ascending vagus nerve that projects to the nucleus ofthe solitary tract (NTS) (Williams and McGaugh 1993;Roozendaal et al. 1999a; Clayton and Williams 2000a, b).The NTS induces noradrenergic activation of forebrain viadirect projections as well as indirectly via projections to thelocus coeruleus (McGaugh and Roozendaal 2002). Con-siderable evidence indicates that noradrenergic activation ofthe basolateral nucleus of the amygdala (BLA) is critical inmediating epinephrine-induced modulation of memoryconsolidation. Infusions of β-adrenoceptor antagonists intothe BLA block epinephrine-induced memory enhancement(Liang et al. 1986). Moreover, posttraining infusions ofnorepinephrine into the BLA produce dose- and time-dependent memory enhancement (e.g., Liang et al. 1986,1990, 1995; Hatfield and McGaugh 1999; Ferry et al. 1999;LaLumiere et al. 2003; Huff et al. 2005).

Corticosterone passes freely into the brain where itactivates GRs in many regions, including the BLA.Moreover, GR agonists infused into the BLA posttrainingproduce dose- and time-dependent memory enhancement.Infusions of β-adrenoceptor antagonists into the BLA blockthe memory-enhancing effects of systemically administeredGR agonists as well as GR agonists infused posttraininginto the BLA (Quirarte et al. 1997; Roozendaal and McGaugh1997; Roozendaal 2000; McGaugh and Roozendaal 2002;Roozendaal et al. 2002, 2006a, b). Emotional arousal andnoradrenergic activation of the BLA appear to be essentialfor obtaining corticosterone-induced enhancement of mem-ory consolidation. However, with low-arousing trainingconditions (i.e., object recognition) administration of yohim-

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bine, which is known to enhance norepinephrine release byblocking noradrenergic autoreceptors, enables glucocorticoid-induced memory enhancement (Okuda et al. 2004;Roozendaal et al. 2006b). With object recognition trainingthat produces 1-h but not 24-h memory, posttraining intra-BLA infusions of norepinephrine induce dose-dependentenhancement of 24 h memory. Furthermore, with trainingconditions that result in 24 h memory, posttraining intra-BLA infusions of the adrenoceptor antagonist propranololinduce dose-dependent impairment of object recognitionmemory (Roozendaal et al. 2008).

The findings summarized above strongly support thehypothesis that stress hormones released by emotionalarousal modulate memory consolidation and that noradren-ergic activation of the BLA is critical in mediating themodulation. Importantly, other findings suggest that norad-renergic activation of the BLA may also be essential inmediating the effects of drugs known to modulate memoryconsolidation. For example, the GABAergic antagonistspicrotoxin and bicuculline, found to enhance memoryconsolidation when administered systemically, also enhancememory when infused into the BLA posttraining, and intra-amygdala infusions of a β-adrenoceptor antagonist blockthe memory enhancement (McGaugh et al. 1990). Moreover,intra-amygdala infusions of GABAergic agonists impairconsolidation (Brioni et al. 1989; Izquierdo et al. 1992;Wilensky et al. 2000; Huff et al. 2005). Intra-amygdalainfusions of a β-adrenoceptor antagonist also blockbicuculline-induced enhancement of extinction (Berlauand McGaugh 2006).

Findings of studies using in vivo microdialysis and high-performance liquid chromatography to measure norepineph-rine levels in the amygdala provide additional evidence thatdrugs may influence memory consolidation by regulatingnorepinephrine release in the amygdala. As is shown inTable 1, hormones and drugs that enhance consolidationincrease amygdala norepinephrine levels, and treatmentsthat impair consolidation decrease amygdala norepineph-rine levels. Furthermore, the finding that amygdala norepi-nephrine levels assessed following inhibitory avoidancetraining correlate highly with subsequent long-term mem-

ory provides additional support for the hypothesis thatnorepinephrine release in the amygdala plays an important,if not essential, role in the modulating memory consolida-tion (McIntyre et al. 2002).

Amygdala interactions with other brain regions in modulatingmemory consolidation Memory-modulatory effects of post-training amygdala treatments have been obtained in experi-ments using a variety of training tasks that are known toengage different brain systems. Considerable evidenceindicates that noradrenergic activation of the BLA influen-ces memory processing occurring in these other brainregions (McGaugh 2002, 2004). Amphetamine infusedposttraining into the caudate nucleus selectively enhancesmemory of visually cued water-maze training, whereasinfusions administered into the dorsal hippocampus selec-tively enhance memory of spatial training. In contrast,amphetamine infused into the amygdala posttrainingenhances memory for both types of training (Packardet al. 1994).

Noradrenergic stimulation of the BLA that enhancesmemory consolidation also increases levels of activity-regulated cytoskeletal (Arc) protein in the dorsal hippo-campus (McIntyre et al. 2005). Furthermore, posttraininginactivation of the BLA impairs memory consolidation anddecreases hippocampal Arc mRNA and protein levels(McIntyre et al. 2005; Huff et al. 2006). Other findingsindicate that training known to involve the amygdalainduces the expression of several transcriptionally regulatedgenes implicated in synaptic plasticity in many brain areas,including the hippocampus, caudate nucleus, and cortex, aswell as the amygdala (Ressler et al. 2002).

