BEHAVIOURAL BRAIN RESEARCH ELSEVIER Behavioural Brain Research 77 (1996) 1-21

Review article Psychopharmacology of memory modulation: Evidence for multiple interaction among neurotransmitters and hormones Claudio Castellano a.,, Simona Cabib ", Stefano Puglisi-Allegra b " Istituto di Psicobiologia e Psicofarmacologia (CNR), via Reno 1, Rome 1-00198, Italy b Department of Psychology (Neuroscience section), University of Rome 'La Sapienza', Rome, Italy Received 16 January 1995; revised 26 June 1995; accepted 26 June 1995

Abstract

Experimental results are reviewed which indicate that memory storage can be altered by a number of post-training treatments that affect different hormones and neurotransmitters. Moreover, evidence was reported which suggests that the action of treatments effective on memory processes involves interactions among different systems, consistently with the complexity of brain systems. In the last decade, inbred strains have been exploited to investigate the role of neurotransmitter and hormone systems in learning and memory, leading to behavioural and neurochemical correlations based on strain differences that provide unique information on the biological systems underlying behaviour. Research carded out on the inbred strains of mice C57BL/6 (C57) and DBA/2 (DBA), demonstrates that the genetic makeup plays an important role in modulating response to drug administration. Thus, recent results have shown that in C57 mice, similarly to what occurs in outbred strains of mice or in rats, GABAergic agonists impair memory and antagonists improve it, whilst the opposite is evident in the DBA strain. By contrast, post-training administration of selective Ell or D2 agonists impairs and post-training administration of selective antagonists improves retention in DBA mice, whilst these agents have opposite effects in the C57 strain. Dose- and strain-dependent effects are evident also following post-training cort:icosterone as well as opioid agonists and antagonists administration. On the other side, these two strains react similarly to oxotremorine (improvement) and to atropine (impairment) administration, DBA mice being more responsive to the effects of both drugs than C57 mice. Data on the interactions between agents acting upon different neurotransmitter and/or hormonal systems in these strains indicate strain-dependent synergistic or antagonistic interactions among some of these systems, pointing to inbred strains of mice as an important methodological tool in the study of neural and hormonal factors involved in emotion and in its effects on cognition. In particular, these studies have been carried out on inbred strains of mice from which recombinant inbred (RI) strains are available that have recently been proposed as a choice experimental method in psychopharmacogenetics.

Keywords: Memory;One-way passive avoidance; Strain differences; Acetylcholine;Dopamine; Norepinephrine; Epinephrine; ACTH; Glucocorticoid; Peptide; GABA; Benzodiazepine; Serotonin; Excitatory amino acids; Opioid; Neurotransmitters interaction

1. Introduction ermnestic or hypomnestic property of pharmacological compounds or to investigate how the brain accomplishes In the last decades growing evidence has been pro- memory processes. In the last case, drugs can be viewed vided in support of an involvement in memory processes as tools to dissect the neural mechanisms involved in for a number of different hormonal and neurotransmitter memory and to elucidate as much as possible neurotrans- systems. A number of experimental paradigms have been mitter functioning [163]. Drugs may also be used as used for the study of the involvement of these systems tools to investigate structural principles of memory, i.e., in the complex processes associated with memory. Most memory changes over time and how many processes are have been aimed at asses:~ing the effects of drug admin- involved (ib). istration on memory processes either to evaluate hyp- Although a common strategy in memory pharma- cology lies on administering a drug treatment prior to learning, the post-trial treatment strategy evolved to * Corresponding author. Fax: + 39 6 8553561 eliminate a number of potential problems the former

