Synergistic enhancing-memory effect of donepezil and S 47445, an AMPA positive allosteric modulator, in middle-aged and aged mice.

Positive allosteric modulators of AMPA receptors (AMPA-PAMs) are described to facilitate cognitive processes in different memory-based models. Among them, S 47445 is a novel potent and selective AMPA-PAM. In order to assess its efficacy after repeated administration, S 47445 effect was evaluated in two aging-induced memory dysfunction tasks in old mice, one short-term working memory model evaluated in a radial maze task and one assessing contextual memory performance. S 47445 was shown to improve cognition in both models sensitive to aging. In fact, administration of S 47445 at 0.3 mg/kg (s.c.) reversed the age-induced deficits of the working memory model whatever the retention interval. Moreover, in the contextual task, S 47445 also reversed the age-induced deficit at all tested doses (from 0.03 to 0.3 mg/kg, p.o.). Since donepezil, an acetylcholinesterase inhibitor, induces only moderate symptomatic effects on memory in Alzheimer's disease patients, an alternative strategy for treatment of cognitive symptoms could be to act simultaneously on both glutamatergic AMPA receptors and cholinergic pathways by combining pharmacological treatments. The present study further examined such effects by assessing combinations of S 47445 and donepezil given orally during 9 days in aged C57/Bl6J mice using contextual memory task (CSD) and the working memory model of serial alternation task (AT). Interestingly, a significant synergistic memory-enhancing effect was observed with the combination of donepezil at 0.1 mg/kg with S 47445 at 0.1 mg/kg p.o. in the CSD or with S 47445 at 0.1 and 0.3 mg/kg in AT in comparison to compounds given alone and without any pharmacokinetic interaction.

Effects of diazepam and beta-CCM on working memory in mice: relationships with emotional reactivity.

This study was aimed at determining the effects of systemic administration of diazepam and methyl beta-carboline-3-carboxylate (beta-CCM) both on spatial working memory and on emotional reactivity in mice. Results showed that diazepam and beta-CCM induced opposite effects in both memory and emotional reactivity tests. Indeed, as a function of dose, diazepam reduced anxiogenic-like reactions but increased vulnerability to interference in the memory task at a 30-s but not at a 5-s delay interval. As a function of dose, beta-CCM reduced vulnerability to interference and increased emotional reactivity, these effects being antagonised by concurrent administration of flumazenil (RO 15-1788). Thus, our study showed the bidirectional effects of these two drugs on a spatial working memory task involving a spontaneous processing of information and suggested a direct link between the emotional effects of the drugs and memory performance.

[An animal model of human declarative (relational) memory and of its dysfunction]. / Modèle animal de la mémoire déclarative (relationnelle) humaine et de ses dysfonctionnements.

The present work was aimed at determining, both at the psychological and at the neurobiological levels, aspects of rodent memory that fall into line with human declarative memory which is known to be selectively impaired in amnesic subjects and during the course of ageing. The ability to compare and to contrast items in memory, and to support inferential use of memories in novel situations (flexibility), were considered to be the two key psychological features of human declarative memory that were altered by both hippocampal lesions and hippocampal dysfunction. Adult and aged mice were trained on learning tasks using two-stage paradigms, the aim of which was to assess memory performance through these two psychological aspects in the same subjects. Results suggest that ageing specifically impairs the ability to both compare and contrast items in memory (declarative/relational memory based on complex associations), without altering memory based on simple S-R associations (procedural memory). Hippocampal lesions in adult mice produced the same dissociation between relational memory (impaired) and procedural memory (spared). Pharmacological experiments showed that, depending on the drug used, the relational memory deficit of aged mice may be selectively reversed (i.e. without changes in procedural memory) and that the behavioural efficacy of certain treatments was shown to parallel their potency in re-establishing normal (i.e. adult) levels of hippocampal plasticity-related mechanisms. Together with previous findings, these results suggest that the storage and use of relational representations would critically depend on the plasticity of hippocampal synapses, which via their connections with cortical areas, would support the storage of associations between perceptual, behavioral and cognitive events.

Effects of mammillary bodies and mediodorsal thalamic lesions on the acquisition and retention of a learning set in mice: paradoxical effect of the intersession interval.

The effects of ibotenic acid lesions of either the mediodorsal thalamus (MD) or the mammillary bodies (MB) on the acquisition and retention of a reversal learning set in a T-maze were studied in mice. Both the MB and MD lesions disrupted performance in this task, but only MD lesions slowed down the rate of learning, MD-lesioned subjects requiring more trials than the other two groups to master the discrimination at the end of the learning phase. Surprisingly, increasing the intersession interval from 24 h to 10 days totally alleviated the deficit of MD-subjects and even improved their performance as compared to the last (8th day) session. The overall results of the study show that both MD and MB lesions do not induce important learning deficits nor anterograde amnesia in the reversal learning set task.

Effects of mammillary body and mediodorsal thalamic lesions on elevated plus maze exploration.

This study investigates the effects of lesioning the mamillary bodies (MB) or the dorsomedian nucleus (MD) of the thalamus on exploration of an elevated plus maze in mice. Exploration of 'open' and 'enclosed' arms of the maze has been used to evaluate anxiety in rodents. Normal rodents visit the enclosed arms more often than the open ones (innate agoraphobia). As operationally defined, the less the activity in the open arms, the more anxious is the subject. MB-lesioned mice entered the open alleys more often, and spent more time in them, than did controls, whereas the opposite was observed in MD-damaged subjects. It is suggested that, in mice given this task, MB lesions decrease anxiety and that MD lesions increase anxiety.