Infusions of a GR agonist into the dorsal hippocampusalso enhance memory consolidation. The finding that BLAlesions or intra-BLA infusions of a β-adrenoceptor antag-onist block the memory enhancement indicates thatactivation of the BLA is required to enable the hippocampalinfluence on memory (Roozendaal and McGaugh 1997;Roozendaal et al. 1999b). Evidence from several studiessuggests that this influence involves activation of thenucleus accumbens. Lesions of the nucleus accumbens

Table 1 Treatment effects on memory and amygdala norepinephrine levels

Treatment Effect on memory Effect on amygdala norepinephrine levels Reference

Footshock Varies directly with footshock intensity Varies with footshock intensity Quirarte et al. 1998Epinephrine Enhances Increases Williams et al. 1998Corticosterone Enhances Increases McIntyre et al. 2004Muscimol Impairs Decreases Hatfield et al. 1999Picrotoxin Enhances Increases Hatfield et al. 1999β-endorphin Impairs Decreases Quirarte et al. 1998Naloxone Enhances Increases Quirarte et al. 1998Orphanin FQ/nociceptin Impairs Decreases Kawahara et al. 2004

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block the memory enhancement induced by posttrainingsystemic, intra-BLA or hippocampal administration of GRagonists (Setlow et al. 2000; Roozendaal et al. 2001). Asthe hippocampus is known to project to the nucleusaccumbens, this projection may provide a critical locus ofconverging BLA and hippocampal modulation of memoryconsolidation. Other findings indicate that dopamine acti-vation of both the BLA and nucleus accumbens shell iscritical for memory modulation induced by posttraininginfusions of dopamine administered into either brain region(LaLumiere et al. 2005)

Posttraining infusions of drugs into various corticalregions can also enhance the consolidation of memory forseveral kinds of training (Izquierdo et al. 1997; Ardenghi etal. 1997; Baldi et al. 1999; Sacchetti et al. 1999; Malin andMcGaugh 2006). Importantly, such enhancement requiresan intact and functional BLA. Lesions of the BLA preventthe memory enhancement induced by 8-bromo-cAMPinfused posttraining into the entorhinal cortex (Roesler etal. 2002). Additionally, infusion of a β-adrenoceptorantagonist into the BLA prevents the memory-enhancingeffects of drugs infused into the insular cortex (Miranda andMcGaugh 2004) and the rostral anterior cingulate cortex(Malin et al. 2007).

The BLA also influences memory consolidation via itsprojection to the nucleus basalis, which provides cholinergicactivation of the cortex. Lesions of cortical nucleus basaliscorticopetal cholinergic projections block the memory-modulatory effects of posttraining intra-BLA infusions ofnorepinephrine (Power et al. 2002). This finding, as well asfindings of other studies (Dalmaz et al. 1993; Introini-Collison et al. 1996), indicate that cholinergic influenceswithin the BLA act downstream from noradrenergicactivation. Intra-BLA infusions of the muscarinic choliner-gic agonist oxotremorine, like those of norepinephrine andbicuculline, enhance memory when administered post-training and enhance extinction when administered afterextinction sessions (Boccia et al. 2008). Stimulation of theBLA activates the cortex, as indicated by EEG desynchro-nization, and potentiates nucleus basalis influences oncortical activation. (Dringenberg and Vanderwolf 1996;Dringenberg et al. 2001). Figure 1 summarizes the inter-action of the BLA with other systems regulating memoryconsolidation.

Memory modulation: some implications concerning“cognitive enhancers”

The evidence summarized above clearly indicates thatdrugs and hormones can enhance memory when infuseddirectly into any of several brain regions, including corticalregions as well as subcortical regions. But the findings also

indicate that BLA functioning, including noradrenergicactivation of the BLA is essential for such modulatoryinfluences. The findings further indicate that, at least forseveral drugs that have been examined, memory-modulatoryinfluences induced by systemic administration involvenoradrenergic activation of the BLA. Such findings suggestthat potential “cognitive enhancers” may work via norad-renergic activation of the BLA or through influences thatrequire coactivation of the BLA (Roozendaal et al. 2006b).Additionally, as the findings suggest that arousal-inducedrelease of adrenal stress hormones initiates memory-modulatory influences, novel drugs may act by influencingarousal or stress and thus trigger a modulatory cascadeinvolving noradrenergic activation of the BLA and conse-quent influences on efferent brain regions involved inprocessing memory. However, drugs may also influencememory consolidation via mechanisms that act downstreamfrom amygdala noradrenergic activation. Muscarinic cho-linergic influences on memory do not require BLAnoradrenergic activation (Introini-Collison et al. 1996;Power et al. 2003).

The extensive evidence that the dose–response effects ofmemory-enhancing drugs and hormones are not linear maywell pose serious problems for the development of drugs toenhance long-term memory in human subjects. Memoryenhancement is typically found with a narrow range ofdoses, and higher doses are less effective and are sometimesmemory impairing. Additionally, the doses found to be

Fig. 1 Schematic summarizing interactions of the basolateral amyg-dala with other brain regions in mediating emotional arousal-inducedmodulation of memory consolidation. Experiences initiate memoryconsolidation in many brain regions involved in the forms of memoryrepresented. Emotionally arousing experiences also release adrenalepinephrine and glucocorticoids and activate the release of norepi-nephrine in the basolateral amygdala. The basolateral amygdalamodulates memory consolidation by influencing neuroplasticity inother brain regions. From McGaugh (2000)

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optimal for inducing memory enhancement depend criti-cally on the experimental conditions used in training. Suchfindings suggest that it may be difficult to determine theeffective doses of drugs to be used clinically for humanmemory enhancement.

As emphasized in the discussions above, drugs andhormones enhance the consolidation of memory for manykinds of training experiences, and there is considerableevidence that these treatments produce long-lasting mem-ory enhancement. However, consolidation of long-termmemory is but one aspect of memory that is susceptible orpotentially susceptible to “cognitive enhancers.” A questionof critical importance is that of whether drugs have effectson other aspects of memory, including short-term orworking memory and memory retrieval (e.g., Barros et al.2005). Is it reasonable to presume, on the basis of currentunderstanding of memory, that “cognitive enhancers” willhave comparable effects on all aspects of memory? Someevidence suggests that it is not reasonable to draw thatconclusion. Some drugs appear to enhance long-termmemory without influencing short-term or working memory(Izquierdo et al. 2002; Barros et al. 2002; Vianna et al.2000). Additionally, and importantly, corticosterone, indoses that enhance memory consolidation, impairs short-term or working memory as well as memory retrieval (deQuervain et al. 1998; Roozendaal et al. 2002, 2003, 2004a,b; Barsegyan et al. submitted). Furthermore, such impair-ment, as with enhancement of memory consolidation,involves influences on noradrenergic activation within thebrain (Barsegyan et al. submitted). Clearly, drugs andhormones can, and do, have quite different effects ondifferent aspects of memory.

