Selective GABAA α5 benzodiazepine inverse agonist antagonizes the neurobehavioral actions of alcohol

Background: Previous research has implicated the alpha 5-containing GABA(A) receptors of the hippocampus in the reinforcing properties of alcohol. In the present study, a selective GABA(A) alpha 5 benzodiazepine inverse agonist (e.g., RY 023) was used in a series of in vivo and in vitro studies to determine the significance of the alpha 5-receptor in the neurobehavioral actions of alcohol. Methods: In experiment one, systemic injections of RY 023 (1 to 10 mg/kg IP) dose-dependently reduced ethanol-maintained responding by 52% to 86% of controls, whereas bilateral hippocampal infusions (0.3 to 20 mu g) reduced responding by 66% to 84% of controls. Saccharin responding was reduced only with the highest intraperitoneal (e.g., 10 mg) and microinjected (e.g., 20 mu g) doses. In experiment two, RY 023 (3.0 to 15 mg/kg IP) reversed the motor-impairing effects of a moderate dose of alcohol (0.75 g/kg) on an oscillating bar task in the absence of intrinsic effects. In the open field, RY 023 (3.0 to 7.5 mg/kg) produced intrinsic effects alone but attenuated the suppression of the 1.25 g/kg ethanol dose. Because the diazepam-insensitive receptors (e.g., alpha 4 and alpha 6) have been suggested to play a role in alcohol motor impairing and sedative actions, experiment three compared the efficacy of RY 023 with Ro 15-4513 and two prototypical benzodiazepine antagonists (e.g., flumazenil and ZK 93426) across the alpha 4 beta 3 gamma 2-, alpha 5 beta 3 gamma 2-, and alpha 6 beta 3 gamma 2-receptor subtypes in Xenopus oocytes. Results: RY 023 produced classic inverse agonism at all receptor subtypes, whereas Ro15-4513 and the two antagonists displayed a neutral or agonistic profile at the diazepam-insensitive receptors. Conclusions: Overall, the results extend our previous findings by demonstrating that an alpha 5-subtype ligand is capable of attenuating not only the rewarding action of alcohol but also its motor impairing and sedative effects. We propose that these actions are mediated in part by the alpha 5-receptors of the hippocampus. The hippocampal alpha 5-receptors could represent novel targets in understanding the neuromechanisms regulating the neurobehavioral actions of alcohol in humans.