Effects of different classes of partial benzodiazepine agonists on punished and unpunished responding in pigeons

Abstract

  Rationale: Although all of the benzodiazepines in use for the treatment of anxiety are presumably full agonists, it is conceivable that partial benzodiazepine agonists may also be clinically effective on the basis of their effects in preclinical models of anxiety. Objectives: To compare the anxiolytic-like effects of different pharmacological/chemical classes of partial benzodiazepine agonists in the pigeon conflict procedure. Methods: Anticonflict effects in pigeons whose responding was maintained under a multiple FR30 food:FR30 food+shock schedule were characterized by 1) the magnitude of punished responding or 2) the percentage of pigeons (n=5–7/dose) showing significant increases in punished responding. Results: The partial allosteric modulators bretazenil and imidazenil produced anticonflict effects comparable with or superior to those observed following administration of the relatively full agonist midazolam. In contrast, neither the β-carbolines CGS 9896, ZK 95962 and ZK 91296, nor the imidazopyridines, alpidem and zolpidem, produced anticonflict effects comparable to either bretazenil and imidazenil or the relatively full benzodiazepine agonist, midazolam, at the doses examined in this study. Conclusions: Although the β-carboline ZK 95962 produced some anticonflict effects, none of the other compounds had anxiolytic-like effects like those observed with midazolam, bretazenil or imidazenil. However, because bretazenil and imidazenil produced robust anticonflict activity, the results indicate that partial allosteric modulators could have anxiolytic effects similar to those produced by higher efficacy compounds. Altogether, the results indicate that partial benzodiazepine agonists differ in their ability to produce robust anticonflict effects in the pigeon.