The evidence reviewed above focused primarily onposttraining neuromodulatory influences regulating the con-solidation of newly acquired information. Although most ofthe evidence concerned effects on original learning, somefindings indicated that neuromodulatory treatments havecomparable effects in enhancing the consolidation of extinc-tion memory. A series of papers published in the 1960s and1970s reported evidence suggesting that the retrieval ofwell-consolidated memories destabilizes the memories andinitiates a “reconsolidation” of the memories, thus makingthem susceptible to postretrieval treatments (e.g., Misanin etal. 1968; Mactutus et al. 1979). This “reconsolidationhypothesis” was recently reactivated (e.g., Przbyslawskiand Sara 1997; Sara 2000; Nader et al. 2000). Support forthe “reconsolidation hypothesis” is mixed (Tronson andTaylor 2007; Amaral et al. 2008). Some studies have failedto replicate evidence of postretrieval memory impairment(e.g., Dawson and McGaugh 1969; Biedenkapp and Rudy2004), and others have reported evidence of recovery frompostretrieval memory impairment over hours or days follow-ing the postretrieval treatment (e.g., Judge and Quartermain

1982; Lattal and Abel 2004; Power et al. 2006; Prado-Alcala et al. 2006; Luft et al. 2008).

In the context of the present review, evidence of“reconsolidation” has suggested the possibility of admin-istering treatments after retrieval of anxiety-producingmemories, including traumatic memories, in order tointerfere with their “reconsolidation” and, thus, weakenthem (Debiec and LeDoux 2006; Tronson and Taylor2007). In view of the finding suggesting that administrationof the β-adrenoceptor antagonist propranolol to traumatizedhumans shortly after the trauma decreases signs ofposttraumatic stress disorder assessed weeks later (Pitmanet al. 2002), assessment of the effects of postretrievaltreatment with propranolol would seem to be a reasonableexperiment. A recent study reported evidence of effective-ness of postretrieval propranolol in reducing subsequentresponsiveness to traumatic stimuli (Brunet et al. 2008).

However, there is extensive evidence that retrieval ofmemories can induce extinction. As discussed above, extinc-tion is enhanced by post-extinction systemic administrationof picrotoxin and D-cycloserine (McGaugh et al. 1990;Ledgerwood et al. 2003) as well as intra-BLA administrationof norepinephrine, bicuculline, and oxotremorine. Thus, ifthe aim of a postretrieval drug treatment is to change theconsequences of retrieving a memory, it is not at all clear, onthe basis of presently available evidence, whether β-adrenergic receptors (or receptors of any other class) shouldbe activated or inactivated after retrieval. Furthermore, atpresent, the evidence evaluating the “reconsolidation hy-pothesis” appears to be too conflicting to allow any clearconclusions to guide the use of postretrieval drug treatmentsto decrease the strength of traumatic memories.

Concluding comments

The findings of animal experiments provide strong evi-dence that drugs and hormones can enhance the consolida-tion of long-term memory. The evidence that enhancementis obtained with a wide variety of training tasks that vary inmotivational and response requirements provides strongsupport for the view that the enhanced performance is dueto actions on systems that regulate memory formation. Theevidence that posttraining drug or hormone administrationis as effective as pretraining administration provides furthersupport for the view that the treatments enhance retentionby influencing memory consolidation. There is alsoextensive evidence that many drugs and hormones modu-late memory consolidation, either directly or indirectly, viathe same neurobiological mechanisms: noradrenergic acti-vation of the BLA whose efferents influence memoryprocessing in many other brain regions. All of these con-clusions concerning memory enhancement are restricted to

10 Psychopharmacology (2009) 202:3–14

drug and hormone effects on memory consolidation. Theevidence indicating that such treatments have quite differenteffects on short-term, working memory, and retrievalprovides new insights into the neurobiology of memory aswell as serious challenges for the development of “cognitiveenhancers.”

References

Amaral OB, Osan R, Roesler R, Tort A (2008) A synapticreinforcement-based model for transient amnesia followingdisruptions of memory consolidation and reconsolidation. Hippo-campus 18:584–601

Andry DK, Luttges MW (1971) Facilitated habituation: strychninedose–response effects on neural and behavioral habituation.Agents Actions 3:103–117

Ardenghi P, Barros D, Izquierdo LA, Bevilaqua L, Schroeder N,Quevedo J, Rodrigues C, Madruga M, Medina JH, Izquierdo I(1997) Late and prolonged post-training memory modulation inentorhinal and parietal cortex by drugs acting on the cAMP/proteinkinase A signalling pathway. Behav Pharmacol 8:745–751

Baldi E, Ambrogi Lorenzini C, Sacchetti B, Tassoni G, Bucherelli C(1999) Effects of combined medial septal area, fimbria–fornixand entorhinal cortex tetrodotoxin inactivations on passiveavoidance response consolidation in the rat. Brain Res 821:503–510

Barco A, Pittenger C, Kandel ER (2003) CREB, memory enhance-ment and the treatment of memory disorders: promises, pitfallsand prospects. Expert Opinion Thera Targets 7:101–114

