BEHAVIORAL AND BIOCHEMICAL-CHARACTERIZATION OF BENZODIAZEPINE RECEPTOR PARTIAL AGONISTS IN PIGEONS

The ability of benzodiazepine receptor partial agonists to exhibit ful l efficacy in preclinical anxiolytic tests, in conjunction with initia l clinical results, has suggested the possibility of a reduced clinica l side-effect profile compared to benzodiazepine receptor full agonist s like diazepam. Because punished behavior of pigeons has been useful in detecting effects of novel anxiolytic drugs, effects of imidazobenz odiazepine and beta-carboline benzodiazepine receptor partial agonists and some related compounds were evaluated in this species. The abilit ies of these compounds to substitute for the discriminative stimulus e ffects of the full agonist midazolam also was determined. Intrinsic ef ficacy was assessed by the degree to which gamma-aminobutyric acid inc reased ligand potency to displace [H-3]Ro 15-1788 (flumazinil) from me mbranes of pigeon cerebrum, and ranged from full agonist-like efficacy {Ro 19-5470; pyl-1,2,4-oxodiazol-5-yl)-5,6-dihydro-5-methyl-4H- imida zo[1,5a]-thieno[3,2-f]diazin-4-one} to minimal gamma-aminobutyric acid potentiations close to that of the antagonist flumazenil {abecarnil a nd Ro 41-7812; thyl-6H-imidazo[1,5-a]-[1,4]benzodiazepine-6-one}. Puni shed responding was increased markedly by midazolam and by all partial agonists, except Ro 41-7812 and Ro 42-8773 ethyl-6H-imidazo[1,5-a][1, 4]benzodiazepine-6-one}, at doses that did not affect nonpunished resp onding. In contrast to the full substitution generally observed in mam mals, all of the partial agonists produced incomplete substitution (40 -70%) in the midazolam drug discrimination procedure in pigeons. A pos itive relationship was observed between the degree of substitution and intrinsic efficacy. The benzodiazepine antagonists, flumazenil and ZK 93,426 hyl-5-isopropoxy-4-methoxymethyl-beta-carboline-3- carboxylate }, neither increased punished responding nor substituted for midazolam . The results of the present study suggest that benzodiazepine recepto r partial agonists and related compounds may provide full anxiolytic a ctivity at doses that do not fully reproduce the subjective effect pro file of full agonists.