LOCALIZATION AND PHARMACOLOGICAL CHARACTERIZATION OF PIGEON DIAZEPAM-INSENSITIVE GABA(A) RECEPTORS

Transduction mechanisms associated with ligand binding at diazepam-ins ensitive subtypes of GABA(A) receptors remain largely unknown, but uni que behavioral effects of ligands binding at these sites have been rep orted in pigeons. The present study further evaluated the pharmacologi cal characteristics of diazepam-insensitive GABA(A) receptors in pigeo n brain, using [H-3]Ro 15-4513. Autoradiography detected diazepam-inse nsitive benzodiazepine sites on GABA(A) receptors in a number of brain regions, with the highest densities present in the olfactory bulb, hi ppocampus, thalamic nuclei and cerebellar granule cell layers, with de nsities of similar to 10-20% of total benzodiazepine receptor binding. Saturation analysis revealed significant densities (similar to 10% of total benzodiazepine receptor binding) of extracerebellar diazepam-in sensitive benzodiazepine receptors in optic lobe, hippocampus, and bra instem compared to 27% in cerebellum. As reported for mammalian diazep am-sensitive benzodiazepine receptors, GABA (50 mu M) generally increa sed the affinities of agonists and partial agonists, had little effect on the affinities of antagonists, and decreased the affinity of an in verse agonist for pigeon cerebellar diazepam-sensitive benzodiazepine receptors. GABA modulation of ligand binding to diazepam-insensitive b enzodiazepine receptors was less than that observed for diazepam-sensi tive sites, and no positive modulation was observed. These results dem onstrate the presence of cerebellar and extracerebellar diazepam-insen sitive benzodiazepine receptors in pigeon brain, with distribution pat terns and pharmacology similar to those reported in mammals. The compa rable central localization and pharmacological properties of drugs at diazepam-sensitive and -insensitive benzodiazepine receptors in pigeon s and rats attests to the evolutionary conservation of GABA(A) systems .