Research article summary (published 12 May 2004):

The serotonin1A 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.

Full Abstract

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 microg) into dorsal hippocampus blocked amnesic effects of the 5-HT(1A) agonist 8-hydroxy-2-dipropylaminotetralin (0.5 microg). 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.

Author information

Author/s: Millan, Mark J (MJ); Gobert, Alain (A); Roux, Sylvain (S); Porsolt, Roger (R); Meneses, Alfredo (A); Carli, Mirjana (M); Di Cara, Benjamin (B); Jaffard, Robert (R); Rivet, Jean-Michel (JM); Lestage, Pierre (P); Mocaer, Elisabeth (E); Peglion, Jean-Louis (JL); Dekeyne, Anne (A);

Affiliation: Department of Psychopharmacology, Institut de Recherches Servier, Centre de Recherches de Croissy, 125 chemin de Ronde 78290 Croissy/Seine, France. mark.millan(-atsign-)fr.netgrs.com

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther), published in United States. (Language: eng)

Reference: 2004-Oct; vol 311 (issue 1) : pp 190-203

Dates: Created 2004/09/17; Completed 2004/12/15; Revised 2006/11/15;

PMID: 15146031, status: MEDLINE (last retrieval date: 2/18/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

8-Hydroxy-2-(di-n-propylamino)tetralin - pharmacology Acetylcholine - metabolism Aging - physiology Amnesia - chemically induced Animals Dialysis Discrimination Learning - drug effects Drug Interactions Hippocampus - drug effects; metabolism Male Maze Learning - drug effects Memory - drug effects; physiology

Memory - drug effects; physiology Mice Mice, Inbred C57BL Piperazines - pharmacology Prefrontal Cortex - drug effects; metabolism Rats Rats, Wistar Receptor, Serotonin, 5-HT1A - metabolism Recognition (Psychology) - drug effects Scopolamine - pharmacology Serotonin Agonists - pharmacology Spatial Behavior - drug effects; physiology

Associated Chemicals: Piperazines (0) ; Serotonin Agonists (0) ; Receptor, Serotonin, 5-HT1A (112692-38-3) ; 4-(benzodioxan-5-yl)-1-(indan-2-yl)piperazine (146998-34-7) ; Scopolamine (51-34-3) ; Acetylcholine (51-84-3) ; 8-Hydroxy-2-(di-n-propylamino)tetralin (78950-78-4)

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