We have shown previously that the severity of handling-induced convulsions during ethanol withdrawal was reduced in A_2Areceptor knock-out (A_2AR^−/−) mice. In the present report, we further characterize the role of adenosine A_2A receptors in ethanol consumption and neurobiological responses to this drug of abuse. Male A_2AR^−/− mice showed increased consumption of solutions containing 6 and 20% (v/v) ethanol compared with wild-type (A_2AR^+/+) control mice; female A_2AR^−/− mice showed increased consumption of solutions containing 6 and 10% ethanol. This slightly higher ethanol consumption was also related to increased ethanol preference. In contrast, A_2AR^−/− mice showed normal consumption of solutions containing either sucrose or quinine. Relative to A_2AR^+/+ mice, A_2AR^−/− mice were found to be less sensitive to the sedative effect of 3.0 gm/kg ethanol, as measured by more rapid recovery from ethanol-induced loss of righting reflex, and to the hypothermic effects of 1.5, 3.0, and 4.0 gm/kg ethanol, although plasma ethanol levels did not differ significantly between the two genotypes. The selective adenosine A_2A receptor antagonist ZM 241385 (4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol) (10–30 mg/kg) significantly attenuated ethanol-induced (4.0 gm/kg) hypothermia in CD1 mice. To assess whether ethanol administration would induce differential tolerance in A_2AR^−/− and wild-type mice, we administered ethanol (3.0 gm/kg) over 4 consecutive days and found no difference in the development of tolerance; however, female A_2AR^−/− mice showed a lower tolerance-acquisition rate. These data suggest that activating the A_2A receptors may play a role in suppressing alcohol-drinking behavior and is associated with the sensitivity to the intoxicating effects of acute ethanol administration.