Barros DM, Pereira P, Medina JH, Izquierdo I (2002) Modulation ofworking memory and of long, but not short-term memory bycholinergic mechanisms in the basolateral amygdala. BehavPharmacol 13:163–167

Barros DM, Ramirez MR, Izquierdo I (2005) Modulation of working,short- and long-term memory by nicotinic receptors in thebasolateral amygdala in rats. Neurobiol Learn Mem 83:113–118

Battig K (1970) The effect of pre- and post-trial application of nicotineon the 12 problems of the Hebb-Williams-test in the rat.Psychopharmacologia 18:68–76

Biedenkapp JC, Rudy JW (2004) Context memories and reactivation:constraints on the reconsolidation hypothesis. Behav Neurosci118:956–964

Berlau DJ, McGaugh JL (2006) Enhancement of extinction memoryconsolidation: the role of the noradrenergic and GABAergicsystems within the basolateral amygdala. Neurobiol Learn Mem86:123–132

Boccia MM, Blake MG, Baratti CM, McGaugh JL (2008) Involve-ment of the basolateral amygdala in muscarinic cholinergicmodulation of extinction memory consolidation. Neurobiol LearnMem (in press)

Bovet D, McGaugh JL, Oliverio A (1966) Effects of posttrialadministration of drugs on avoidance learning of mice. Life Sci5:1309–1315

Breen RA, McGaugh JL (1961) Facilitation of maze learning withposttrial injections of picrotoxin. J Comp Physiol Psychol54:498–501

Brioni JD, McGaugh JL (1988) Posttraining administration ofGABAergic antagonists enhance retention of aversively motivatedtasks. Psychopharmacology 96:505–510

Brioni JD, Nagahara AH, McGaugh JL (1989) Involvement of theamygdala GABAergic system in the modulation of memorystorage. Brain Res 487:105–112

Brunet A, Orr SP, Tremblay J, Robertson K, Nader K, Pitman RK(2008) Effect of post-retrieval propranolol on psychophysiologicresponding during subsequent script-driven traumatic imagery inpost-traumatic stress disorder. J Psychiatr Res 42:503–506

Castellano C, McGaugh JL (1989) Retention enhancement withposttraining picrotoxin: lack of state dependency. Behav NeuralBiol 51:165–170

Clayton EC, Williams CL (2000a) Adrenergic activation of thenucleus tractus solitarius potentiates amygdala norepinephrinerelease and enhances retention performance in emotionallyarousing and spatial tasks. Behav Brain Res 112:151–158

Clayton EC, Williams CL (2000b) Noradrenergic receptor blockade ofthe NTS attenuates the mnemonic effects of epinephrine in anappetitive light–dark discrimination learning task. NeurobiolLearn Mem 74:135–145

Dalmaz C, Introini-Collison IB, McGaugh JL (1993) Noradrenergicand cholinergic interactions in the amygdala and the modulationof memory storage. Behav Brain Res 58:167–174

Dawson RG, McGaugh JL (1969) Electroconvulsive shock effects ona reactivated memory: further examination. Science 166:525–527

Debiec J, LeDoux JE (2006) Noradrenergic signaling in the amygdalacontributes to the reconsolidation of fear memory: treatmentimplications for PTSD. Ann N Y Acad Sci 1071:521–524

Decker MW, Curzon P, Brioni JD, Arneric SP (1994a) Effects ofABT-418, a novel cholinergic channel ligand, on place learningin septal-lesioned rats. Eur J Pharmacol 26:217–222

Decker MW, Brioni JD, Sullivan JP, Buckley MJ, Radek RJ,Raszkiewicz JL, Kang CH, Kim DJ, Giardina WJ, Wasicak JRet al. (1994b) (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole(ABT 418): a novel cholinergic ligand with cognition-enhancingand anxiolytic activities: II. In vivo characterization. J PharmacolExper Thera 270:319–328

de Quervain DJ-F, Roozendaal B, McGaugh JL (1998) Stress andglucocorticoids impair retrieval of long-term spatial memory.Nature 394:787–790

Doty BA, Doty LA (1966) Facilitating effects of amphetamine onavoidance conditioning in relation to age and problem difficulty.Psychopharmacologia 9:234–241

Dringenberg H, Vanderwolf C (1996) Cholinergic activation of theelectrocorticogram: an amygdaloid activating system. Exp BrainRes 108:285–296

Dringenberg H, Saber AJ, Cahill L (2001) Enhanced frontal cortexactivation in rats by convergent amygdaloid and noxious sensorysignals. NeuroReport 12:1295–1298

Duncan CP (1949) The retroactive effect of electroshock on learning.J Comp Physiol Psychol 42:32–44

Evangelista AM, Gattoni RC, Izquierdo I (1970) Effect of amphet-amine, nicotine and hexamethonium on performance of aconditioned response during acquisition and retention trials.Pharmacology 3:91–96

Ferry B, Roozendaal B, McGaugh JL (1999) Role of norepinephrinein mediating stress hormone regulation of long-term memorystorage: a critical involvement of the amygdala. Biol Psychiatry46:1140–1152

Gold PE, McGaugh JL (1975) A single-trace, two-process view ofmemory storage processes. In: Deutsch D, Deutsch JA (eds)Short-term memory. Academic, New York, pp 355–378

Gold PE, van Buskirk R (1975) Facilitation of time-dependentmemory processes with posttrial epinephrine injections. BehavBiol 13:145–153

Greenough WT, McGaugh JL (1965) The effect of strychnine sulphateon learning as a function of time of administration. Psychophar-macologia 8:290–294

Hatfield T, McGaugh JL (1999) Norepinephrine infused into thebasolateral amygdala posttraining enhances retention in a spatialwater maze task. Neurobiol Learn Mem 71:232–239

