Caffeine reduces hypnotic effects of alcohol through adenosine A 2A receptor blockade

Abstract

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 A 1 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.