0166-4328/96 $15.00 © 1996 Elsevier Science B.V. All rights reserved SSDI 0166-4328 (96) 00200-.6 2 Claudio Castellano et al./Behavioural Brain Research 77 (1996) 1 21 strategy presents 1-78]. In post-training treatment, a involvement in memory processes. In fact, they are drug is administered at some time after the learning or different in a number of neurochemical parameters con- acquisition phase. This strategy eliminates the potential cerning neurotransmitter systems such as GABA [42], problems of the pre-training administration such as acetylcholine [136], dopamine [19,150], endogenous alteration of sensory and motor events involved in opioids 38, as well as in the behavioral effects of drugs learning, focusing its action on memory trace, rather acting on these systems [26,33,42,135]. Thus they allow than on performance-related events (ib). to focus on possible strain-dependent modulatory factors Lasting memory is not formed at the moment that related to neurotransmitter functioning that may help new information is acquired, and retention can be to investigate the neural mechanisms underlying memory affected by treatments administered shortly after learn- processes (Table 1). ing, a phenomenon that has generally been interpreted as indicating that the treatments affect retention by altering post-training neural processes underlying the 2. Acetylcholine storage of newly acquired information [ 124]. Although the effects of post-trial administration of Acetylcholine (ACh) received considerable attention various agents have been interpreted as indications of concerning its possible involvement in memory processes their affecting memory traces. However, they did not for historical as well as conceptual reasons. A large body allow to conclude that the neurotransmitters, modula- of evidence points to brain cholinergic systems as playing tors or hormones they act upon play a specific role in a major role in memory storage [3,53]. Moreover, in the process of memory storage [78]. the last two decades clinical evidence has shown that A large body of evidence now shows that retention Alzheimer disease is accompanied by a decline in cholin- can be modulated by the administration of hormones ergic functioning [3,124]. Although recent studies have and neuromodulators that are normally released by shown that other brain neurotransmitter systems, such experiences comparable to those used in training, and as dopamine, norepinephrine, GABA, serotonin, soma- that retention can be altered by treatments that alter tostatin systems are involved in Alzheimer's disease, a the functioning of these systems, therefore indicating reduction of cells is evident in the basal cholinergic brain that memory storage processes are modulated by the systems, including the nucleus basalis of Meynert and action of endogenous systems activated by learning the septum, which are known to project cholinergic experiences [124]. In particular, treatments affecting axons to the cortex and the hippocampus. It has also hormone or neurotransmitter functioning would affect been shown that the functioning of the cholinergic memory processes by interfering with those mechanisms systems declines with aging [3,124]. involved in memory storage [59]. Research on ACh involvement in memory processes Moreover, these studies indicate that different hor- has taken distinct experimental approaches consisting mone and neurotransmitter systems play a role in in the use of inhibitors of cholinesterase enzymes such physiological processes underlying memory storage. as physostigmine and disisopropylfluorophosphate Indeed, the figure emerging from recent evidence suggests (DPF) or cholinomimetic agents such as nicotine and that the action of treatments effective on memory pro- arecoline or oxotremorine or anticholinergic agents such cesses involves interactions among different systems, as atropine and scopolamine [78]. consistently with the complexity of brain systems. Thus, A number of studies have shown that post-training in this review we will pay special attention to evidence administration of physostignine enhances memory in a in support of these interactions reviewing data on the number of tasks such as appetitively motivated learning, facilitating or impairing effects of post-training treat- active avoidance, inhibitory avoidance, and aversively ments with hormones or neurotransmitters. In the last decade a growing interest in the study of Table 1 genotype-related response to aversive as well rewarding Summary of the effectsof postrial administration of direct and indirect agonists acting on differentneurotransmitters or hormones on memory stimuli has pointed to inbred strains of mice as an storage in rodents important methodological tool in the study of neural and hormonal factors involved in emotion and in its Neurotransmitter/hormone Rats Mice strains effects on cognition. In the present review strain studies on memory storage will receive particular attention, CD1/SWISS C57BL/6 DBA/2 since from this approach and from possible further ACh + + + + behaviour genetics studies important experimental DA + + + - results are likely to clarify the biological basis of memory GABA -- - - + processes. Corticosterone + + ÷ - Opioids + ? - + - C57 BL/6 and DBA/2 strains will be considered, since they appear suited for the study of neurotransmitter Note: +, improvement; -, impairment. Claudio Castellano et al./Behavioural Brain Research 77 (1996) 1-21 3 motivated discrimination learning [124]. Accordingly, systems play a similar role in the modulation of memory secoverine, a muscarinic ~Lntagonist that blocks autore- storage in the mouse, while other neurotransmitter sys- ceptors mediating the inhibition of acetylcholine release, tems such as DA, GABA, opioids, serotonin, glutamate, enhances retention of an inhibitory avoidance when whose manipulation leads to opposite effects in the administered post-training in rats. Moreover, secoverine afore-mentioned strains, may have a role that depends in a dose ineffective when injected alone, was shown to on genotype-related anatomical and functional neural potentiate the memory-enhancing effects of physostig- pattern. mine. These results indicate that ACh released by train- Recent results on the role of DA systems in the effects ing is involved in the modulation of memory storage. produced by oxotremorine and atropine are in line with The effects of secoverine may explain some previous this view. Indeed, pretreatment with either selective D1 results that showed post-t~raining administration of atro- or D2 dopamine (DA) receptor agonists SKF 38393 pine at low doses to improve retention [60]. In fact, at and LY 171555 at per se non-effective doses (5 and low dose the muscarinic ~tntagonists may block presyn- 0.25 mg/kg, respectively) have been shown to potentiate aptic receptors. the effects of a dose of oxotremorine (0.04 mg/kg) in Post-training administration of nicotine facilitates C57 mice, while either selective D1 or D2 receptor memory processes in a number of experimental para- antagonists SCH 23390 and (-)-sulpiride administered digms [78]. Also post-tr~tining systemic administration at per se non-effective doses (0.025 and 6 mg/kg, respec- of muscarinic receptor ag,anists, including arecoline and tively), antagonised the effects of the muscarinic receptor oxotremorine improves rnemory (in ib), dose- and time- agonist on memory consolidation in this strain. Both dependently. D1 and D2 selective agonists antagonised the effects of Post-training administration of cholinergic antago- a dose of atropine (3 mg/kg), while selective D1 or D2 nists such as atropine and scopolamine have been antagonists potentiated it (in C57 mice). By contrast, in reported to impair memory consolidation [73,124], DBA mice both D1 and D2 selective agonists antagon- although a few studies failed to show any effect [80,82]. ised the effects (of a dose) of oxotremorine (0.02 mg/kg) Pharmacological studies indicate that retention is while potentiating the effects (of a dose) of atropine affected by post-training alteration of cholinergic sys- (2 mg/kg). Selective D1 or D2 antagonists potentiated tems, thus strongly suggesting that these systems are the effects of oxotremorine, while they antagonised those activated during training and such activation plays a of atropine in this strain. role in memory processes. These results indicate that selective D1 or D2 agonists It is worth noting that the effects of cholinergic drugs and antagonists affect oxotremorine and atropine action summarised here are to be ascribed to brain processes on memory consolidation in an opposite manner in the since memory is not affected by cholinergic drugs that two inbred strains, pointing to genotype-dependent do not pass the blood-brain barrier [ 124]. interaction between cholinergic and dopaminergic activ- Recent results have shown strain-dependent effects of ity in memory consolidation. muscarinic receptor agoniist, oxotremorine (0.01, 0.02 or In such strain-dependent interaction between DA and 0.04 mg/kg), and antagonist, atropine (1, 2 or 3 mg/kg), ACh systems in memory processes, both D1 and D2 in C57BL/6 and DBA/2 mice. receptors play a similar role in modulating ACh activity, Post-training intraperitoneal (i.p.) administration of consistent with previous results showing similar (inter- the muscarinic receptc,r agonist dose-dependently changeable) effects of selective D1 or D2 agonists on improves retention of an inhibitory avoidance response memory consolidation [41,42,47,149,150]. in C57 as well as in DBA mice, while