Chronic ethanol consumption differentially alters GABA(A) receptor alpha 1and alpha 4 subunit peptide expression and GABA(A) receptor-mediated Cl-36(-) uptake in mesocorticolimbic regions of rat brain

Background: Gamma-aminobutyric acid type A (GABAA) receptors in the brain a re modulated by chronic ethanol exposure via the regulation of their functi on and expression throughout the central nervous system. Recent studies sho w that chronic ethanol exposure alters subsequent ethanol self-administrati on, effects that are believed to be mediated by subcortical regions of the rat brain including the amygdala (AMG), the nucleus accumbens (NAC), and th e ventral tegmental area (VTA). Methods: We evaluated GABA(A) receptor subunit expression using subunit spe cific (alpha1 and alpha4) immunoblotting of small tissue punches from AMG, NAC, and VTA. GABA(A) receptor-mediated Cl-36(-) uptake was measured in the se brain areas after chronic ethanol consumption for 2 weeks. Results: Regional differences in the effect of chronic ethanol on alpha1 an d alpha4 subunit expression were found. In the AMG, alpha1 and alpha4 subun it expressions were significantly decreased by 21.1 +/- 5.5% and 22.0 +/- 7 .1%, respectively. In the NAC, there was a decrease of 28.1 +/- 1.3% in alp ha4 subunit expression (p < 0.0001), but no change in cel subunit expressio n was observed. In the VTA, there were no changes in <alpha>1 and alpha4 su bunit expressions. Muscimol-stimulated Cl- uptake was enhanced in the exten ded AMG, but not the extended NAC of ethanol-dependent rats. The muscimol c oncentration response curve was left-shifted with a 74% decrease (p < 0.01) in the EC50 and a 42% increase (p < 0.05) in the E-max in the AMG of ethan ol-dependent rats. Conclusions: These results suggest that chronic ethanol exposure alters GAB A(A) receptor expression in the AMG and NAC. Decreased expression of alpha4 subunits is associated with increases in GABAA receptor function in the AM G, but not the NAC. These changes may contribute to alcohol drinking behavi or and the development of ethanol dependence.