Psychopharmacology (2009) 202:3–14 11

Hatfield T, Spanis C, McGaugh JL (1999) Response of amygdalarnorepinephrine to footshock and GABAergic drugs using in vivomicrodialysis and HPLC. Brain Res 835:340–345

Hebb DO (1949) The organization of behavior. Wiley, New YorkHock FJ, McGaugh JL (1985) Enhancing effects of HOE 175 on

memory in mice. Psychopharmacology 86:114–117Hudspeth WJ (1964) Strychnine: its facilitation effect on the solution

of a simple oddity problem by the rat. Science 145:1331–1333Huff NC, Wright-Hardesty KJ, Higgins EA, Matus-Amat P, Rudy JW

(2005) Context pre-exposure obscures amygdala modulation ofcontextual-fear conditioning. Learn Mem 12:456–460

Huff NC, Frank M, Wright-Hardesty K, Sprunger D, Matus-Amat P,Higgins E, Rudy JW (2006) Amygdala regulation of immediate-early gene expression in the hippocampus induced by contextualfear conditioning. J Neurosci 26:1616–1623

Humphrey GL (1968) Effects of post-training strychnine on memoryof stage I and stage II sensory of preconditioning in rats. (Ph.D.thesis, University of California Los Angeles.) Ann Arbor, MI:University Microfilms Limited No. 69–7247

Hunt EG, Bauer RH (1969) Facilitation of learning by delayedinjections of pentylenetetrazol. Psychopharmaologia 16:139–146

Hunt EB, Krivanek J (1966) The effects of pentylenetetrazol andmethylphenoxypropane on discrimination learning. Psychophar-macologia (Berl) 9:1–16

Hunter B, Zornetzer SF, Jarvik ME, McGaugh JL (1977) Modulationof learning and memory: Effects of drugs influencing neuro-transmitters. In: Iversen L, Iversen S, Snyder S (eds) Handbookof Psychopharmacology (Vol 8, Drugs, Neurotransmitters, andBehavior). Plenum, New York, pp 531–577

Introini-Collison IB, McGaugh JL (1986) Epinephrine modulateslong-term retention of an aversively-motivated discrimination.Behav Neural Biol 45:358–365

Introini-Collison IB, Dalmaz C, McGaugh JL (1996) Amygdala β-noradrenergic influences on memory storage involve cholinergicactivation. Neurobiol Learn Mem 65:57–64

Izquierdo I, McGaugh JL (2000) Behavioural pharmacology and itscontribution to the molecular basis of memory consolidation.Behav Pharmacol 11:517–534

Izquierdo I, Medina JH (1991) GABAA receptor modulation ofmemory: the role of endogenous benzodiazepines. TrendsPharmacol Sci 12:260–265

Izquierdo I, da Cunha C, Rosat R, Jerusalinsky D, Ferreira MB,Medina JH (1992) Neurotransmitter receptors involved in post-training memory processing by the amygdala, medial septum,and hippocampus of the rat. Behav Neural Biol 58:16–26

Izquierdo I, Quillfeldt JA, Zanatta MS, Quevedo J, Schaeffer E,Schmitz PK, Medina JH (1997) Sequential role of hippocampusand amygdala, entorhinal cortex and parietal cortex in formationand retrieval of memory for inhibitory avoidance in rats. Eur JNeurosci 9:786–793

Izquierdo LA, Barros DM, Vianna MR, Coitinho A, deDavid e SilvaT, Choi H, Moletta B, Medina JH, Izquierdo I (2002) Molecularpharmacological dissection of short- and long-term memory. CellMolec Neurobiol 22:269–287

Judge ME, Quartermain D (1982) Characteristics of retrograde amnesiafollowing reactivation of memory in mice. Physiol Behav 28:585–590

Kawahara Y, Hesselink MB, van Scharrenburg G, Westerink BHC(2004) Tonic inhibition by orphanin FQ/nociceptin of noradren-aline neurotransmission in the amygdala. Eur J Pharmacol485:197–200

Kelemen K, Bovet D (1961) Effect of drugs upon the defensivebehavior of rats. Acta Physiologica, Acad Sci Hung 19:143–154

Krivanek J (1971) Facilitation of avoidance learning by pentylenetetrazolas a function of task difficulty, deprivation and shock level.Psychopharmacologia 20:213–229

Krivanek JA, McGaugh JL (1968) Effects of pentylenetetrazol onmemory storage in mice. Psychopharmacologia 12:303–321

Krivanek JA, McGaugh JL (1969) Facilitating effects of pre- andposttrial amphetamine administration on discrimination learningin mice. Agents Actions 1:36–42

LaLumiere RT, Buen T-V, McGaugh JL (2003) Posttraining intra-basolateral amygdala infusions of norepinephrine enhance con-solidation of memory for contextual fear conditioning. J Neurosci23:6754–6758

LaLumiere RT, Nawar EM, McGaugh JL (2005) Modulation ofmemory consolidation by the basolateral amygdala or nucleusaccumbens shell requires concurrent dopamine receptor activa-tion in both brain regions. Learn Mem 12:296–301

Lashley KS (1917) The effect of strychnine and caffeine upon rate oflearning. Psychobiology 1:141–170

Lattal KM, Abel T (2004) Behavioral impairments caused byinjections of the protein synthesis inhibitor anisomycin aftercontextual retrieval reverse with time. Proc Natl Acad Sci USA101:4667–4672

Ledgerwood L, Richardson R, Cranney J (2003) Effects of D-cycloserineon extinction of conditioned freezing. Behav Neurosci 117:341–349

Liang KC, Bennett C, McGaugh JL (1985) Peripheral epinephrinemodulates the effects of posttraining amygdala stimulation onmemory. Behav Brain Res 15:93–100

Liang KC, Juler RG, McGaugh JL (1986) Modulating effects of post-training epinephrine on memory: involvement of the amygdalanoradrenergic system. Brain Res 368:125–133