atropine impairs These results are consistent with previous results that memory consolidation i~ both strains, the DBA mice have shown opposite effects of D1 or D2 selective being more responsive to the effects of both drugs than agonists or antagonists as well as of indirect DA agonists C57 mice (Castellano et al., in preparation), [141]. In on memory consolidation in C57 and DBA mice. In fact, oxotremorine and atropine at the doses of 0.02 and fact, both D1 and D2 agonists enhance memory in C57 2 mg/kg, respectively, were effective in DBA mice but mice while impair it in the DBA strain, and the antago- not in C57 which responded to the doses of 0.04 (oxo- nists impair consolidation in the former strain and tremorine) and 3 mg/kg (atropine). It is worth noting enhance it in the latter [41,47,150]. that the strain-dependent effects of cholinergic manipula- Recent results have show that D1 or D2 DA receptor tion, differently from what was observed with pharm- agonists as well as psychostimulants increase acetylcho- acological manipulation of other neurotransmitter line release in the hippocampus and the caudate nucleus systems or hormones (Cabib et al., in preparation) [85,86]. These data seem consistent with our results [41,42,47,150], did not lead to opposite behavioural and suggest that strain dependent differences in DA-ACh effects in mice of the C57 and the DBA strain but only functional interaction may be ascribed to a different to a different sensitivity to the effects of the drugs used. strain-dependent distribution in the brain of DA recep- Therefore, it may be argued that (brain) cholinergic tors of D1 and D2 type [ 18,41,149], leading to opposite 4 Claudio Castellano et al./Behavioural Brain Research 77 (1996) 1~1 activation of brain areas and/or neurotransmitters be related to improved memory consolidation. In this involved in memory processes. framework, the opposite effects on memory storage Although the interaction between ACh and DA in observed in DBA mice receiving post-training DAergic memory processes may involve a number of brain sys- or GABAergic agents, compared with C57 mice, need tems which pharmacological and behavioural data sug- the presence of an additional GABA interneuron to be gest as possible sites mediating ACh-DA interaction in explained. Pharmacological results militate against this memory processes, such as the caudate nucleus, the view, whatsoever. Actually, GABA agonists and antago- amygdala and the hippocampus [16,96,138,145,159, nists systemically administered are likely to affect GABA 168,171], peripheral DA system [162] must be also receptor on the last step of septo-hippocampal GABA- taken into account. ACh connection, therefore overcoming the involvement Functional interactions in modulation of memory of the hypothetical functional sequence of GABA neu- storage between ACh and GABA have been pointed out rons projecting to ACh cells. Consequently their effects by results showing that GABA agonist muscimol injected should be similar in the strain characterised by one in the basal forebrain impairs retention [133]. These GABA interneuron and in that provided by two results are likely to depend on the GABA neurons interneurons. On the other hand, as we have seen, GABA projecting to the basal forebrain that would inhibit ACh agonists or antagonists produce in DBA mice opposite release in this brain area [23]. effects of those produced in C57. Therefore, the presence It must be pointed out that evidence exists indicating of an additional interneuron placed between the GABA a GABA interneuron in the septum projecting to cholin- interneuron and the cholinergic neuron is consistent ergic neurons of the septo-hippocampal system inhibiting with the data considered, but such an additional the release of ACh in the hippocampus. interneuron cannot be GABAergic in nature. A dopa- The presence of two GABA interneurons has also minergic neuron could explain the behavioural data on been hypothesized [85,86]. A GABAergic interneuron the effects of DA, GABA and ACh compounds on in the septo-hippocampal system may also account for memory consolidation of passive avoidance in C57 and the interaction of DA and ACh manipulation on memory DBA mice considered here, although it seems unlikely storage. A number of recent studies are consistent with that individuals belonging to the same species (such as earlier evidence that retention is enhanced by post- inbred mice) present such differences in brain circuitry: training systemic administration of GABA receptor antagonists and impaired by GABA agonists [124], effects that appear to be centrally mediated, since reten- 3. Dopamine tion is not affected by post-training systemic injection of bicuculline methiodide, a peripherally acting GABA The interest in dopamine (DA) systems involvement receptor antagonist [ 14]. in memory processes is related to different aspects of Recent results on the effects of GABA receptor ago- these neurotransmitters, above all to the fact that nists or antagonist on memory consolidation of an psychostimulants have received particular attention inhibitory avoidance in C57 and DBA strains [42] have because of their well-known facilitating effects, and more shown that in the C57 mice, similarly to what occurs in recently to the fact that DA systems have been known outbred mice or in the rat, GABA agonists impair to play a major role in the emotional response to memory and antagonists improve it. By contrast, in rewarding as well to aversive stimuli [ 114]. DBA mice GABA agonists improve memory while Post-training administration of psychostimulants has antagonists impair it [42]. been reported to increase memory [ 91,111,122,137,150], As shown by the afore-mentioned study on the effects while reserpine, which decreases catecholamine levels, of oxotremorine and atropine, the cholinergic activation produces memory impairment [122]. Since these drugs has similar effects on memory processes in the two are active on DA systems a role of DA in memory strains. Thus, the effects of DA agents in these strains consolidation has been envisaged, although conflicting compared with those of GABAergic compounds and results have been reported that suggest either an amnes- with those showing a strain dependent interaction tic effect of the DA receptor agonist apomorphine or between DA and ACh systems point to a different an impairing effect of haloperidol [1,61,98,103,107, genotype-related involvement of GABA interneuron in 113,158]. the septo-hippocampal system. Indeed, concerning C57 A large body of evidence has shown that D1 and D2 mice (as well as outbred mice or rats) it is conceivable DA receptor types are characterized by distinct biochem- that DA receptors on GABA interneuron in the septum ical and pharmacological profiles [50]. Consistently, when activated inhibit GABA release from such an memory facilitation was produced by post-training interneuron, thus leading to increased ACh release from administration of LY 171555 but not SKF 38393 in the cholinergic neuron on which the GABA interneuron rats tested in the 8-arm radial maze [ 138-140]. projects. Increased ACh release in the hippocampus may More recently, post-training administration of the Claudio Castellano et al./Behavioural Brain Research 77 (1996) 1-21 5 selective D1 or D2 agonists SKF 38393 and LY 171555 the compounds used in the present study were adminis- dose-dependently facilitated retention of an inhibitory tered at doses known to act selectively on D1 or D2 avoidance response in mice, while the selective D1 or receptors [ 12,20,164,169]. In particular SKF 38393 was D2 antagonists SCH 23390 and (-)-sulpiride produced shown to activate D1 receptors selectively, without an impairment of retention [41,43]. affecting D2 subtypes at the doses used in these studies These results showing a similar role of D1 and D2 [ 12,146,147,164]. receptor types on memo:ry storage appear not to be The similar role of D1 and D2 receptors in memory consistent with a body of :aeuropharmacological, neuro- storage showed by our results may be tentatively physiological and behavioural evidence pointing to a explained by different factors. different functional role of these types of DA receptors Since drugs have been administered systemically, it [41,149,150]. may be that stimulation of one type of receptor in a Moreover, they are consistent with previous ones given brain area or system involved in memory processes showing memory improvement in animals receiving produces effects similar to that produced by stimulation post-trial psychostimulants [83,91] or memory impair- of the other type in a different brain area or system ment following DA depletion [78,123] or haloperidol involved in memory processes as well [ 57,123,161,171]. [ 113]. A trend towards improvement of memory consol- If so, independent pharmacological stimulation of either idation has been reported Ibllowing post-training admin- receptors would produce similar effects. istration of the mixed D1/D2 agonist apomorphine Evidence exists that shows a role of peripheral cate- (1 mg/kg) in a single-trial passive avoidance test in mice cholamines in memory development [162]. That the [84] (Fig. 1). effects produced by stimulation of one type of receptor It must be pointed out that the two agonists and the are peripherally mediated while the effects of the other two antagonists were effective on memory storage at type would be mediated by central DA systems, must doses that were likely to act post-synaptically. Moreover, be taken into account. Lastly, the effects of D1 or D2

