Effects of benzodiazepine agonists on punished responding in pigeons and their relationship with clinical doses in humans

Abstract

 Anxiolytic drugs generally produce anticonflict effects in both pigeons and rats, although relatively few anxiolytics have been examined in the pigeon and the procedure has not been as completely validated as the rat model. In this study, we examined the antipunishment effects of a variety of benzodiazepine agonists in pigeons and compared the relationship between their potencies to engender anxiolytic-like effects and their clinical doses in humans. In pigeons whose responding was maintained under a multiple FR30^food:FR30^food+shock schedule, the benzodiazepine agonists diazepam, flunitrazepam, alprazolam, chlordiazepoxide, lorazepam, flurazepam, bromazepam, medazepam, and clorazepate produced dose-related increases in punished responding, and, with the exception of medazepam, decreased unpunished responding at higher doses. Potencies calculated from the percentage of pigeons showing significant increases in punished responding ranged from 0.081 to 11 mg/kg, and these potencies were invariably lower than those for decreases in unpunished responding by factors ranging from 2.2 to more than 14. The comparison of relative potencies of benzodiazepine receptor agonists in pigeons and humans revealed a high positive correlation (0.90, P<0.005), thus demonstrating the predictive validity of this preclinical animal model for anxiolytic benzodiazepines. The results agree with previous findings of robust anticonflict effects of benzodiazepine receptor agonists and extend further the pharmacological characterization to compounds that have not been examined previously in pigeons.