Cognitive effects of SL65.0155, a serotonin 5-HT 4 receptor partial agonist, in animal models of amnesia

Abstract

Given that several data suggest the involvement of serotonergic (5-HT) system, particularly the serotonin 5-HT 4 receptors, in memory processes; this study was undertaken to investigate the role of serotonin 5-HT 4 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 β-amyloid 1–42 fragment (BAP 1–42; 400 pmol/mouse) or of galanin (GAL) 1–29 (3 μg/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-dihydro-1,4-benzodioxin-5-yl)-3-[1-(2-phenylethyl)-4-piperidinyl]-1,3,4-oxadiazol-2(3 H)-one-monohydrochloride), a serotonin 5-HT 4 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.