Chronic ethanol intoxication enhances [H-3]CCPA binding and does not reduce A(1) adenosine receptor function in rat cerebellum

The effects of acute and chronic treatment with ethanol on the function of A(1) adenosine receptor in the rat cerebellar cortex were investigated. Acute administration of ethanol (0.5-5 g/kg) had no effect on the binding of the A(1)-receptor agonist [H-3]2-chloro-N-6-cyclopentyladenosine ([H-3]CCPA) or that of the antagonist [H-3]8-cyclopentyl-1-3-dipropylxanthine ([H-3]DPCPX) in rat cerebellar cortical membranes. Rats were rendered ethanol dependent by repeated forced oral administration of ethanol (12-18 g/kg per day) for 6 days. [H-3]CCPA binding was increased by 23% in cerebellar cortical membranes prepared from rats killed 3 h after ethanol withdrawal compared with saline-treated animals. The increase in [H-3]CCPA binding was still apparent 12-24 h after the last ethanol administration, but was no longer detectable 3-6 days after ethanol withdrawal. In contrast, the binding of [H-3]DPCPX was not modified in the cerebellar cortex of rats killed at various times after ethanol withdrawal. The acute administration of CCPA [0.25-1 mg/kg, intraperitoneally (IP)] suppressed the tremors and audiogenic seizures apparent 24 h after ethanol withdrawal. Moreover, repeated coadministration of CCPA (0.5 mg/kg, IP, four times daily) and ethanol did not prevent the generation of audiogenic seizures during withdrawal but completely prevented mortality. Finally, CCPA antagonized with similar potencies and efficacies the isoniazid-induced convulsions observed in control and ethanol-withdrawn rats. These results indicate that long-term treatment with intoxicating doses of ethanol enhances [H-3]CCPA binding but does not reduce the anticonvulsant efficacy of CCPA or the function of A(1) adenosine receptors.