In the present study, we investigated the effect of chronic ethanol (CE) administration on the polypeptide levels of the delta-subunit of GABA(A) receptors and [(3)H]muscimol binding to the immunoprecipitated delta-subunit-containing GABA(A) receptor assemblies in the rat brain. CE administration resulted a down-regulation of polypeptide levels of the delta-subunit of GABA(A) receptors in the rat cerebellum and hippocampus, whereas there were no changes in the delta-subunit polypeptide levels in the rat cerebral cortex. Further, CE administration caused a down-regulation of native delta-subunit-containing GABA(A) receptor assemblies in the rat cerebellum as determined by [(3)H]muscimol binding to the immunoprecipitated receptor assemblies. These results indicate that the delta-subunit-containing GABA(A) receptors may play a role in chronic ethanol-induced tolerance and dependence.