EFFECTS OF MORPHINEALONE OR IN COMBINATION WITH DA AGONISTAND ,a~TAGONISTS ON RETENTION OF A ONE TRIAL PASSINVE AVOIDANCE TASK IN C01 MICE

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Fig. 1. Strain-dependent effects of postrial administration of drugs acting as agonists or antagonists on different neurotransmitter systems in a single-trial passive avoidance test. Results are expressed as mean (___SE) step-through latencies on test day (24h from training). *(P<0.01) in comparison with saline-treated (0). 6 Claudio Castellano et al./Behavioural Brain Research 77 (1996) 1-21 receptor activation may be due to second messenger independent stimulation of either D1 or D2 receptors activation by both D1 and D2 receptor types. Second by selective agonists is sufficient to affect memory consol- messengers are ions or chemicals that are released intra- idation [-41]. These data would suggest that each type cellularly as a result of extracellular neurotransmitter or of receptor has a role in memory storage processes hormonal action, carrying the message of neurotransmis- possibly because they both involve the same post-synap- sion within the nerve cells and modifying protein synthe- tic mechanism [41]. The contradiction between the data sis, intermediary metabolism, ionic conductance or other concerning the selective DA receptor agonists and those internal chemical events [173]. Engram formation and obtained with indirect DA agonists indicate that current expression within the nerve cells have been considered hypotheses on DA receptors' functioning should be to be controlled by temporal and spatial-concentration considered cautiously in the case of memory consolida- relationships between these agents and their bioproducts tion processes, since other receptor subtypes are possibly [67,173]. involved which would be similarly affected by com- Although D1 receptors are positively coupled with pounds shown to be selective for D 1 or D2 receptors in Adenylate Cyclase while D2 receptors are inversely or different experimental paradigms. non-coupled according to regional distribution [169], Nevertheless, in these experiments, all the pharmaco- data exist which suggest cAMP-independent protein logical treatments were given post-trial, i.e., following a kinases may mediate some of the effects of DA in the shock experience. Exposure to aversive experiences has brain [112]. Therefore, it may be that both D1 and D2 been shown to activate several brain DA systems receptors stimulate similar metabolic events, such as [- 19,151 ] thus it is conceivable that post-trial treatments protein phosphorylation, which play a role in cell activity act on a DAergic modulation of memory consolidation. underlying memory processes [ 67,157,173 ]. Considering Selective antagonists would interfere with the synergistic this, it can tentatively be hypothesised that a sort of interaction between D1 and D2 receptors promoted by common mechanism involving second messenger pro- endogenously released DA by blocking one of the two cesses may be responsible for the similar role of DA types of receptors. On the other hand, selective agonists receptor types in memory storage processes reported would enhance the effects of DA by involving a larger here. number of receptors in the synergistic interaction. Further evidence of the similar involvement of D1 Moreover, indirect agonists would act by increasing DA and 2 receptors in memory storage comes from studies availability at synapses and their effects could be pre- on the effects of uptake inhibitors such as the psychosti- vented by blocking part of the receptors involved in the mulant cocaine or nomifensine or other compounds interaction. This hypothesis needs to be tested by further involving DA functioning in passive avoidance test. experiments using co-administration of different doses Post-training administration of cocaine (1-10 mg/kg) of DA agonists and antagonists. Nevertheless, it should or nomifensine (1-10 mg/kg) dose-dependently improve be pointed out that the effects of selective D1 and D2 retention of an inhibitory avoidance response in mice, agonists on memory consolidation could represent an and the effects of an intermediate dose (5 mg/kg) of both in vivo model of synergistic interaction between these cocaine and nomifensine were reversed by pretreatment subtypes of receptors in intact animals. with either selective D1 or D2 DA receptor antagonists Evidence of the interchangeable role of D1 and D2 SCH 23390 and (-)-sulpiride administered at per se receptor also comes from data showing that post-train- non-effective doses (0.025 and 6 mg/kg, respectively), ing administration of the antidepressant minaprine thus suggesting that D1 and D2 receptor types are improve retention of an inhibitory avoidance response similarly involved in modulating memory processes in mice, an effect that is potentiated by subchronic [149]. minaprine administration. Pretreatment with per se non- These results could indicate that the two indirect effective dose of both (-)-sulpiride and SCH 23390, agonists make active a synergistic interaction between reverses the effects of the antidepressant on memory D1 and D2 DA receptor subtypes [50,169]. In fact a consolidation [149]. synergistic functional interaction could explain why Post-training administration of the selective D1 or D2 blockade of each type of receptor is sufficient to prevent agonists SKF 38393 and LY 171555 dose-dependently the effects on memory consolidation. The synergistic impairs retention of an inhibitory avoidance response in interaction could involve D1 and D2 receptors located DBA/2 mice. By contrast, the selective D1 or D2 antago- in different neural systems both in brain [74,156] and nists SCH 23390 and (-)-sulpiride improve retention. periphery [162], or receptors on the same neurons These effects are opposite to those observed in the [- 142]. Moreover, this interpretation would be consistent C57BL/6 strain, as previously reported. Moreover, with previously reported data indicating no difference B6D2F1 hybrids present a response to SKF 38393, between the effects of selective D1 and D2 receptor LY 171555, SCH 23390 and (-)-sulpiride that parallels antagonists on memory consolidation. that of C57BL/6 strain, thus suggesting that the neural On the other hand, previous data also indicate that mechanisms underlying the effects of DA agonists or Claudio Castellano et al./Behavioural Brain Research 77 (1996) 1-21 7 antagonists on memory processes may be inherited the hormone, has been reported to facilitate retention of through a dominant mode of inheritance. This hypothe- inhibitory avoidance and Y-maze discrimination task, sis needs further detailed genetic analysis that may when administered post-training to mice. The effects of provide a useful tool in the study of biological factors dipivefrin were attenuated by pretreatment with the fl- involved in the dopaminergic modulation of memory adrenergic antagonist propranolol but not by ~-adrener- processes in the laboratory mouse. gic antagonists prazosin, yohimbine and phentolamine. The neural substrate of this opposite role of D1 and Since the peripherally acting fl-adrenergic antagonist D2 receptors in memory consolidation in C57 and DBA sotalol did not affect the enhancement of memory consol- mice may tentatively be envisaged in a different strain- idation produced by dipiverfrin [78], an involvement of dependent distribution DI and D2 receptors in the brain brain fl-adrenergic receptors is strongly suggested. [18,41,148], that could explain opposite activation of A body of evidence indicating the involvement of NE brain areas and/or neurotransmitters involved in in memory processes comes from a number of studies memory processes. Moreover, opposite strain-dependent aimed at assessing the role of brain regions responsible effects of DA receptor activation on second messengers for supplying NE-containing axons and terminals as the have to be taken into account [41,173]. Lastly, since locus coeruleus (LC) and the amygdaloid formation. peripheral catecholamines are involved in memory devel- Post-trial electrolytic lesions of the LC result in a opment [162], a role of peripheral DA system cannot dramatic extension of the period following learning be ruled out. during which the recently formed memory remains sus- Further studies on brain areas and on biochemical ceptible to electroconvulsive shock (ECS)-induced retro- mechanisms involved in the effects reported here as well grade amnesia; moreover this kind of lesion induces a as a deeper genetic analysis of these effects may provide ~-noradrenergic receptor supersensitivity [78]. Clinical information on the role of brain DA system in memory reports have also pointed to a crucial role of LC in processes. memory disorders in general and in Alzheimer's senile Post-training administration of cocaine or nomifen- dementia [78]. These data, coupled with preclinical sine dose-dependently improve retention of an inhibitory results showing that LC activation, either pharmacologi- avoidance response in C57 mice, while they impair cally or electrically, can improve memory loss in senes- memory consolidation in the DBA strain. The strain- cent mice [78] further indicate a role of brain NE in dependent effects of an intermediate dose (5 mg/kg) of memory processes. both cocaine and nomifensine were reversed by pretreat- A number of studies have shown that amygdaloid ment with either selective D1 or D2 DA receptor antago- complex has a major role in memory processing. Post- nists SCH 23390 and (-)-sulpiride administered at training injection of NE, clenbuterol and other com- per se non-effective dose:~ (0.025 and 6 mg/kg, respec- pounds which potentiate NE functioning has been shown tively), thus suggesting tl~.at D1 and D2 receptor types to improve retention [93]. By contrast post-training are similarly involved in modulating memory processes. injection of fl-adrenergic blockers DL-propranolol or DL- The strain-dependent effects of cocaine and nomifen- alprenolol bilaterally into the amygdala impairs reten- sine are consistent also with previous results on the tion in rats [70]. That these effects are related to NE is effects of the selective D1 or D2 agonists SKF 38393 supported by the finding that the effects of propranolol and LY 171555 on mem,ary consolidation in C57 and are prevented by combining the intra-amygdala injection DBA mice [41,47]. of the adrenergic antagonist with NE.

