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In modelling memory and amnesia, the different forms of cognition must be distinguished. For memory, distinctions between acquisition, storage, and retrieval must be made and the different kinds of memory (e.g., immediate, working, reference) identified. Other notions, such as attention, orientation, and vigilance also belong under the heading "cognition". Thus the term "cognition enhancer" is imprecise because it does not indicate which kind of cognition is to be enhanced. Animal models should be developed for each type of cognition, be based on information from the clinic, and attempt to be specific. Examples of models more specific than the passive avoidance test were discussed and included the radial maze, in which different kinds of memory could be analyzed and correlated with, for example, changes in central cholinergic activity. From the point of view of drug development an important distinction was made between "empirical" and "simulation" models. In other areas of psychopharmacology "empirical" models have been widely used because they show predictable responses to known reference compounds. In the field of cognition there are no generally recognized reference compounds and therefore no "empirical" models. There is therefore a need for "simulation" models which imitate the various aspects of cognition and its pathology. The major criterion for validating this kind of model is that it should show changes similar to those observed in humans either resulting from a particular pathology or from a particular drug treatment.

The present study was built on the original report of Eichenbaum et al. [Eichenbaum, H., Fagan, A., Mathews, P. and Cohen, N.J. (1988), Behav. Neurosci., 102, 3531-3542] on the contrasting effects of fornix lesion in different versions of an odour-guided discrimination task in rats, and attempted to extend this into a mouse model for the preferential loss of declarative memory seen in human senescence. Each of the two experiments reported here consisted of a two-stage paradigm, with an initial learning phase followed by a test phase. The information acquired in the first stage was identical in both experiments, i.e. the valence or reward contingency associated with six (three positive and three negative) arms of a radial maze. The only parameter which was varied between Experiment A and B, and also between the two successive stages within each experiment, was the way of presenting the arms to the mice, i.e. either in pairs (simultaneous discriminations) or one at a time (successive go : no-go discrimination). Performance in the first stage demonstrated that our aged mice were impaired in learning concurrent simultaneous discriminations but not successive go/no-go discrimination, thereby resembling that reported in rats with hippocampal damage. Most importantly, our present set of data supports the conclusion that two forms of memory expression for the same piece of acquired experience can be assessed in the same subjects by manipulating the way of presenting two arms that were previously experienced separately. These two forms of memory expressions are differentially affected in aged mice, thereby demonstrating the highly selective and specific deleterious effect of ageing.

In these studies, we characterized the influence of the novel benzodioxopiperazine serotonin (5-HT)1A ligand, S 15535, on the release of 5-HT in rat hippocampus and compared its potential anxiolytic properties with those of the 5-HT1A receptor partial agonist, buspirone, the 5-HT1A antagonist, WAY 100,635 and the benzodiazepine, diazepam (DZM). (Doses are in milligrams per kilogram s.c., unless otherwise specified.) S 15535 dose-dependently (0.3-3.0) reduced dialysate concentrations of 5-HT in the hippocampus of anesthetized rats. This action of S 15535 (3.0) was blocked by WAY 100,635 (0.3), (-)-penbutolol (2.0) and (-)-tertatolol (8.0), antagonists at 5-HT1A autoreceptors. In rats, fear-induced ultrasonic vocalizations (USVs) were dose-dependently abolished by S 15535 (0.16-2.5 s.c. and 0.63-10.0 p.o.), an action mimicked by buspirone (0.02-2.5) and DZM (0.16-10.0). Further, the action of S 15535 (0.63) was abolished by WAY 100,635 (0.16) and (-)-penbutolol (10.0), which were inactive alone. S 15535 dose-dependently (0.63-10.0 s.c. and 2.5-40.0 p.o.) blocked aggressive encounters in isolated mice; buspirone (0.16-10.0) and, at high doses, DZM (2.5-40.0) were also effective. WAY 100,635 (0.16), which was inactive alone, fully antagonized the antiaggressive actions of S 15535 (2.5). In an elevated plus-maze, neither S 15535 (0.0025-10.0), buspirone (0.0025-10.0) nor WAY 100,635 (0.00063-0.63) significantly increased open-arm entries, whereas they were increased by DZM (0.16-0.63). In the pigeon conflict test, S 15535 (0.04-0.16 i.m.) markedly increased punished responses and only slightly decreased unpunished responses, even at a 64-fold higher dose. In contrast, buspirone (0.16-2.5 i.m.) and DZM (0.04-2.5 i.m.) showed no or a less marked (4-fold) separation between doses increasing punished and decreasing unpunished responses. In the presence of the 5-HT1A antagonist, (-)-alprenolol (10.0 mg/kg i.m.), S 15535 did not increase punished responses. In a Geller conflict paradigm in rats, S 15535 dose dependently (0.3-3.0) increased punished responses, and its action (1.0) was blocked by (-)-penbutolol (8.0). S 15535 (0.63-40.0 s.c. and 2.5-40.0 p.o.) exerted little influence on motor behavior. In conclusion, in line with its net inhibition of serotoninergic transmission by activation of 5-HT1A autoreceptors and blockade of postsynaptic 5-HT1A receptors, S 15535 expresses anxiolytic activity. In addition, it displays antiaggressive (and antidepressant, accompanying paper) properties. Further, S 15535 does not compromise motor behavior at doses over which it expresses its anxiolytic properties. Thus, S 15535 represents a promising candidate for the treatment of anxious states in man.