Zolpidem is a potent stoichiometry-selective modulator of α1β3 GABAA receptors: evidence of a novel benzodiazepine site in the α1-α1 interface

Zolpidem is not a typical GABA(A) receptor hypnotic. Unlike benzodiazepines, zolpidem modulates tonic GABA currents in the rat dorsal motor nucleus of the vagus, exhibits residual effects in mice lacking the benzodiazepine binding site, and improves speech, cognitive and motor function in human patients with severe brain injury. The receptor by which zolpidem mediates these effects is not known. In this study we evaluated binary alpha 1 beta 3 GABA(A) receptors in either the 3 alpha 1:2 beta 3 or 2 alpha 1:3 beta 3 subunit stoichiometry, which differ by the existence of either an alpha 1-alpha 1 interface, or a beta 3-beta 3 interface, respectively. Both receptor stoichiometries are readily expressed in Xenopus oocytes, distinguished from each other by using GABA, zolpidem, diazepam and Zn2+. At the 3 alpha 1:2 beta 3 receptor, clinically relevant concentrations of zolpidem enhanced GABA in a flumazenil-sensitive manner. The efficacy of diazepam was significantly lower compared to zolpidem. No modulation by either zolpidem or diazepam was detected at the 2 alpha 1:3 beta 3 receptor, indicating that the binding site for zolpidem is at the alpha 1-alpha 1 interface, a site mimicking the classical alpha 1-gamma 2 benzodiazepine site. Activating alpha 1 beta 3 (3 alpha 1:2 beta 3) receptors may, in part, mediate the physiological effects of zolpidem observed under distinct physiological and clinical conditions, constituting a potentially attractive drug target.