4. Norepinephrine 5. Epinephrine

The role of brain nor,epinephrine (NE) in memory Epinephrine administered post-training affects reten- processes has been originally assessed through post- tion of different tasks enhancing it at low or moderate training intracerebroventricular administration of the doses and impairing it at high doses [124]. This neurotransmitter, as well as of reserpine [78,92]. While inverted-U dose-response effects is typical of most treat- NE improves memory, reserpine impairs it. However, ments. Many kinds of aversive stimulation, including since the monoamine depleting compound is not selec- those typically used in studies on learning and memory tive for NE, the involvement of other neurotransmitters in animals, produce an increased release of epinephrine such as dopamine or serotonin, whose role in memory from adrenal medulla, therefore the findings indicating modulation is well known, cannot be ruled out. that post-training administration of the hormone affects More recent results have pointed to a role of brain memory are consistent with the view that retention is adrenergic receptors in memory modulation. Dipivefrin, modulated by endogenous epinephrine [75,77]. Since a lipophilic prodrug of epinephrine which penetrates the most studies of the effects of epinephrine on memory lipid barriers at a rate several hundred-fold faster than have used aversive tasks, it would be conceivable that 8 Claudio Castellano et al./Behavioural Brain Research 77 (1996) 1-21 the aversiveness of the training procedures may make pointing to ACTH as an endogenous modulator of the retention uniquely susceptible to epinephrine that is memory. well known to be released by aversive stimulation. If so, ACTH analogs including ACTH4-10 and ACTH4-9 post-training administration of epinephrine would have been shown to affect retention of both active and amplify the after-effects of noxious stimulation (punish- passive avoidances when administered post-training, ment) used in the training procedure [22]. A number although contrasting results have been reported [123]. of results have shown that this is not the case. In fact, Since the ACTH analogs do not affect the adrenal cortex post-training epinephrine does not affect retention of their behavioural effects do not involve adrenal hor- inhibitory training in animals not receiving shock. mones, thus indicating that ACTH and ACTH analogs Moreover, memory enhancing effects of the hormone may affect memory through different mechanisms. The have been found in appetitive motivated tasks [ 124]. action of ACTH on memory processes may involve Since epinephrine is a polar substance not readily corticosterone released by adrenal cortex. Some studies crossing the blood-brain barrier, the effects of systemi- on the effects of ACTH on retention of learned changes cally administration of the hormone are likely to depend in social behaviour have shown that corticosterone is on involvement of adrenergic receptors in the periphery involved in the effects of ACTH. In fact, ACTH adminis- [93], which may, in turn, activate brain neural systems tered after an attack from a conspecific increases submis- through visceral afferents or hormones. Some evidence sion on subsequent tests in mice, and similar effects are suggests a role of hyperglycaemia in brain mediated produced by corticosterone [ 115,116]. Corticosterone, effects of epinephrine [77]. The effects of epinephrine as well as hydrocortisone and dexamethasone have been on memory involve fl-adrenergic peripheral receptors shown to enhance retention of passive or active avoid- where the action of the hormone on memory is initiated. ance when administered post-training in rodents [64] Although this action is further mediated by brain areas an effect produced by glucocorticoid injection into the such as the amygdala, the mechanisms underlying this hippocampus, therefore pointing to the role of the limbic central action of epinephrine are not clear. The involve- area in mediating these behavioural effects of the hor- ment of alteration in circulating glucose is a candidate mones [52]. Recently, corticosterone has been reported as mediating the peripheral effects on the brain [77]. to enhance long-term retention of passive avoidance learning in 1-day-old chicks [ 160], pointing to the major role of glucocorticoids in memory processes in an evolu- tionary perspective. 6. ACTH and glucocorticoids Some evidence points to an interaction of epinephrine and ACh systems in modulating memory processes. The involvement of pituitary hormones has been Recently, it has been shown that post-training admin- extensively studied, given the main role that such com- istration of atropine blocked the memory-facilitating pounds play in the response of the organism to mild effects of low doses of epinephrine in an inhibitory stressful conditions such as those resulting from the avoidance task and a Y-maze discrimination task. training procedures. In the last decade attention has Moreover, oxotremorine and physostigmine attenuated been focused on ACTH and ACTH analogs, to answer the memory-impairing effects of a high dose of epineph- some questions of interest in the neurobiology of rine, and low doses of epinephrine potentiated the memory, such as whether ACTH affects memory storage improvement of memory produced by both oxotremo- and whether ACTH release during learning procedures fine and physostigmine [90]. acts as an endogenous modulator of memory consolida- Recently, an interaction between the effects of cortico- tion [-123]. These questions are also of interest in the sterone on memory consolidation and DA systems in domain of other hormones and their role in memory the mouse has been also envisaged (Cabib et al., in processes. The effects of ACTH on memory storage have preparation). been pointed out by studies that showed that post- Recent results have shown that post-training admin- training hormone administration attenuates the impair- istration of corticosterone affects retention of a passive ing effects of hypophysectomy on retention of a one- avoidance task in mice dose- and strain-dependently trial inhibitory avoidance response as well as of a Y-maze (Cabib et al., in preparation). In particular, corticoste- discrimination task in the rat. Post-training ACTH rone (0.1, 0.5, 1 mg/kg, i.p.) produced an improvement affects retention in intact animals dose-dependently (low of retention of an inhibitory avoidance task in C57 mice, and intermediate dose enhance memory, while high while it impaired memory in the DBA strains. doses impair it), and its effects vary with the intensity These results are consistent with previous ones [38], of footshocks used in the training 1-76]. These data that showed an improvement of post-trial stressful suggest that ACTH administered post-training sum- experience (restraint) in C57 mice and an impairment in mates to that endogenously released during and DBA mice, thus suggesting that the effects of stress on following training in modulating memory storage, thus memory consolidation may be at least in part, ascribed Claudio Castellano et al./Behavioural Brain Research 77 (1996) 1-21 9 to increased release of glucocorticoids. Pretreatment (in tures (ventral or dorsal hippocampus or the dorsal raphe the post-trial administration) with (-)-sulpiride or nucleus). Facilitation of passive avoidance behaviour, SCH 23390, reversed the effects of corticosterone in more evident after injection into the ventral hippocam- both strains, thus confirming the main role of DA system pus, was observed when AVP1-9 was injected into either in memory consolidation, and the interchangeable role brain structure. The other two peptides were more of D1 and D2 recepto~rs in it. Further studies are effective than the parent nonapeptide. Also in this case desirable to ascertain the involvement of brain areas in the ventral hippocampus appeared to be the more the effects of corticosterone and the site of interaction sensitive brain structure [ 110]. Research carried out by between glucocorticoids and DA. It is worth noting that Kovacs et al. [109] in rats tested in passive avoidance glucocorticoid receptors in the hippocampus may play conditions have shown that memory consolidation is an important role in such effects [24]. oppositely influenced by local applications of low amounts of either oxytocin (OXT) or arginine 8-vasopressin into limbic structures, and that modula- 7. Neurohypophysealpeptides tion of catecholamine turnover after AVP administration may be related to this effect. In particular, post-learning A number of experiments have been carried out in microinjections of OXT in the hippocampal dentate which the neurohypophyseal peptides vasopressin and gyrus or in the brain dorsal raphe nucleus attenuated oxytocin were injected after training [54, 55]. Increase passive avoidance behaviour, while facilitation of consol- of resistance to extinction has been shown in rats tested idation was observed when OXT was injected into the in a pole-jumping active ~tvoidance task and injected i.p. dorsal septal nucleus. Moreover, AVP administered into with lysine 8-vasopressin. The peptide was much less hippocampal dentate gyrus, dorsal raphe nucleus or effective when given 3 h after training [56]. I.c.v. admin- dorsal septal nucleus facilitated passive avoidance behav- istration of arginine 8-vasopressin (1 