TY - JOUR T1 - The Serotonin<sub>1A</sub> 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 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 190 LP - 203 DO - 10.1124/jpet.104.069625 VL - 311 IS - 1 AU - Mark J. Millan AU - Alain Gobert AU - Sylvain Roux AU - Roger Porsolt AU - Alfredo Meneses AU - Mirjana Carli AU - Benjamin Di Cara AU - Robert Jaffard AU - Jean-Michel Rivet AU - Pierre Lestage AU - Elisabeth Mocaer AU - Jean-Louis Peglion AU - Anne Dekeyne Y1 - 2004/10/01 UR - http://jpet.aspetjournals.org/content/311/1/190.abstract 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-HT1A autoreceptors. The American Society for Pharmacology and Experimental Therapeutics ER -