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.
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.
Millan
Mark J
MJ
Department of Psychopharmacology, Institut de Recherches Servier, Centre de Recherches de Croissy, 125 chemin de Ronde 78290 Croissy/Seine, France. mark.millan@fr.netgrs.com
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
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism; D000375:Aging / Q000502:physiology; D000647:Amnesia / Q000139:chemically induced; D000818:Animals; D003956:Dialysis; D004193:Discrimination Learning / Q000187:drug effects; D004347:Drug Interactions; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D010879:Piperazines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects; D012601:Scopolamine / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology
D010879:Piperazines; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; C079549:4-(benzodioxan-5-yl)-1-(indan-2-yl)piperazine; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D012601:Scopolamine; D000109:Acetylcholine