ng) improved reten- iour. No effect was observed when either nonapeptide tion of rats tested in a passive avoidance task. The effect was injected into the central amygdaloid nucleus. One was evident when the animals were injected immediately week after the behavioural experiments a repeated injec- but not 6 h after learning [6]. Another series of experi- tion of AVP into the hippocampal dentate gyrus ments was carried out in the homozygous variant increased the disappearance of norepinephrine in the (HO-DI) of Brattleboro rats, which were tested in a dentate gyrus and in the nucleus ruber. Moreover NE passive avoidance situation, in which their memory disappearance in the dorsal septal nucleus was decreased function is impaired. Vasopressin restored the disturbed and in the nucleus ruber was increased by injection of passive avoidance behaviour of the animals [57]. AVP into the dorsal septal nuclei. Finally, an increase Moreover, vasopressin antiserum was injected i.c.v, in in the disappearance of dopamine in the locus coeruleus rats tested in a passive avoidance task. Memory deficit and in the nucleus ruber was observed following injection was observed in animals tested 6 h or more after training of AVP in the dorsal raphe nucleus. More recently and injection, no effect was evident in animals tested 2 h Borrell et al. [8] reported that epinephrine is required after administration and intermediate effect appeared for obtaining memory enhancement following post-train- 3 h and 4 h after treatment [ 167]. Facilitation of reten- ing administration of vasopressin. tion following desglycin.amide-lysine vasopressin i.p. administration in rats tested in a T-maze task has been shown by Bohus [5]. Further, memory impairment was 8. Opiates and opioids observed following oxytocin, and improvement following vasopressin i.c.v, treatme, nt in doses between 0.1 and A number of experiments have shown that opiate 1.0 ng, while at higher d,ases the effect disappeared, in agonists and antagonists may influence memory consoli- rats tested in a passive avoidance situation [7]. Other dation in laboratory animals. experiments [58] have e~:amined the effects on consoli- Castellano [25], by using mice tested in a Y-maze dation following i.c.v, administration, to rats tested in a discrimination task, observed memory impairment passive avoidance condit:ion, of the hexapeptide p-Glu- following post-training intraperitoneally (i.p.) morphine As-Cys (Cys)-Pro-Arg-Gly-NH2, a putative brain metab- administration. This effect was antagonized by a per se olite of vasopressin, and related fragments Cyt AVP 5-9 ineffective dose of naloxone. Amnesia following mor- and Cyt6-AVPS-8. They were found considerably more phine post-training i.p. administration and memory facil- effective than vasopressin in facilitating avoidance itation following administration of naloxone have been behaviour. In the same experimental conditions the observed by Izqulerdo [-94] in rats tested in an active effects of arginine-vasopressin (AVP 1-9) and of its avoidance task. Jensen et al. [104] in F344 rats tested behaviourally active fragments Cyt6-AVP5-8 and in a passive avoidance situation showed an inverted-U Cyt6-AVP5-9 on consolidation were studied following shaped dose-response curve following i.c.v, post-trial microinjection into various limbic and midbrain struc- injections of morphine. In their experiments 0.3/~g of 10 Claudio Castellano et al./Behavioural Brain Research 77 (1996) 1-21 the opiate had no effect, 3.0/~g induced amnesia while istration of low doses of enkephalins (30 #g or lower per 40/~g and more induced memory facilitation. subject) in rats tested in a passive avoidance step- Impairment of consolidation following low to moderate through apparatus. Always in rats, tested in a step-down doses of morphine (1.0 or 30 mg/kg, i.p.), and improve- inhibitory avoidance task, Met- and Leu-enkephalin ment following naloxone administration, have been were injected in the lateral ventricle at doses of 100 or observed in passive avoidance conditions by Messing 200/~g per injection [4]. The 200/~g dose of Met- et al. [129,130] in rats. Memory impairment following enkephalin given immediately after training significantly intraamygdala injections of levorphanol, and improve- facilitated retention, while no significant effect was ment following naloxone administration, have been evi- observed following either dose of Leu-enkephalin. denced by Gallagher and Kapp 1,69] and Kapp and Interestingly, in these experiments, the 100 g dose of Gallagher 1,106] in rats. Moreover peripheral (i.p.) Met-enkephalin induced a not statistically evident amne- administrations of naioxone, naltrexone, levallorphan sia. Amnesia following the administration of 10/~g/kg and diprenorphine all increased retention of rats tested of Leu-enkephalin and 2.0 #g/kg of Met-enkephalin and in a passive avoidance task. The effects of levallorphan des-Tyr-Met-enkephalin has been reported, in rats were stereospecific, since dextrallorphan did not signifi- injected i.p. immediately after training in a shuttle avoid- cantly alter retention 1-68]. In rats tested in a passive ance situation, or when the habituation of a rearing avoidance situation amnesia induced by amygdaloid response to a tone was assessed [101]. Finally, in mice stimulation was attenuated by naloxone given peripher- tested in a passive avoidance situation, retention was ally (i.p.) or injected bilaterally into the bed nucleus of improved by 5 mg/kg and impaired by 40 mg/kg post- stria terminalis (BNST). Naloxone injected into the training i.p. administration of the enkephalin analogue caudate nucleus was ineffective. The attenuation of nal- FK 33-824 [26]. oxone effect was antagonized by injection of levorphanol It must be underlined that the role of peripheral into the BNST [ 119]. Memory improvements have been mechanisms in modulating the behavioural effects of demonstrated in some studies following post-training Leu- and Met-enkephalin has been demonstrated by morphine i.p. treatment. This effect was observed in mice experiments showing that adrenal medullectomy, which tested in a passive avoidance situation by Mondadori removes an endogenous store of enkephalins, antago- and Waser [ 131 ] following the administration of 40 and nizes the impairing effect exerted by the i.p. administra- 100 mg/kg, but not of 1 mg/kg, of the opiate, and in tion of these peptides on avoidance conditioning in rats tested in a step-down situation by Staubli and rats [155]. Huston [ 165 ], following the administration of 30 mg/kg, A number of experiments have been carried out by but not of 10 mg/kg, of morphine. Moreover memory using the two inbred strains of mice DBA/2 (DBA) and facilitation following i.c.v, injections of morphine (20 #g) C57BL/6 (C57). In these experirdents mice were injected in rats tested in the latter situation was observed by post-training with opiate agonists or antagonists or with Belluzzi and Stein [4]. opioid peptides. Contrasting results have been also obtained when the Retention improvements in both strains after the i.p. effects of opioid peptides on memory consolidation have administration of 0.5 mg/kg of heroin, and retention been considered. improvement in the C57 strain and impairment in the Retrograde amnesia following the post-training i.p. DBA strain following the administration of 5 mg/kg of injection of//-endorphin has been evidenced in Wistar the opiate, were observed in subjects tested in a pattern rats tested in a shuttle avoidance situation at doses up discrimination test 1-26]. Enhancement of consolidation to 10/~g/kg while higher doses were ineffective [95,98]. in DBA, and impairment in C57 strain, were observed Similar results (with the Dutch Wistar rats) were following i.p. naloxone administration in Y-maze and obtained by Martinez and Rigter 1,120] using a step- pattern discrimination tests [27]. In other experiments through task. In their experiments retrograde amnesia dermorphin, a heptapeptide with very potent opiate-like was observed with 0.1, but not 1.0/~g/kg, or more, of/~- activity, and D-AIa2-D-Leu 5 enkephalin were injected icv endorphin. It must be stressed that the existence of a in these strains of mice after training in a passive physiologic amnesic mechanism mediated by /~-endor- avoidance task. Dose- and strain-dependent effects were phin (and perhaps by other opiates) has been postulated observed. In fact 5 ng of both drugs impaired retention which operates through the inhibition of central dopa- in both strains, while 50 ng impaired retention in DBA minergic and/%noradrenergic systems active in the con- but improved it in C57 mice. Naloxone, 0.3 pg i.c.v., solidation of memory 1-75,102,175]. On the other hand antagonised both effects [33]. facilitation (1.5 #g) of passive avoidance retention or no The strain differences observed following opiate effect (10.0/~g) following s.c. post-training/3-endorphin administration have been interpreted by some investiga- treatment have been reported in rats [108]. tors in terms of strain differences in opiate receptors. It As concerns the enkephalins, Rigter [ 156], described has been shown [ 153,154] that DBA mice display lower antiamnesic effects following the systemic (s.c.) admin- number of striatal opiate binding sites than C57 mice. Claudio Castellano et al./Behavioural Brain Research 77 (1996) 1-21 11

