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The Journal of Neuroscience, December 1, 2002, 22(23):10487-10493

Low Ethanol Sensitivity and Increased Ethanol Consumption in Mice Lacking Adenosine A_2A Receptors

Mickaël Naassila¹, Catherine Ledent², and Martine Daoust¹

¹ Laboratoire de Physiologie-Alcoologie, Université de Picardie Jules Verne, Faculté de Pharmacie, 80000 Amiens, France, and ² Institut de Recherche Interdisciplinaire, Université Libre de Bruxelles, B-1070 Brussels, Belgium

We have shown previously that the severity of handling-induced convulsions during ethanol withdrawal was reduced in A_2A receptor 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.

Key words: adenosine; A_2A receptor; ethanol; hypothermia; knock-out mice; sensitivity; tolerance; ZM 241385

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Copyright © 2002 Society for Neuroscience  0270-6474/02/222310487-07$05.00/0

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