Stereospecific transduction of behavioral effects via diazepam-insensitive GABA A receptors

Abstract

Previous studies reported a positive correlation between ligand affinities at diazepam-insensitive GABA A receptors and substitution for the discriminative stimulus effects of the benzodiazepine receptor antagonist, flumazenil, in pigeons. In the present experiments, bretazenil and Ro 14-5974 (ethyl-( S)-11,12,13,13a-tetrahydro-9-oxo-9 H-imidazo[1,5-a]-pyrrolo-[2,1-c][1,4]benzodiazepine-1-carboxylate) partially substituted for, and blocked the discriminative stimulus effects of midazolam, congruent with their actions at diazepam-sensitive GABA A receptors in vitro. In addition, bretazenil and Ro 14-5974, but not their R-enantiomers, had high affinity for diazepam-insensitive receptors and fully substituted for the discriminative stimulus effects of flumazenil. The R-enantiomers of these compounds had low affinity ( K i > 1 μM) for diazepam-sensitive and diazepam-insensitive receptors, and did not share discriminative stimulus effects with flumazenil or midazolam. Ro 19-0528 (7-chloro-3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydro-5-methyl-6 H-imidazo[1,5-a][1,4]benzodiazepin-6-one), a structurally related compound with full agonist actions at diazepam-sensitive GABA A receptors, had high diazepam-insensitive receptor affinity ( K i = 96 nM) and partially substituted for the discriminative stimulus effects of flumazenil. These results are consistent with stereospecific mediation of the discriminative stimulus effects of flumazenil through high affinity binding to diazepam-insensitive receptors in pigeons.