Moreover, strain differences have been reported in mu- agonist clenbuterol, which, given alone, facilitated or and delta-type binding, results supporting the concept impaired retention as function of the dose. According to of multiple opiate receptors in that mouse brain [151]. these results central 8-adrenergic mechanisms seem to The strain-dependent effects on locomotor activity be involved in the effects of naloxone on memory [88]. observed in DBA and C57 mice following opiate agonists Experiments carried out in rats [97] have moreover [27,131,134,135] or antagonists [37] administration shown that post-training epinephrine and naloxone might be ascribed to str~dn differences in type, number administered at doses ineffective alone enhance retention and/or distribution of opioid receptors in some brain when administered together. It is interesting to note that areas. The same hypothesis might account for the strain- lesions of stria terminalis, which connects amygdala and dependent effects exertedl on memory by opiates in the other brain structures, block the memory modulating above cited researches. It must, moreover, be underlined effects of post-trial injections of epinephrine [ 118] and that DBA and C57 mice differ in the level and turnover of post-training naloxone and 8-endorphin [127]. In of mediators in the brain [133] and that complex CFW mice tested in a passive avoidance or a Y-maze interactions exist between opioids and neurotransmitter discrimination task, consolidation was enhanced by low systems active in memory modulation [2,32,95]. Thus, doses of i.p. administered epinephrine, and impaired by strain differences in brairt chemicals might also be at the high doses. In both tasks naloxone facilitated retention basis of the strain differences observed in the above and blocked the memory-impairing effect of 8-endor- studies. phin. Further, low doses of epinephrine and naloxone, In some experiments the effects of opioids on memory which were ineffective when administered alone, signifi- in C57 and DBA mice were dose-dependent. The bipha- cantly enhanced retention when administered together sic effects often observed :following opioid administration [89]. Other experiments have shown that lesions of the have been interpreted by some investigators in terms of dorsal noradrenergic bundle by 6-hydroxydopamine differences in the populLation and distribution of the (6-OHDA), which reduce norepinephrine content in the receptors occupied at different doses [28,126]. Based amygdala, prevent the memory-enhancing effect of post- on this hypothesis the dose-dependent effects observed training naloxone administration into the amygdala. The can be explained by biphasic or bimodal action of the memory enhancing effects of naloxone were restored drugs at a given species of receptors, and of activation when norepinephrine neurons were protected from of different systems depending on the dose, for pharma- 6-OHDA by pretreatment with desmethylimipramine, a codynamic reasons [28]. NE uptake inhibitor [71]. Other experiments [126] A number of researches have demonstrated the exis- have shown that i.p. naloxone-induced enhancement of tence of interactions of opiates with various neurotrans- memory is mediated by the activation of 8- but not ~- mitter systems as concerrts memory consolidation [ 121]. noradrenergic receptors located in the amygdala. In By using rats subjected to habituation of a rearing these experiments, carried out in rats tested in Y-maze response to a tone it has been shown [95] that naloxone discrimination and inhibitory avoidance tasks, post- injected i.p. causes menaory facilitation through the training i.p. naloxone administration facilitated retention release of central dopaminergic and 8-adrenergic mecha- in both experimental conditions. The effect of naloxone nisms from a tonic inhibitory influence of endogenous was antagonised by the 8-noradrenergic antagonist pro- opiate peptide systems. In these experiments consolida- pranolol injected into the amygdala. It was not antagon- tion enhancement was observed following a per se ised when propranolol was injected into the caudate or ineffective dose of naloxone and amphetamine or nico- the cortex dorsal to the amygdala. Moreover, the effect tine. Memory improvement by naloxone was moreover of naloxone was blocked by injections into the amygdala antagonised by haloperid ol, propranolol or phenoxyben- of the 81-adrenoceptor blocker atenolol, and the zamine. In another research, carried out with mice tested 82-adrenoceptor blocker zinterol, but not by post-train- in a passive avoidance task, the memory facilitation ing administration of the ~-antagonists prazosin or induced by naloxone wa~,; blocked by the selective brain- yohimbine. noradrenergic neurotoxi~a DSP4. Pretreatment with the Some research has shown the existence of interactions norepinephrine-uptake inhibitor desmethylimipramine, between opiates and cholinergic system. Baratti et al. but not with the serotonin-uptake inhibitor fluoxetine, [2] have demonstrated that memory facilitation induced prevented this antagonism. Moreover, the 8- by naloxone can be antagonised by atropine but not adrenoceptor blocker L-propranolol blocked the effects methylatropine, mecamilamine or hexametonium. In of naloxone on memory. No effect following the these experiments mutual potentiation for both naloxone administration of D-propranolol, the peripheral 8-adre- and the muscarininc agonist oxotremorine, in doses noceptor blocker sotalol, the ~-adrenoceptor blocker ineffective by themselves, was also observed. Finally, an phenoxybenzamine, or the peripheral ~-adrenoceptor amnesic dose of atropine prevented the enhancement of blocker phentolamine was observed. Finally, naloxone retention induced by naloxone. potentiated the effects of the central 8-adrenoceptor Introini and Baratti [37] have shown, in mice tested 12 Claudio Castellano et al./Behavioural Brain Research 77 (1996) 1-21 in a passive avoidance situation, that administration of the hippocampus, have been observed in rats tested in oxotremorine prevents the retention impairment evident a brightness discrimination task [81]. On the other following fl-endorphin treatment. Attenuation of the hand amnesia following peripheral (i.p.) administration effect of fl-endorphin was also seen following physostig- of picrotoxin has been reported by Nabeshima et al. mine treatment, while the effect of fl-endorphin was not [132] in rats tested in passive avoidance conditions. As modified by neostigmine or hexamethonium [87]. observed by Brioni [13], it is possible that picrotoxin Bostock et al. [9] have demonstrated that post- could induce amnesia at high doses if a high shock is training intraseptal naloxone administration facilitates, used in the passive avoidance test. Finally, enhanced whereas post-training administration of fl-endorphin latent extinction of conditioned fear following post-trial impairs, the acquisition performance on a radial maze i.p. administration of picrotoxin has been described in task in rats. mice tested in a visual discrimination test [125]. Also GABAergic mechanisms seem to be involved in The effects on memory consolidation exerted by the the effects of opioids on memory consolidation. GABA-A antagonist bicuculline have been examined by Picrotoxin or bicuculline i.p. administration enhance, a number of researches. while muscimol treatment attenuates, the effects of nalox- Retention improvement in rats tested in a two-way one or naltrexone on retention in CD1 mice tested in a avoidance has been reported by Yonkov and Georgiev passive avoidance task [45]. Moreover a low non- [ 174]. Increased retention following post-training peri- effective dose of muscimol (i.p.) potentiated, while low pheral (i.p.) bicuculiine administration has been observed non-effective doses of picrotoxin and bicuculline attenu- in mice tested in passive and visual discrimination tasks ated the retention-impairing effect of fl-endorphin in [14,35]. Bicuculline methiodide injected bilaterally in CD1 mice tested in the same experimental conditions the amygdala also enhanced retention in rats tested in [46]. a passive avoidance task [ 15 ]. Working memory impair- As concerns the dopaminergic system, recent experi- ment following intraseptal administration of bicuculline ments [43], carried out in CD1 mice tested in a passive in rats trained to perform a delayed-non-match-to- avoidance task, have shown that the effect of morphine sample 8-arm radial maze has been also reported [48]. (i.p.) on memory consolidation involve both D1 and D2 On the contrary memory impairment following bicucul- dopamine receptors. In these experiments i.p. pretreat- line i.p. administration, possibly linked to the dose ment of mice with either selective D1 or D2 dopamine employed, was reported by Nabeshima et al. [132] As receptor antagonists SCH 23390 and (-)-sulpiride, concerns the GABA-A receptor agonist muscimol administered at per se ineffective doses, potentiated the memory consolidation impairment has been observed in amnesic effect of morphine, while ineffective doses of mice injected i.p. with the drug and tested in a passive either selective D1 or D2 dopamine receptor agonists avoidance task [30,35,45]. Again memory impairment SKF 38393 and LY 1715555 antagonized the effect of following muscimol administration has been observed the opiate (Fig. 2). in rats tested in an 8-arm radial maze and injected with the drug in the septum [49], and in rats injected with muscimol in the amygdala and tested in passive avoid- 9. GABAergic system ance conditions [ 15]. The effects on memory consolida- tion exerted by the GABA-B receptor agonist baclofen The first experiment showing an effect of picrotoxin have been studied by some researchers. Impairment of on memory consolidation was carried out by Breen and retention has been reported following immediately but McGaugh [11] in rats tested in an appetitively moti- not 10 or 60 min post-training baclofen i.p. administra- vated T-maze. These authors observed a significant tion in rats tested in a passive avoidance task [ 166]. In reduced number of errors following post-trial i.p. admin- the same experimental conditions impaired retention of istration of this drug. Facilitation of consolidation mice was observed following post-trial i.p. as well intra- following post-trial i.p. administration of picrotoxin was amygdala baclofen administration [40,45]. Recent also observed in rats tested in a Hebb Williams maze experiments, carried out in CD1 mice tested in a passive [72], in mice tested in an active avoidance task [10] avoidance task, have provided evidence that GABAergic and in mice tested in passive avoidance conditions drugs affect memory storage through influences on the [ 29, 39 ]. Moreover retention improvement following i.p. cholinergic system. In these experiments i.p. post-training and impairment following injection of picrotoxin into administrations of muscimol and baclofen impaired con-

