ALLOSTERIC UNCOUPLING AFTER CHRONIC BENZODIAZEPINE EXPOSURE OF RECOMBINANT GAMMA-AMINOBUTYRIC ACID(A) RECEPTORS EXPRESSED IN SF9 CELLS - LIGAND EFFICACY AND SUBTYPE SELECTIVITY

By using the baculovirus expression system, we report decreases in all osteric coupling at individual gamma-aminobutyric acid (GABA)(A) recep tor subtypes (alpha-1, beta-2 and gamma-2, alpha-2, beta-3 and gamma-2 and alpha-5, beta-3 and gamma-2) after chronic benzodiazepine exposur e that replicate coupling changes measured in rat cortical membranes a fter in vivo benzodiazepine exposure. The appearance of uncoupling was time-dependent and the magnitude of uncoupling at expressed GABA(A) r eceptor subtypes after chronic exposure was dependent upon the efficac y of the ligand in a subtype-specific manner. In addition, the express ion of uncoupling was not accompanied by changes in benzodiazepine rec eptor number or affinity at any expressed GABA(A) subtype examined. Th e specificity of the coupling change was further shown by the ability of a brief exposure to the benzodiazepine receptor antagonist, Ro15-17 88, to reverse the uncoupling induced by chronic benzodiazepine exposu re. These findings suggest that alterations at the GABA(A) receptor co mplex after chronic benzodiazepine exposure are mediated directly by a gonist effects at the GABA(A) receptor complex and are not the product of the changes in the surrounding neuronal environment. Furthermore, the present study shows that drug efficacy, and not simply affinity, p lays a critical role in determining the degree of uncoupling, and perh aps, in the development of tolerance and dependence.