Imidazenil: A low efficacy agonist at α1- but high efficacy at α5-GABA A receptors fail to show anticonvulsant cross tolerance to diazepam or zolpidem

Abstract

Whereas advances in the molecular biology of GABA A receptor complex using knock-out and knock-in mice have been valuable in unveiling the structure, composition, receptor assembly, and several functions of different GABA A receptor subtypes, the mechanism(s) underlying benzodiazepine (BZ) tolerance and withdrawal remain poorly understood. Studies using specific GABA A receptor subunit knock-in mice suggest that tolerance to sedative action of diazepam requires long-term activation of α1 and α5 GABA A receptor subunits. We investigated the role of long-term activation of these GABA A receptor subunits during anticonvulsant tolerance using high affinity and high intrinsic efficacy ligands for GABA A receptors expressing the α5 subunit (imidazenil) or α1 subunit (zolpidem), and a non-selective BZ recognition site ligand (diazepam). We report here that long-term activation of GABA A receptors by zolpidem and diazepam but not by imidazenil elicits anticonvulsant tolerance. Although anticonvulsant cross-tolerance occurs between diazepam and zolpidem, there is no cross-tolerance between imidazenil and diazepam or zolpidem. Furthermore, diazepam or zolpidem long-term treatment decreased the expression of mRNA encoding the α1 GABA A receptor subunit in prefrontal cortex by 43% and 20% respectively. In addition, diazepam but not zolpidem long-term treatment produced a 30% increase in the expression of the α5 GABA A receptor subunit mRNA in prefrontal cortex. In contrast, imidazenil which is devoid of anticonvulsant tolerance does not elicit significant changes in the expression of α1 or α5 GABA A receptor subunit. These findings suggest that long-term activation of GABA A receptors containing the α1 or other subunits but not the α5 receptor subunit is essential for the induction of anticonvulsant tolerance.