Fig. 2. Effectsof postrial administrationof differentdoses of morphine (upper part). Lower: Effectsof co-administrationof 0.5 mg/kg of morphine and selective DA agonists and antagonists in a single trial passive avoidance test. SKF=SKF38393 (5 mg/kg); LY=LY171555 (0.25 mg/kg); SCH = SCH23390 (0.025 mg/kg); SULP =(-)-sulpiride (6 mg/kg). Results are expressed as mean (__+SE) step-through latencies on test day (24 h from training). *(P < 0.01 ) in comparison with saline-treated(VEH or VEH/VEH). C/audio Castellano et al./Behavioural Brain Research 77 (1996) 1-21 13

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9G 90 ! • . 41 41 io o o OOl ~ 0.04 o 1 2 3 OXOTIE~OmI~m (me/ks) Al~Ol~m (ml/~S) 14 Claudio Castellano et al./Behavioural Brain Research 77 (1996) 1-21 solidation; this memory impairment was attenuated by tal paradigm appears a suitable method to investigate concurrent injections of a low, and otherwise ineffective, drug effects on memory consolidation, since it allows to dose of oxotremorine [ 31 ]. assess either hypomnestic or hypermnestic effects of drug Strain-dependent effects of post-training GABA treatment. In fact, CCK-8S, a peptide that produces receptor agonists and antagonists have been observed memory improvement in conventionally used memory in C57BL/6 (C57) and DBA/2 (DBA) mice, tested in tasks, also improves memory in the nose-poke paradigm passive avoidance conditions [42]. In these experiments [ 172]. Flunitrazepam injected i.p. post-training impaired muscimol and baclofen injected i.p. impaired memory memory consolidation in C57BL/6 and DBA/2 mice consolidation in C57 and improved it in DBA mice. tested in a passive avoidance task [34,44]. Impairment Further, picrotoxin, bicuculline and the new GABA-B of retention performance in CD 1 mice (passive avoidance antagonist CGP 35348 improved consolidation in C57, task) has been finally observed following i.p. post-train- and impaired it in DBA mice. These results indicate that ing administration of the partial inverse agonist at GABA receptors have an opposite role on memory benzodiazepine receptor Ro 15-4513 [36]. consolidation in these two strains of mice. The neural Some experiments have been carried out in which substrate of this opposite role may tentatively be envis- the benzodiazepine receptor antagonist flumazenil aged in a different strain distribution of GABA in (Ro 15-1788) was injected post-training into different discrete brain areas. C57 mice have been shown to be brain structures. Retention was enhanced by immediate characterised by higher GABA concentrations in the post-training bilateral injection of the drug into the amygdala, raphe and hippocampus, while lower concen- medial septum and the amygdala of rats tested in a trations of the neurotransmitter in the olfactory tubercle passive avoidance task. No effect on habituation was and the frontal cortex are evident in comparison with observed. In both tasks retention was enhanced by the DBA mice [51,162]. The different distribution of intrahippocampal post-training administration of flu- GABA in the brain could be related to strain-dependent mazenil [99]. According to Izquierdo [99] this effect differences in the afore-mentioned behavioural effects of could be attributed to antagonism of the benzodiazepines pharmacological manipulation. Moreover, it must be released during and/or after training in these structures. underlined that the involvement of other brain neuro- Finally, in a research carried out in rats submitted to transmitter systems may account for the strain-depen- step-down inhibitory avoidance [100] the immediate dent differences observed. post-training intraamygdala injection of flumazenil facil- itated memory and that of the GABA-A agonist musci- mol caused amnesia. Further, pretraining i.p. flumazenil 10. Benzodiazepines administration attenuated the memory impairing effect of post-training muscimol treatment. According to the The majority of studies failed to find effects of post- authors these data suggest that post-training consolida- training systemically administered benzodiazepines tion is down regulated by a GABA-A mechanism in the [99 ]. This is because benzodiazepine ligands, if adminis- amygdala, modulated by endogenous benzodiazepines tered systemically, reach the brain too late, when consoli- released during training and at the time of consolidation. dation has occurred. Only a few experiments have revealed effects of post- training systemically administered benzodiazepines, and 11. Serotonin in general following high doses of drugs. Jensen et al. [ 105] have shown that post-training i.p. administration Some researches have studied the effects of serotoner- of flurazepam, but not of diazepam or lorazepam, pro- gic drugs on memory consolidation. duced retrograde amnesia in mice tested in a passive Microinjections of 5-HT into the hippocamous avoidance condition. Platel and Porsolt [143] found following acquisition of a passive avoidance task in mice memory impairment in mice following post-training i.p. induced retention impairment when the animals were administration of chlordiazepoxide in a test of habitua- tested 24h later [58]. Rake [152] showed that post- tion of exploratory activity. The effect of i.p. administra- training i.p. administration of 5HTP (and DOPA), at tion of diazepam on retention of an inhibitory avoidance doses ineffective by themselves, antagonize the memory task was investigated in mice by Cahill et al. [21]. A impairment induced by reserpine (which lowers both pretraining injection caused amnesia, whereas a post- CNS levels of catechol- and indoleamines), in rats tested training injection, while ineffective per se, facilitated in a passive avoidance task. In a further series of retention of the task when it was followed by exposure experiments PCPA (which induces a depletion of brain to a habituation procedure (Y-maze). However, post- indole amines) was administered, and 2 weeks after training administered diazepam has been recently memory enhancement became evident. Moreover, reported to produce hypomnestic effects in nose-poke 5-HTP, which restores CNS indole amines, antagonized habituation memory task in rats [ 172]. This experimen- the PCPA-improved memory when given immedi- Claudio Castellano et al./Behavioural Brain Research 77 (1996) 1-21 15 ately after training. In rats performing a passive dependent manner while NMDA receptor antagonists avoidance task and injected i.p. pretrial with produced dose-dependent impairment of retention. Some 6-methoxy-l,2,3,4-tetrahydro-fl-carboline, deficit in experiments were carried out recently [62] in rats tested retention was observed. No effect was evident when the in habituation to a novel environment or in step-down drug was given post-trial, due perhaps to the time it inhibitory avoidance. In these experiments the NMDA takes to increase brain 5-HT [ 17]. receptor antagonist D-2-amino-5-phosphopentanoic acid Retention impairment following post-trial intrahyppo- (AP5) and the GABA-A receptor agonist muscimol were campal injection of 5/~g of 5-HT in rats tested in a infused bilaterally into the amygdala or the enthorinal brightness discrimination task (Y-maze) has been cortex immediately after training. While intraamygdala described [170]. In this research biochemical experi- injections of AP5 or muscimol were amnestic when given ments showed that leucine incorporation into hyppo- 0 but not 90 min after inhibitory avoidance training, the campal proteins in vivo was 32% inhibited by 5-HT. two drugs were amnestic for both inhibitory avoidance These results agree with previous observations [58] that and habituation when injected into the enthorinal cortex post-trial intracranial injection of 5-HT produces reten- 90 or 180 min after training, but not when given 0 or tion deficit due to decreased protein synthesis. 360 min after training. Some recent researches have studied the effects of the These results suggest that enthorinal cortex plays a serotonin uptake inhibitor fluoxetine on memory consol- late role in post-training memory processing; this role idation in mice and rats. iPost-trial i.p. fluoxetine admin- involves glutamatergic NMDA receptors and is inhibited istration enhanced 1 week memory retention in rats by GABA-A receptors. In particular, according to the tested in a T-maze or in a passive avoidance task. In authors, the intervention of the enthorinal cortex in these experiments the amnesia induced by the protein post-training memory processing is subsequent, and synthesis inhibitor anisotnycin or by the anticholinergic could be secondary, to that of the amygdala and other drug scopolamine was blocked by i.p. post-training limbic structures [63]. Further research (step-down injection of fluoxetine [6:5]. In a further series of experi- inhibitory avoidance task) confirmed these data and ments [-93] fluoxetine ir~jected i.p. post-trial facilitated showed in addition that stimulation of NMDA receptors retention assessed 48 h later in rats tested in a passive by glutamate or blockade of GABA-A receptor activity avoidance task. In contrast, post-training intraamygdala by picrotoxin 90 min after training had no effect [66]. injections of the drug did. not modify retention, suggest- These results show that the role of the enthorinal cortex ing that amygdala serot,anergic system is not involved in memory 90 min after training requires the mainte- in the modulation of menaory in this task. nance of the normal function of this structure rather Other experiments [141] examined the effect of oxo- than its hyperactivation. tremorine (OXO) on passive avoidance behaviour in the A complex interaction between dopamine and gluta- two inbred strains of mice DBA/2 (DBA) and C57BL/6 mate in modulating memory has been finally observed (C57) and the interaction with the serotonergic agonist in C57BL/6 mice tested in a passive avoidance task 5-methoxy-N,N-dimethyiltryptamine (5-MeODMT). In [128]. In these experiments immediately post-training both strains post-trial oxotremorine administration facil- administration of the NMDA receptor competitive itated, while 5-MeODMT inhibited, memory consolida- antagonist CPP impaired retention. Post-training tion, and DBA mice were more sensitive to these effects. subeffective doses of selective D1 (SKF 38393) or D2 Combination of the two drugs inhibited performance (LY 171555) dopaminergic receptor agonists antago- improvement by OXO alone in both strains of mice. nized the action of CPP. Further, a potentiation of the These results suggest the existence of a functional inter- memory-impairing effect of CPP was observed following action between cholinergic and serotonergic systems on a 10-day daily treatment with haloperidol. Interestingly, memory consolidation (l?ig. 3). the post-training i.p. administration of CPP exerted opposite effects in mice belonging to the DBA/2 strain (Castellano et al., in preparation). 12. Excitatory amino acids

Some studies have shown an effect of excitatory 13. Conclusions aminoacids system, and in particular of competitive and non-competitive NMDA antagonists and of NMDA The experimental results reviewed here indicate that receptor agonists on memory. In some cases the drugs memory storage can be altered by a number of post- were administered after the learning trial. training treatments that affect hormones or neurotrans- Flood et al. [66] injected i.c.v, post-training NMDA mitters. Most of the hormonal and the neurotransmitter receptor agonists and antagonists in mice tested in a systems involved in the modulator effects of these treat- T-maze footshock avoidance apparatus. They found that ments on memory are known to be affected by environ- NMDA receptor agonists enhanced retention in a dose- mental factors such as those which characterise the 16 Claudio Castellano et al./Behavioural Brain Research 77 (1996) 1-21

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Fig. 3. Strain-dependent effects of coadministration of oxotremorine (OXO) or atropine (ATR) and selective DA agonists and antagonists in a single trial passive avoidance test. SKF=SKF38393 (5 mg/kg); LY=LY171555 (0.25mg/kg); SCH=SCH23390 (0.025mg/kg); SULP= (-)-sulpiride (6 mg/kg). Oxotremorine and atropine were administered at the first effective dose in each strain (see Fig. 1). Results are expressed as mean (+ SE) step-through latencies on test day (24 h from training). *(P < 0.01) in comparison with sVEH/VEH. §(P < 0.01) in comparison with VEH/OXO or VEH/ATR. training procedure. More generally such factors lead to others, and that each system does not produce necessar- hormone and/or neurotransmitter activation typical of ily effects that parallel that of the others. For instance, the organism's response to novelty or to stress [78]. ACh activity potentiation leads to memory improvement Therefore, the effects of treatments that affect such while GABA potentiation normally induce an impair- neurochemical systems are likely to modulate processes ment of retention, thus suggesting that the involvement that are made active by learning and whose role in of ACh and GABA systems in memory storage should memory storage is to be considered in the frameworks be characterised by opposite level of activity: high for of neural networks in which each system is functionally ACh and low for GABA. What is more important, the relate to others. evidence that GABA activation antagonises the memory Support for the importance of interactions between enhancement effects of ACh, while GABA activity and among neurotransmitter systems comes from the impairment potentiate the effects of ACh, points to evidence that the systems involved in memory processes functional interactions between these neurotransmitter if potentiated by experimental manipulation do not systems. The variety of hormone and neurotransmitter produce all the same effects on retention. This indicates systems interaction considered in the present review that the role of a given hormone or neurotransmitter presents a figure of multiple functional relationships system is not always interchangeable with that of the among neurochemical systems that are consistent with Claudio Castellano et al./Behavioural Brain Research 77 (1996) 1-21 17 the complexity of brain organisation. 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