Liang KC, McGaugh JL, Yao H-Y (1990) Involvement of amygdalapathways in the influence of posttraining amygdala norepineph-rine and peripheral epinephrine on memory storage. Brain Res508:225–233

Liang KC, Chen L, Huang T-E (1995) The role of amygdalanorepinephrine in memory formation: involvement in the memoryenhancing effect of peripheral epinephrine. Chin J Physiol 38:81–91

Luft T, Amaral OB, Schwartsmann G, Roesler R (2008) Transientdisruption of fear-related memory by post-retrieval inactivationof gastrin-releasing peptide or N-methyl-D-aspartate receptors inthe hippocampus. Curr Neurovasc Res 5:21–27

Luttges MW, McGaugh JL (1971a) Facilitating effects of bemegride onretention of a visual discrimination task. Agents Actions 1:234–239

Luttges MW, McGaugh JL (1971b) Facilitation of avoidance condi-tioning in mice by posttraining administration of bemegride.Agents Actions 3:118–121

Mactutus CF, Riccio DC, Ferek JM (1979) Retrograde amnesia for old(reactivated) memory: Some anomalous characteristics. Science204:1319–1320

Malin EL, McGaugh JL (2006) Differential involvement of thehippocampus, anterior cingulate cortex and basolateral amygdalain memory for context and footshock. Proc Natl Acad Sci USA103:1959–1963

Malin EL, Ibrahim DY, Tu JW, McGaugh JL (2007) Involvement ofthe rostral anterior cingulate cortex in consolidation of inhibitoryavoidance memory: interaction with the basolateral amygdala.Neurobiol Learn Mem 87:295–302

McGaugh JL (1959) Some neurochemical factors in learning. Doctoraldissertation, University of California, Berkeley

McGaugh JL (1961) Facilitative and disruptive effects of strychninesulphate on maze learning. Psychol Reports 8:99–104

McGaugh JL (1966) Time-dependent processes in memory storage.Science 153:1351–1358

McGaugh JL (1973) Drug facilitation of learning and memory. AnnuRev Pharmacol 13:229–241

McGaugh JL (1989a) Dissociating learning and performance: drugand hormone enhancement of memory storage. Brain Res Bull23:339–345

12 Psychopharmacology (2009) 202:3–14

McGaugh JL (1989b) Involvement of hormonal and neuromodulatorysystems in the regulation of memory storage. Annu Rev Neurosci12:255–287

McGaugh JL (1990) Significance and remembrance: the role ofneuromodulatory systems. Psychol Sci 1:15–25

McGaugh JL (1999) The perseveration-consolidation hypothesis:Müller and Pilzecker, 1900. Brain Res Bull 50:445–446

McGaugh JL (2000) Memory: a century of consolidation. Science287:248–251

McGaugh JL (2002) Memory consolidation and the amygdala: asystems perspective. Trends Neurosci 25:456–461

McGaugh JL (2004) The amygdala modulates the consolidation ofmemories of emotionally arousing experiences. Annu RevNeurosci 27:1–28

McGaugh JL, Cahill L (2002) Emotion and memory: central andperipheral contributions. In Davidson RJ, Scherer KR, GoldsmithHH (eds) Handbook of affective science. Oxford UniversityPress, pp 93–116

McGaugh JL, Herz MJ (1972) Memory Consolidation. Albion, SanFrancisco

McGaugh JL, Izquierdo I (2000) The contribution of pharmacology toresearch on the mechanisms of memory formation. TrendsPharmacol Sci 21:208–210

McGaugh JL, Krivanek J (1970) Strychnine effects on discriminationlearning in mice: effects of dose and time of administration.Physiol Behav 5:1437–1442

McGaugh JL, Petrinovich L (1959) The effect of strychnine sulphateon maze-learning. Am J Psychol 72:99–102

McGaugh JL, Petrinovich L (1963) Comments concerning the basis oflearning enhancement with central nervous system stimulants.Psychol Reports 12:211–214

McGaugh JL, Petrinovich LF (1965) Effects of drugs on learning andmemory. Internatl Rev Neurobiol 8:139–196

McGaugh JL, Roozendaal B (2002) Role of adrenal stress hormonesin forming lasting memories in the brain. Curr Opin Neurobiol12:205–210

McGaugh JL, Thomson CW (1962) Facilitation of simultaneousdiscrimination learning with strychnine sulphate. Psychopharma-cologia 3:166–172

McGaugh JL, Westbrook W, Burt G (1961) Strain differences in thefacilitative effects of 5–7-diphenyl-1–3- diazadamantan-6-o1(1757 I.S.) on maze learning. J Comp Physiol Psychol 54:502–505

McGaugh JL, Thomson CW, Westbrook WH, Hudspeth WJ (1962a)A further study of learning facilitation with strychnine sulphate.Psychopharmacologia 3:352–360

McGaugh JL, Westbrook WH, Thomson CW (1962b) Facilitation ofmaze learning with posttrial injections of 5-7-diphenyl-1-3-diazadamantan-6-o1 (1757 I.S.). J Comp Physiol Psychol55:710–713

McGaugh JL, Liang KC, Bennett C, Martinez JL Jr, Messing RB,Ishikawa K (1982) Modulating influences of peripheral hor-mones on memory storage. In: Saito S, Yanagita T (eds) Learningand memory drugs as reinforcer. Excerpta Medica, Amsterdam,pp 70–82

McGaugh JL, Castellano C, Brioni JD (1990) Picrotoxin enhanceslatent extinction of conditioned fear. Behav Neurosci 104:262–265

McGaugh JL, Cahill L, Ferry B, Roozendaal B (2000) Brain systemsand the regulation of memory consolidation. In: Bolhuis JJ (ed)Brain, perception, memory: advances in cognitive neuroscience.Oxford University Press, London, pp 233–251

