Cognitive effects of SL65.0155, a serotonin 5-HT4 receptor partial agonist, in animal models of amnesia

Given that several data suggest the involvement of serotonergic (5-HT) system, particularly the serotonin 5-HT4 receptors, in memory processes; this study was undertaken to investigate the role of serotonin 5-HT4 receptors in different experimental models of amnesia in male Swiss mice or in male Sprague-Dawley rats, tested in learning and memory tasks. Amnesia was induced in mice by intracerebroventricular (i.c.v.) injection of beta-amyloid 1-42 fragment (BAP 1-42; 400 pmol/mouse) or of galanin (GAL) 1-29 (3 mu g/mouse). Another group of animals was exposed to carbon monoxide (CO). Treatments were made 14 days, 15 min or 8 days prior to the learning trial of a step-through passive avoidance paradigm, respectively. Latency to re-enter the dark box appeared to be reduced in all treatment groups. Intraperitoneal (i.p.) administration of SL65.0155 (5-(8-amino-7-chloro-2,3-dihydro1,4-benzodioxin-5-yl)-3-[1-(2-phenylethyl)-4-piperidinyl] -1,3,4-oxadiazol-2 (3H) -one-monohydrochloride), a serotonin 5-HT4 receptor partial agonist (1 mg/kg/day), for 7 days prior to the learning trial, inhibited the amnesic effect of both peptides increasing the latency to re-enter the dark box also in mice exposed to CO. In rats with ibotenate-induced lesions of the nucleus basalis magnocellularis (NBM) or prenatally exposed to methylazoxymethanol (MAM), SL65.0155 (1 mg/kg/day, i.p.) administered for 7 days, improved the learning and memory capacity in animals tested in shuttle-box active avoidance and radial maze tests. These findings give further support to the hypothesis of SL65.0155 cognition-enhancing activity across a range of tasks. (c) 2006 Elsevier B.V. All rights reserved.