Caffeine reduces hypnotic effects of alcohol through adenosine A2A receptor blockade

The role of the adenosine A_2A receptor in the hypnotic effects of ethanol was assessed in mice. The duration of the loss of righting reflex following acute ethanol administration was shorter for A_2A receptor-deficient mice (A_2AR KO) than for wild-type mice (A_2AR WT), whereas the fall in body temperature was not different between the two phenotypes. In contrast, the duration of the loss of righting reflex was increased in A_2AR KO mice versus controls after administration of pentobarbital. Dipyridamole, an inhibitor of adenosine uptake, increased the sleep time observed following administration of ethanol in CD1 mice and in A_2AR WT but not in A_2AR KO mice. SCH 58261, a selective A_2A receptor antagonist, unlike DPCPX, a selective A₁ receptor antagonist, shortened the duration of the loss of righting reflex induced by ethanol, thus mimicking the lack of receptor in deficient mice. Finally, the non-selective adenosine receptor antagonist caffeine (25 mg/kg) reduced ethanol-induced hypnotic effects. These results indicate that the activation of A_2A receptors that follows an increase in extracellular adenosine levels caused by the administration of high doses of ethanol plays a role in its hypnotic effects. Thus, A_2A receptor antagonists may be useful therapeutic agents for alleviating ethylic coma.