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GABA(A) receptors containing alpha5 subunits have been suggested to mediate the rewarding effects of ethanol. We tested this hypothesis in mice with deletion of alpha5 subunits. alpha5 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 GABA(A) 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 alpha5 subunits are not essential for ethanol reward, but the reduction of operant responding for ethanol by Ro 15-4513 is mediated by alpha5-containing GABA(A) receptors. In measures of ethanol consumption, alpha5 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 alpha5 subtype. Secondly, we tested the ability of a novel alpha5-efficacy-selective benzodiazepine receptor ligand, alpha5IA-II, that possesses greater inverse agonist activity at alpha5- than at alpha1-, á2- or alpha3-containing GABA(A) receptors, to influence operant responding. alpha5IA-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 alpha5-containing receptors reduce ethanol self-administration, alpha5 subunits may not be essential to signaling ethanol reward.