Low ethanol sensitivity and increased ethanol consumption in mice lacking adenosine A2A receptors.
We have shown previously that the severity of handling-induced convulsions during ethanol withdrawal was reduced in A2A receptor knock-out (A2AR-/-) 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 A2AR-/- mice showed increased consumption of solutions containing 6 and 20% (v/v) ethanol compared with wild-type (A2AR+/+) control mice; female A2AR-/- 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, A2AR-/- mice showed normal consumption of solutions containing either sucrose or quinine. Relative to A2AR+/+ mice, A2AR-/- 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 A2A 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 A2AR-/- 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 A2AR-/- mice showed a lower tolerance-acquisition rate. These data suggest that activating the A2A receptors may play a role in suppressing alcohol-drinking behavior and is associated with the sensitivity to the intoxicating effects of acute ethanol administration.
Naassila
Mickaël
M
Laboratoire de Physiologie-Alcoologie, Université de Picardie Jules Verne, Faculté de Pharmacie, 80000 Amiens, France. mickael.naassila@u-picardie.fr
Ledent
Catherine
C
Daoust
Martine
M
D000284:Administration, Oral; D000428:Alcohol Drinking / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002755:Choice Behavior / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics; D004361:Drug Tolerance; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D005260:Female; D007035:Hypothermia / Q000139:chemically induced / Q000188:drug therapy; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058915:Purinergic P1 Receptor Antagonists; D011803:Quinine / Q000494:pharmacology; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000172:deficiency* / Q000235:genetics; D012018:Reflex / Q000187:drug effects; D012737:Sex Factors; D013395:Sucrose / Q000494:pharmacology; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
D058915:Purinergic P1 Receptor Antagonists; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; D000431:Ethanol; D013395:Sucrose; D011803:Quinine