THE INTERACTION OF A BENZODIAZEPINE RECEPTOR ANTAGONIST (RO15-1788) WITH GABA AND GABA RECEPTOR ANTAGONISTS AT THE GABA(A) RECEPTOR CHLORIDE IONOPHORE COMPLEX

The effect of the GABA(A) receptor antagonists bicuculline and SR 95531 was compared with that of the antidepressants amoxapine and amitriptyline on GABA-stimulated CL-36- uptake using membrane vesicles from the rat cerebral cortex. The interaction of Ro15-1788 with these drugs and the effect of Ro15-1788 on GABA-stimulated uptake of Cl-36- were also investigated. GABA(A) receptor antagonists and the antidepressants inhibited 30-mu-M GABA-mediated uptake of Cl-36- with the rank order of potency of SR 95531 > bicuculline > amoxapine > amitriptyline. Ro15-1788 potentiated the effect of these inhibitors on 30-mu-M GABA-stimulated chloride uptake. Ro15-1788 alone did not alter the effect of 30-mu-M GABA on Cl-36- uptake. However, it did inhibit the Cl-36- uptake produced by 100-mu-M GABA, and enhanced Cl-36- uptake mediated by 10-mu-M GABA. The data show variations in the apparent intrinsic efficacy of Ro15-1788 at the chloride channel with respect to different experimental conditions. It is suggested that the activity of Ro15-1788 depends on changes in the conformational state of benzodiazepine-GABA(A) receptor chloride-ionophore complex produced by GABA and GABA receptor antagonists.