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Front Neurosci. 2011 Feb 10;5:15. doi: 10.3389/fnins.2011.00015. eCollection 2011.

Voluntary Ethanol Consumption Induced by Social Isolation Reverses the Increase of α(4)/δ GABA(A) Receptor Gene Expression and Function in the Hippocampus of C57BL/6J Mice.

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  • 1Section of Neuroscience, Department of Experimental Biology, Center of Excellence for the Neurobiology of Dependence, University of Cagliari Monserrato, Cagliari, Italy.


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 γ-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 3α-hydroxy-5α-pregnan-20-one (3α,5α-TH PROG) and was associated with molecular and functional changes of the GABA(A)R. The gene expression of the α(4) and δ subunits was increased in the hippocampus of SI C57BL/6J mice; the expression of the γ(2) subunit was decreased whereas that of the α(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 α-(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 3α,5α-TH PROG induced by SI. EtOH self-administration blocked the changes in gene expression of the α(4) subunit but not those of the δ and γ(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 α(4) subunit but not other neurochemical, molecular, and functional modifications induced by SI prolonged mild stress.


GABAA receptor; allopregnanolone; ethanol; gene expression; hippocampus; patch-clamp; social isolation; stress

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