McIntyre CK, Hatfield T, McGaugh JL (2002) Amygdala norepi-nephrine levels after training predict inhibitory avoidanceretention performance in rats. Eur J Neurosci 16:223–1226

McIntyre CK, Roozendaal B, McGaugh JL (2004) Glucocorticoidtreatment enhances training-induced norepinephrine release in theamygdala. Soc Neurosci Abstr 772:12

McIntyre CK, Miyashita T, Setlow B, Marjon KD, Steward O,Guzowski JF, McGaugh JL (2005) Memory-influencing intra-basolateral amygdala drug infusions modulate expression of Arcprotein in the hippocampus. Proc Natl Acad Sci USA 102:10718–10723

Miles WR (1929) Drug effects measured by acquired patterns ofresponse. Am J Physiol 90:451

Miranda MI, McGaugh JL (2004) Enhancement of inhibitoryavoidance and conditioned taste aversion memory with insularcortex infusions of 8-Br-cAMP: involvement of the basolateralamygdala. Learn Mem 11:312–317

Misanin JR, Miller RR, Lewis DJ (1968) Retrograde amnesiaproduced by electroconvulsive shock after reactivation of aconsolidated memory trace. Science 160:554–555

Müller GE, Pilzecker A (1900) Experimentelle Beitrage zur Lehrevom Gedachtniss. Z Psychol 1:1–288

Nader K, Schafe GE, LeDoux JE (2000) The labile nature ofconsolidation theory. Nat Rev Neurosci 1:216–219

Okuda S, Roozendaal B McGaugh JL (2004) Glucocorticoid effectson object recognition memory require training-associated emo-tional arousal. Proc Natl Acad Sci USA 101:853–858

Oliverio A (1968) Effect of nicotine and strychnine on transfer ofavoidance learning in the mouse. Life Science 7:1163–1167

Orsingher OA, Fulginiti S (1971) Effects of alpha-methyl tyrosine andadrenergic blocking agents on the facilitating action of amphet-amine and nicotine on learning in rats. Psychopharmaologia 19:231–240

Ott T, Matthies H (1971) Influence of orotic acid and pentetrazol uponacquisition and extinction on the model of optic discrimination.Acta Biol Med Germ 26:79–85

Packard MG, Cahill L, McGaugh JL (1994) Amygdala modulation ofhippocampal-dependent and caudate nucleus-dependent memoryprocesses. Proc Natl Acad Sci USA 91:8477–8481

Petrinovich LF (1963) Facilitation of successive discriminationlearning by strychnine sulphate. Psychopharmacologia 4:103–113

Petrinovich L, Bradford D, McGaugh JL (1965) Drug facilitation ofmemory in rats. Psychonom Sci 2:191–192

Pitman RK, Sanders KM, Zusman RM, Healy AR, Cheema F, LaskoNB, Cahill L, Orr SP (2002) Pilot study of secondary preventionof posttraumatic stress disorder with propranolol. Biol Psychiatry51:189–192

Power AE, Thal LJ, McGaugh JL (2002) Lesions of the nucleusbasalis magnocellularis induced by 192 IgG-saporin blockmemory enhancement with posttraining norepinephrine in thebasolateral amygdala. Proc Natl Acad Sci USA 99:2325–2329

Power AE, Vazdarjanova A, McGaugh JL (2003) Muscariniccholinergic influences in memory consolidation. Neurobiol LearnMem 80:178–183

Power AE, Berlau DJ, McGaugh JL, Steward O (2006) Anisomycininfused into the hippocampus fails to block “reconsolidation” butimpairs extinction: The role of re-exposure duration. Learn Mem13:27–34

Prado-Alcalá RA, Díaz del Guante MA, Gárin-Aguilar ME, Díaz-Trujillo A, Quirarte GL, McGaugh JL (2006) Amygdala orhippocampus inactivation after retrieval induces temporarymemory deficit. Neurobiol Learn Mem 86:144–149

Prien RF, Wayner MJ Jr, Kahan S (1963) Lack of facilitation in mazelearning by picrotoxin and strychnine sulfate. Am J Physiol 204:488–492

Przbyslawski J, Sara SJ (1997) Reconsolidation of memory after itsreactivation. Behav Brain Res 84:241–246

Quirarte GL, Roozendaal B, McGaugh JL (1997) Glucocorticoidenhancement of memory storage involves noradrenergic activa-tion in the basolateral amygdala. Proc Natl Acad Sci USA 94:14048–14053

Psychopharmacology (2009) 202:3–14 13

Quirarte GL, Galvez R, Roozendaal B, McGaugh JL (1998)Norepinephrine release in the amygdala in response to footshockand opioid peptidergic drugs. Brain Res 808:134–140

Ressler KJ, Paschall G, Zhou X-L, Davis M (2002) Regulation ofsynaptic plasticity genes during consolidation of fear conditioning.J Neurosci 22:7892–7902

Roesler R, Roozendaal B, McGaugh JL (2002) Basolateral amygdalalesions block the memory-enhancing effect of 8-Br-cAMPinfused into the entorhinal cortex of rats after training. Eur JNeurosci 15:905–910

Roozendaal B (2000) Glucocorticoids and the regulation of memoryconsolidation. Psychoneuroendocrinology 25:213–238

Roozendaal B, McGaugh JL (1997) Glucocorticoid receptor agonistand antagonist administration into the basolateral but not centralamygdala modulates memory storage. Neurobiol Learn Mem67:176–179

Roozendaal B, Williams CL, McGaugh JL (1999a) Glucocorticoidreceptor activation in the rat nucleus of the solitary tractfacilitates memory consolidation: involvement of the basolateralamygdala. Eur J Neurosci 11:1317–1323

