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

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.