Role of GABAA a5-containing receptors in ethanol reward in the mouse: the effects of targeted gene deletion and a selective inverse agonist

GABAA receptors containing a5 subunits have been suggested to mediate the rewarding effects of ethanol. We tested this hypothesis in mice with deletion of a5 subunits. a5 knockout mice did not differ from wildtypes in operant responding for 10% ethanol/10% sucrose, but responded less for 10% sucrose. The benzodiazepine (BZ) site inverse agonist, Ro 15-4513, has higher affinity for GABAA receptors containing 5 subunits and dose-dependently (0–27 mg/kg, i.p.) reduced lever pressing for ethanol/sucrose in wildtype mice, but had less effect in knockout mice; lever pressing for sucrose was unaffected. These data suggest that a5 subunits are not essential for ethanol reward, but the reduction of operant responding for ethanol by Ro 15-4513 is mediated by a5-containing GABAA receptors. In measures of ethanol consumption, a5 knockout mice did not differ from wildtypes at low ethanol concentrations (2–8%), but consumed less ethanol at higher concentrations; these differences were not attributable to increased behavioural disruption of the knockout by ethanol, since no differences were seen in sensitivity to ethanol's sedative or ataxic effects. Ro 15-4513's ability to reduce ethanol consumption was unaffected, suggesting that this effect is not mediated by the a5 subtype. Secondly, we tested the ability of a novel a5-efficacy-selective benzodiazepine receptor ligand, a5IA-II, that possesses greater inverse agonist activity at a5- than at a1-, á2- or a3-containing GABAA receptors, to influence operant responding. a5IA-II (0.03–3 mg/kg) dose-dependently decreased lever pressing for 10% ethanol, the minimally effective dose of 1 mg/kg, corresponding to over 90% receptor occupancy, but did not affect lever pressing for 4% sucrose. Although inverse agonists acting at a5-containing receptors reduce ethanol self-administration, a5 subunits may not be essential to signaling ethanol reward.