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dc.contributor.authorHarder, Josie A.*
dc.contributor.authorWomack, Matthew D.*
dc.contributor.authorSchechter, L.E.*
dc.contributor.authorSmith, D.L.*
dc.contributor.authorChilders, W.*
dc.contributor.authorRosenzweig-Lipson, S.*
dc.contributor.authorSukoff, S.*
dc.date.accessioned2009-10-19T10:47:54Z
dc.date.available2009-10-19T10:47:54Z
dc.date.issued2005
dc.identifier.citationHarder, J.A., Womack, M., Schechter, M.E. and Smith, D.L. et al. (2005). Lecozotan (SRA-333): a selective serotonin1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties. Journal of Pharmacology and Experimental Therapeutics. Vol. 314, No. 3, pp. 1274-1289.en
dc.identifier.urihttp://hdl.handle.net/10454/3679
dc.descriptionNoen
dc.description.abstractRecent data has suggested that the 5-HT1A receptor is involved in cognitive processing. A novel 5- HT1A receptor antagonist, 4-cyano-N- [(2R)-[4- (2,3-dihydrobenzo [1,4] dioxin-5-yl) piperazin-1-yl] propyl]-N-pyridin-2-yl-benzamide hydrochloride (lecozotan), which has been characterized in multiple in vitro and in vivo pharmacologic assays as a drug to treat cognitive dysfunction, is reported. In vitro binding and intrinsic activity determinations demonstrated that lecozotan is a potent and selective 5-HT1A receptor antagonist. Using in vivo microdialysis, lecozotan (0.3 mg/kg sc) antagonized the decrease in hippocampal extracellular 5-HT induced by a challenge dose (0.3 mg/kg sc) of 8 OH-DPAT and had no effects alone at doses 10-fold higher. Lecozotan significantly potentiated the potassium chloride-stimulated release of glutamate and acetylcholine in the dentate gyrus of the hippocampus. Chronic administration of lecozotan did not induce 5-HT1A receptor tolerance or desensitization in a behavioral model indicative of 5- HT1A receptor function. In drug discrimination studies, lecozotan (0.01-1 mg/kg im) did not substitute for 8-OH-DPAT and produced a dose-related blockade of the 5-HT1A agonist discriminative stimulus cue. In aged rhesus monkeys, lecozotan produced a significant improvement in task performance efficiency at an optimal dose (1 mg/kg po). Learning deficits induced by the glutamatergic antagonist MK-801 (assessed by perceptually complex and visual spatial discrimination) and by specific cholinergic lesions of the hippocampus (assessed by visual spatial discrimination) were reversed by lecozotan (2 mg/kg im) in marmosets. The heterosynaptic nature of the effects of lecozotan imbues this compound with a novel mechanism of action directed at the biochemical pathologies underlying cognitive loss in AD.en
dc.language.isoenen
dc.relation.isreferencedbyhttp://dx.doi.org/10.1124/jpet.105.086363en
dc.subject5-HT1Aen
dc.subject5-HT1A receptoren
dc.subjectAlzheimer's Diseaseen
dc.subjectCognitionen
dc.subjectLecozotanen
dc.subjectSerotonin antagonisten
dc.titleLecozotan (SRA-333): a selective serotonin1A receptor antagonist that enhances the stimulated release of glutamate and acetylcholine in the hippocampus and possesses cognitive-enhancing properties.en
dc.status.refereedYesen
dc.typeArticleen
dc.type.versionNo full-text available in the repositoryen


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