Pharmacological characterization of in vivo properties of putative mixed 5-HT1A agonist/5-HT2A/2C antagonist anxiolytics. I. Antipunishment effects in the pigeon

MS Kleven and W Koek

Centre de Recherche Pierre Fabre, Castres, France.

A conflict procedure in pigeons was used to characterize the antipunishment effects of the putative mixed 5-hydroxytryptamine (5- HT)1A agonist/5-HT2A/2C antagonists WY 50,324, CGS 18102A, LEK 8804 and FG 5974 and to further investigate interactions between the antipunishment effects of the 5-HT1A agonists buspirone and 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin] administered in combination with the mixed 5-HT2A/2C antagonist ritanserin and the alpha 1 antagonist prazosin. The 5-HT1A agonists, buspirone and 8-OH-DPAT, which lack affinity for 5-HT2A/2C receptors, produced dose-related increases in punished responding. Of the compounds with a mixed binding profile, only WY 50,324 showed effects that were comparable to those observed after 8-OH-DPAT, whereas FG 5974 and CGS 18102A exhibited limited effects on punished responding, and LEK 8804 was ineffective. Administration of a relatively low, behaviorally active dose of ritanserin (0.16 mg/kg) significantly enhanced the potency of 8-OH-DPAT and buspirone to increase punished responding from 8 to 50-fold without altering their effects on unpunished responding. Importantly, ritanserin failed to increase the number of doses of 8-OH-DPAT that significantly increased punished responding. In contrast, prazosin (2.5 mg/kg) significantly enhanced the potency and increased the number of doses of buspirone exerting significant effects on punished responding, but did not alter the effects of 8-OH-DPAT. Taken together, the results neither explain the suggested greater efficacy in producing anxiolytic effects of compounds with putative mixed 5-HT1A agonist and 5-HT2A/2C antagonist properties, nor confirm a proposed interaction between alpha1 adrenoreceptors and 5-HT1A agonists in preclinical tests of anxiolytic activity.

Volume 276, Issue 2, pp. 388-397, 02/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				W. Koek, J.-F. Patoiseau, M.-B. Assié, C. Cosi, M. S. Kleven, E. Dupont-Passelaigue, E. Carilla-Durand, C. Palmier, J.-P. Valentin, G. John, et al. F 11440, a Potent, Selective, High Efficacy 5-HT1A Receptor Agonist with Marked Anxiolytic and Antidepressant Potential J. Pharmacol. Exp. Ther., October 1, 1998; 287(1): 266 - 283. [Abstract] [Full Text]

				M. S. Kleven and W. Koek Discriminative Stimulus Effects of 8-Hydroxy-2-(di-n-propylamino)tetralin in Pigeons and Rats: Species Similarities and Differences J. Pharmacol. Exp. Ther., January 1, 1998; 284(1): 238 - 249. [Abstract] [Full Text]

				M. S. Kleven, M.-B. Assié, and W. Koek Pharmacological Characterization of In Vivo Properties of Putative Mixed 5-HT1A Agonist/5-HT2A/2C Antagonist Anxiolytics. II. Drug Discrimination and Behavioral Observation Studies in Rats J. Pharmacol. Exp. Ther., August 1, 1997; 282(2): 747 - 759. [Abstract] [Full Text]