Blockade of adenosine and dopamine receptors inhibits the development of rapid tolerance to ethanol in mice

Rationale Several reports have suggested the involvement of brain adenosine and dopamine receptors in different actions produced by ethanol such as motor incoordination or anxiolytic, hypnotic and reinforcing effects. The co-localization and interaction between adenosine and dopamine receptors in different brain regions has also been well documented. However, few studies have demonstrated the involvement of these mechanisms in the tolerance induced by ethanol. Objectives The aim of the present study was to evaluate the role of adenosine and dopamine receptors in the development of rapid tolerance to ethanol-induced motor incoordination in mice. Methods In connection with the rota-rod apparatus, the effects of acute administration of the adenosine receptor antagonists caffeine (non-selective), 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, adenosine A₁ receptor antagonist) and 4-(2-7-amino-2-{2-furyl}{1,2,4}triazolo-{2,3-a}{1,3,5}triazin-5-yl-amino]ethyl)phenol (ZM241385, adenosine A_2A receptor antagonist), together with R(+)-7-cloro-8-hidroxi-3-metil-1-fenil-2,3,4,5-tetrahidro-1H-3-benzazepine (SCH23390, dopamine D₁ receptor antagonist) and sulpiride (dopamine D₂ receptor antagonist), alone or in combination with ethanol (2.25 g/kg, i.p.), were studied. Twenty-four hours after, all animals were re-tested on the rota-rod after receiving the same dose of ethanol. Results The repeated administration of ethanol promoted a significant reduction of motor impairment on day 2 (i.e. rapid tolerance). This effect was blocked by caffeine (3.0–30.0 mg/kg, i.p.), DPCPX (3.0–6.0 mg/kg, i.p.) or SCH23390 (0.01–0.03 mg/kg, s.c.), but not with ZM241385 (0.5–1.0 mg/kg, i.p.) or sulpiride (1.0–3.0 mg/kg, i.p.). Conclusions Our results suggest that the rapid tolerance to ethanol-induced motor impairment in mice may be modulated by adenosine A₁ receptors and dopamine D₁ receptors.