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Received for publication April 7, 2004.
Revised May 13, 2004.
Accepted for publication May 13, 2004.
These studies examined the influence of the selective 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, 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. Further, 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 0.63-10.0 and 0.16-2.5, 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-di-propyl-aminotetralin (0.5 µg). Finally, S15535 improved performance (0.16-0.63) in a spatial, delayed non-matching to sample model in mice and, in an operant delayed non-matching to sample model in old rats, increased response accuracy and reduced latency to respond S15535 (1.25-5.0 mg/kg, p.o.). In conclusion, S15535 reinforces frontocortical and hippocampal release of acetylcholine and displays a broad-based pattern of pro-cognitive properties. Its actions involve both blockade of postsynaptic 5-HT1A receptors and engagement of 5-HT1A autoreceptors.
Key words:
5-HT1A, Acetylcholine, Cognition, Frontal cortex, Hippocampus, Scopolamine
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