Roozendaal B, Nguyen BT, Power A, McGaugh JL (1999b)Basolateral amygdala noradrenergic influence enables enhance-ment of memory consolidation induced by hippocampal gluco-corticoid receptor activation. Proc Natl Acad Sci USA 96:11642–11647

Roozendaal B, de Quervain DJ-F, Ferry B, Setlow B, McGaugh JL(2001) Basolateral amygdala-nucleus interactions in mediatingglucocorticoid effects on memory consolidation. J Neurosci21:2518–2525

Roozendaal B, Quirarte GL, McGaugh JL (2002) Glucocorticoidsinteract with the basolateral amygdala β-adrenoceptor-cAMP/PKA system in influencing memory consolidation. Eur J Neurosci15:553–560

Roozendaal B, Griffith QK, Buranday J, de Quervain DJ-F, McGaughJL (2003) The hippocampus mediates glucocorticoid-inducedimpairment of spatial memory retrieval: dependence on thebasolateral amygdala. Proc Natl Acad Sci USA 100:1328–1333

Roozendaal B, de Quervain DJ-F, Schelling G, McGaugh JL (2004a)A systemically administered β-adrenoceptor antagonist blockscorticosterone-induced impairment of contextual memory retrievalin rats. Neurobiol Learn Mem 81:150–154

Roozendaal B, Hahn EL, Nathan SV, de Quervain DJ-F, McGaugh JL(2004b) Glucocorticoid effects on memory retrieval requireconcurrent noradrenergic activity in the hippocampus and baso-lateral amygdala. J Neurosci 24:8161–8169

Roozendaal B, Hui GK, Hui IR, Berlau DJ, McGaugh JL WeinbergerNM (2006a) Basolateral amygdala noradrenergic activity mediatescorticosterone-induced enhancement of auditory fear condi-tioning. Neurobiol Learn Mem 86:249–255

Roozendaal B, Okuda S, Van der Zee EA, McGaugh JL (2006b)Glucocorticoid enhancement of memory requires arousal-inducednoradrenergic activation in the basolateral amygdala. Proc NatlAcad Sci USA 103:6741–6746

Roozendaal B, Castello N, Barsegyan A, McGaugh JL (2008)Noradrenergic activation of the basolateral amygdala modulatesconsolidation of object recognition memory. Neurobiol LearnMem (in press)

Routtenberg A, Rekart JL (2005) Post-translational protein modifica-tion as the substrate for long-lasting memory. Trends Neurosci28:12–19

Sacchetti B, Lorenzini CA, Baldi E, Tassoni G, Bucherelli C (1999)Auditory thalamus, dorsal hippocampus, basolateral amygdala,and perirhinal cortex role in the consolidation of conditionedfreezing to context and to acoustic conditioned stimulus in therat. J Neurosci 19:9570–9578

Sandi C, Rose SPR (1994) Corticosterone enhances long-termpotentiation in one-day-old chicks trained in a weak passiveavoidance learning paradigm. Brain Res 647:106–112

Sara SJ (2000) Strengthening the shaky trace through retrieval. NatRev Neurosci 1:212–213

Setlow B, Roozendaal B, McGaugh JL (2000) Involvement of abasolateral amygdala complex – nucleus accumbens pathway inglucocorticoid-induced modulation of memory storage. Eur JNeurosci 12:367–375

Silva AJ, Kogan JH, Frankland PW, Kida S (1998) CREB andmemory. Annu Rev Neurosci 21:127–148

Sternberg DB, Martinez JL Jr, Gold PE, McGaugh JL (1985) Age-relatedmemory deficits in rats and mice: Enhancement with peripheralinjections of epinephrine. Behav Neural Biol 44:213–220

Stratton LO, Petrinovich L (1963) Post-trial injections of an anti-cholinesterase drug and maze learning in two strains of rats.Psychopharmacologia 5:47–54

Sweatt JD (2007) Behavioural neuroscience: down memory lane.Nature 447:151–152

Thiessen DD, Schlesinger K, CalhounWH (1961) Better learning: neuralenhancement or reduced interference. Psychol Report 9:493–496

Tolman EC (1932) Purposive Behavior in Animals and Men. TheCentury, New York

Tronson NC, Taylor JR (2007) Molecular mechanisms of memoryreconsolidation. Nat Rev Neurosci 8:262–275

Vianna MR, Izquierdo LA, Barros DM, Walz R, Medina JH, IzquierdoI (2000) Short- and long-term memory: differential involvementof neurotransmitter systems and signal transduction cascades.Annu Acad Bras Cienc 72:353–364

Westbrook WH, McGaugh JL (1964) Drug facilitation of latentlearning. Psychopharmacologia 5:440–446

Whishaw IQ, Cooper RM (1970) Strychnine and suppression ofexploration. Physiol Behav 5:647–649

Wilensky AE, Schafe GE, LeDoux JE (2000) The amygdalamodulates memory consolidation of fear-motivated inhibitoryavoidance learning but not classical fear conditioning. J Neurosci20:7059–7066

Williams CL, McGaugh JL (1993) Reversible lesions of the nucleus ofthe solitary tract attenuate the memory-modulating effects ofposttraining epinephrine. Behav Neurosci 107:1–8

Williams CL, Men D, Clayton EC, Gold PE (1998) Norepinephrinerelease in the amygdala after systemic injections of epinephrineor inescapable footshock: contribution of the nucleus of thesolitary tract. Behav Neurosci 112:1414–1422

Zerbolio DJ (1967) Within-strain facilitation and disruption ofavoidance learning by picrotoxin. Psychonomic Sci 9:411–412

Zorawski M, Killcross S (2002) Posttraining glucocorticoid receptoragonist enhances memory in appetitive and aversive Pavloviandiscrete-cue conditioning paradigms. Neurobiol Learn Mem78:458–464

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