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