ANTIBODIES SPECIFIC FOR GABA(A) RECEPTOR ALPHA-SUBUNITS REVEAL THAT CHRONIC ALCOHOL TREATMENT DOWN-REGULATES ALPHA-SUBUNIT EXPRESSION IN RAT-BRAIN REGIONS

Chronic administration of ethanol results in the development of tolera nce and dependence. The molecular mechanism underlying these behaviora l actions of ethanol is poorly understood. Several lines of evidence h ave suggested that some of the pharmacological actions of ethanol are mediated via a potentiation of GABAergic transmission. Chronic ethanol administration results in a reduction in the GABA(A) receptor-mediate d Cl-36- uptake in cortical synaptoneurosomes and primary cultured neu rons. We and others have shown that it also results in a 40-50% reduct ion in GABA(A) receptor alpha-subunit mRNA levels in the rat cerebral cortex. In the present study, we investigated the expression of alpha1 , alpha2, and alpha3 subunits of the GABA(A) receptor in the cerebral cortex and the alpha1 subunit in the cerebellum by immunoblotting usin g polyclonal antibodies raised against alpha1-, alpha2-, and alpha3-Su bunit polypeptides following chronic ethanol treatment. These results reveal that chronic ethanol administration to rats results in a 61 +/- 4% reduction in level of the GABA(A) receptor alpha1 subunit (51 kDa) , 47 +/- 8% reduction in level of the alpha2 subunit (53 kDa), and 30 +/- 7% reduction in level of the alpha3 subunit (59 kDa) in the cerebr al cortex and a 56 +/- 5% reduction in content of the alpha1 subunit i n the cerebellum. In summary, this ethanol-induced reduction in conten t of the GABA(A) receptor alpha subunits may underlie alterations in t he GABA(A) receptor function and could be related to cellular adaptati on to the functional disturbance caused by ethanol.