Chronic ethanol consumption differentially alters GABA(A) receptor alpha1 and alpha4 subunit peptide expression and GABA(A) receptor-mediated 36 Cl(-) uptake in mesocorticolimbic regions of rat brain.

BACKGROUND

Gamma-aminobutyric acid type A (GABA(A)) receptors in the brain are modulated by chronic ethanol exposure via the regulation of their function and expression throughout the central nervous system. Recent studies show that chronic ethanol exposure alters subsequent ethanol self-administration, effects that are believed to be mediated by subcortical regions of the rat brain including the amygdala (AMG), the nucleus accumbens (NAC), and the ventral tegmental area (VTA).

METHODS

We evaluated GABA(A) receptor subunit expression using subunit specific (alpha1 and alpha4) immunoblotting of small tissue punches from AMG, NAC, and VTA. GABA(A) receptor-mediated 36 Cl- uptake was measured in these brain areas after chronic ethanol consumption for 2 weeks.

RESULTS

Regional differences in the effect of chronic ethanol on alpha1 and alpha4 subunit expression were found. In the AMG, alpha1 and alpha4 subunit 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 alpha4 subunit expression (p < 0.0001), but no change in alpha1 subunit expression was observed. In the VTA, there were no changes in alpha1 and alpha4 subunit expressions. Muscimol-stimulated Cl- uptake was enhanced in the extended AMG, but not the extended NAC of ethanol-dependent rats. The muscimol concentration response curve was left-shifted with a 74% decrease (p < 0.01) in the EC50 and a 42% increase (p < 0.05) in the Emax in the AMG of ethanol-dependent rats.

CONCLUSIONS

These results suggest that chronic ethanol exposure alters GABA(A) receptor expression in the AMG and NAC. Decreased expression of alpha4 subunits is associated with increases in GABA(A) receptor function in the AMG, but not the NAC. These changes may contribute to alcohol drinking behavior and the development of ethanol dependence.