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

Mark J. Millan, Alain Gobert, Sylvain Roux, Roger Porsolt, Alfredo Meneses, Mirjana Carli, Benjamin Di Cara, Robert Jaffard, Jean Michel Rivet, Pierre Lestage, Elisabeth Mocaer, Jean Louis Peglion, Anne Dekeyne

Research output: Contribution to journalArticle

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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-HT1A 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-HT1A 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-HT1A receptors and engagement of 5-HT 1A autoreceptors.

Original languageEnglish
Pages (from-to)190-203
Number of pages14
JournalJournal of Pharmacology and Experimental Therapeutics
Volume311
Issue number1
DOIs
Publication statusPublished - Oct 2004

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4-(benzodioxan-5-yl)-1-(indan-2-yl)piperazine
Cognition
Cholinergic Agents
Rodentia
Receptor, Serotonin, 5-HT1A
Scopolamine Hydrobromide
Acetylcholine
Hippocampus
Serotonin
Serotonin 5-HT1 Receptor Antagonists
Serotonin 5-HT1 Receptor Agonists

ASJC Scopus subject areas

  • Pharmacology

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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. / Millan, Mark J.; Gobert, Alain; Roux, Sylvain; Porsolt, Roger; Meneses, Alfredo; Carli, Mirjana; Di Cara, Benjamin; Jaffard, Robert; Rivet, Jean Michel; Lestage, Pierre; Mocaer, Elisabeth; Peglion, Jean Louis; Dekeyne, Anne.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 311, No. 1, 10.2004, p. 190-203.

Research output: Contribution to journalArticle

Millan, Mark J. ; Gobert, Alain ; Roux, Sylvain ; Porsolt, Roger ; Meneses, Alfredo ; Carli, Mirjana ; Di Cara, Benjamin ; Jaffard, Robert ; Rivet, Jean Michel ; Lestage, Pierre ; Mocaer, Elisabeth ; Peglion, Jean Louis ; Dekeyne, Anne. / 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. In: Journal of Pharmacology and Experimental Therapeutics. 2004 ; Vol. 311, No. 1. pp. 190-203.
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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-HT1A 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-HT1A 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-HT1A receptors and engagement of 5-HT 1A autoreceptors.",
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T1 - The serotonin1A receptor partial agonist S15535 [4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine] enhances cholinergic transmission and cognitive function in rodents

T2 - A combined neurochemical and behavioral analysis

AU - Millan, Mark J.

AU - Gobert, Alain

AU - Roux, Sylvain

AU - Porsolt, Roger

AU - Meneses, Alfredo

AU - Carli, Mirjana

AU - Di Cara, Benjamin

AU - Jaffard, Robert

AU - Rivet, Jean Michel

AU - Lestage, Pierre

AU - Mocaer, Elisabeth

AU - Peglion, Jean Louis

AU - Dekeyne, Anne

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N2 - 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-HT1A 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-HT1A 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-HT1A receptors and engagement of 5-HT 1A autoreceptors.

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