PHARMACOLOGICAL CHARACTERIZATION OF IN-VIVO PROPERTIES OF PUTATIVE MIXED 5-HT1A AGONIST 5-HT2A/2C ANTAGONIST ANXIOLYTICS .1. ANTIPUNISHMENTEFFECTS IN THE PIGEON/

A conflict procedure in pigeons was used to characterize the antipunis hment effects of the putative mixed 5-hydroxy-tryptamine (5-HT)(1A) ag onist/5-HT2A/2C antagonists WY 50,324, CGS 18102A, LEK 8804 and FG 597 4 and to further investigate interactions between the antipunishment e ffects 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, antagonist prazosin. The 5-HT1A agonists, buspirone and 8-OH-DPAT, which lack affinity for 5-HT 2A/2C receptors, produced dose-related increases in punished respondin g. Of the compounds with a mixed binding profile, only WY 50,324 showe d effects that were comparable to those observed after 8-OH-DPAT, wher eas FG 5974 and CGS 18102A exhibited limited effects on punished respo nding, and LEK 8804 was ineffective. Administration of a relatively lo w, behaviorally active dose of ritanserin (0.16 mg/kg) significantly e nhanced the potency of 8-OH-DPAT and buspirone to increase punished re sponding from 8 to 50-fold without altering their effects on unpunishe d 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 a nd increased the number of doses of buspirone exerting significant eff ects on punished responding, but did not alter the effects of 8-OH-DPA T. Taken together, the results neither explain the suggested greater e fficacy in producing anxiolytic effects of compounds with putative mix ed 5-HT1A agonist and 5-HT2A/2C antagonist properties, nor confirm a p roposed interaction between alpha(1) adrenoreceptors acid 5-HT1A agoni sts in preclinical tests of anxiolytic activity.