Voluntary ethanol consumption induced by social isolation reverses the increase of alpha(4)/delta GABA(A) receptor gene expression and function in the hippocampus of C57BL/6J mice.

Post-weaning social isolation (SI) is a model of prolonged mild stress characterized by behavioral and neurochemical alterations. We used SI in C57BL/6J mice to investigate the effects of ethanol (EtOH) in the free-choice drinking paradigm on gene expression and function of ?-aminobutyric acid type A receptors (GABA(A)Rs) and the role of neuroactive steroids in the actions of EtOH in the hippocampus. SI stress induced a marked reduction in hippocampal 3?-hydroxy-5?-pregnan-20-one (3?,5?-TH PROG) and was associated with molecular and functional changes of the GABA(A)R. The gene expression of the ?(4) and ? subunits was increased in the hippocampus of SI C57BL/6J mice; the expression of the ?(2) subunit was decreased whereas that of the ?(1) did not change. Patch-clamp recordings in dentate gyrus (DG) granule cells obtained from SI C57BL/6J mice revealed a greater enhancement of tonic currents induced by ?-(4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridin-3-ol (THIP) compared to that in control C57BL/6J mice. These neurochemical, molecular and functional changes observed in SI C57BL/6J mice were associated with an increased EtOH intake and EtOH preference. Nevertheless, the increase in EtOH consumption did not restore the reduction in hippocampal 3?,5?-TH PROG induced by SI. EtOH self-administration blocked the changes in gene expression of the ?(4) subunit but not those of the ? and ?(2) subunits induced by SI. In addition, EtOH self-administration did not block the SI-induced changes in GABA(A)R-mediated tonic inhibition in hippocampal granule cells but increased the frequency of basal GABAergic sIPSCs in DG granule cells. We conclude that self-administration of EtOH selectively abolishes the increase of ?(4) subunit but not other neurochemical, molecular, and functional modifications induced by SI prolonged mild stress.