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-HT1A autoreceptors.
Footnotes
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A.M. was partially supported by Consejo Nacional de Ciencia y Tecnologia Grant 39534.
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doi:10.1124/jpet.104.069625.
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ABBREVIATIONS: FCX, frontal cortex; 5-HT, 5-hydroxytryptamine (serotonin); ACh, acetylcholine; AChEI, acetylcholinesterase inhibitor; DH, dorsal hippocampus; 8-OH-DPAT, 8-hydroxy-2-dipropylaminotetralin; TPSD, two-platform spatial discrimination; ANOVA, analysis of variance; DNMTS, delayed nonmatching to sample; S15535, 4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine; WAY100,635, (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl) cyclo-hexanecarboxamide fumarate.
- Received April 7, 2004.
- Accepted May 13, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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