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NEUROPHARMACOLOGY

The Serotonin_1A Receptor Partial Agonist S15535 [4-(Benzodioxan-5-yl)1-(indan-2-yl)piperazine] Enhances Cholinergic Transmission and Cognitive Function in Rodents: A Combined Neurochemical and Behavioral Analysis

Departments of Psychopharmacology (M.J.M., A.G., B.D.C., J.M.R., A.D.) and Cerebral Pathology (P.L.), Institut de Recherches Servier, Paris, France; Porsolt & Partners Pharmacology (S.R., R.P.), Boulogne-Billancourt, France; Pharmacobiol (A.M.), Centro de Investigación y Estudios Avanzados, Mexico City, Mexico; Istituto di Ricerche Farmacologiche "Mario Negri" (M.C.), Milan, Italy; Université de Bordeaux 1-Centre National de la Recherche Scientifique-Unité de Recherche Associée 339 (R.J.), Laboratoire de Neurosciences Comportementales et Cognitives, Talence cedex, France; Institut de Recherches Internationales Servier (E.M.), Courbevoie cedex, France; and Institut de Recherches Servier (J.L.P.), Suresnes, France

These studies examined the influence of the selective 5-hydroxytryptamine (serotonin) (5-HT)_1A receptor partial agonist S15535 [4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine] upon cholinergic transmission and cognitive function in rodents. In the absence of acetylcholinesterase inhibitors, S15535 dose-dependently (0.04–5.0 mg/kg s.c.) elevated dialysis levels of acetylcholine in the frontal cortex and dorsal hippocampus of freely moving rats. In the cortex, the selective 5-HT_1A receptor antagonist WAY100,635 [(N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclo-hexanecarboxamide) fumarate] dose-dependently (0.0025–0.63) blocked this action of S15535. By contrast, in dorsal hippocampus, WAY100,635 mimicked the induction of acetylcholine release by S15535. In a social recognition paradigm, S15535 dose-dependently (0.16–10.0) improved retention, an action blocked by WAY100,635 (0.16), which was ineffective alone. Furthermore, S15535 dose-dependently (0.04–2.5) and WAY100,635 reversibly abolished amnesic properties of the muscarinic antagonist scopolamine (0.63) in this procedure. Cognitive deficits provoked by scopolamine in autoshaping and Morris water-maze procedures were likewise blocked by S15535 at doses of 0.63 to 10.0 and 0.16 to 2.5, respectively. In a two-platform spatial discrimination task, in which S15535 similarly abrogates cognitive deficits elicited by scopolamine, injection of S15535 (1.0 and 10.0 µg) into dorsal hippocampus blocked amnesic effects of the 5-HT_1A agonist 8-hydroxy-2-dipropylaminotetralin (0.5 µg). Finally, S15535 (0.16–0.63) improved performance in a spatial, delayed nonmatching to sample model in mice, and in an operant delayed nonmatching to sample model in old rats, S15535 (1.25–5.0 mg/kg p.o.) increased response accuracy and reduced latency to respond. In conclusion, S15535 reinforces frontocortical and hippocampal release of acetylcholine and displays a broad-based pattern of procognitive properties. Its actions involve both blockade of postsynaptic 5-HT_1A receptors and engagement of 5-HT_1A autoreceptors.

Address correspondence to: Dr. Mark J. Millan, Institut de Recherches Servier, Centre de Recherches de Croissy, 125 chemin de Ronde 78290 Croissy/Seine, France. E-mail: mark.millan{at}fr.netgrs.com

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