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(2A)R KO) than for wild-type mice (A(2A)R 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(2A)R 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(2A)R WT but not in A(2A)R 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.
El Yacoubi
M
M
UMR 6036 CNRS, IFRMP 23, UFR de Médecine & Pharmacie, 22 Boulevard Gambetta, 76183 Rouen Cedex, France.
Ledent
C
C
Parmentier
M
M
Costentin
J
J
Vaugeois
J-M
JM
D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002110:Caffeine / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000037:antagonists & inhibitors* / Q000506:poisoning; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004176:Dipyridamole / Q000494:pharmacology; D062787:Drug Overdose / Q000188:drug therapy; D000431:Ethanol / Q000037:antagonists & inhibitors* / Q000506:poisoning; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000494:pharmacology; D010424:Pentobarbital / Q000494:pharmacology; D004856:Postural Balance / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000235:genetics; D014230:Triazoles / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058916:Adenosine A1 Receptor Antagonists; D058917:Adenosine A2 Receptor Antagonists; D002492:Central Nervous System Depressants; D000697:Central Nervous System Stimulants; D006993:Hypnotics and Sedatives; D018696:Neuroprotective Agents; D011743:Pyrimidines; D043705:Receptor, Adenosine A2A; D014230:Triazoles; D014665:Vasodilator Agents; D014970:Xanthines; D002110:Caffeine; D000431:Ethanol; D004176:Dipyridamole; C051360:1,3-dipropyl-8-cyclopentylxanthine; D010424:Pentobarbital