Increased Voluntary Ethanol Consumption and Changes in Hippocampal Synaptic Plasticity in Isolated C57BL/6J Mice

Social isolation (SI) is a notable model of prolonged mild stress, characterized by multiple neurochemical and behavioral alterations, that appears particularly suitable for studying different aspects of the interplay between stress and ethanol (EtOH) consumption in order to characterize potential molecular mechanisms, including changes in the function of inhibitory GABAergic synapses, underlying such interaction. In C57BL/6J mice, SI is associated with an altered hippocampal concentration of the neuroactive steroids 3α-hydroxy-5α-pregnan-20-one (3α-5α-THP), an increased expression of the α₄ and δ subunit of γ-aminobutyric acid type A receptors (GABA_ARs) in the dentate gyrus (DG), and a parallel enhancement of the stimulatory action of 4,5,6,7-tetrahydroisoxazolo[5,4-c] pyridin-3-ol (THIP) on GABAergic tonic currents recorded in voltage-clamped DG granule cells (DGGCs). In addition, SI in C57BL/6J mice determines an increase in voluntary EtOH consumption and EtOH preference when compared to group-housed (GH) control animals. Furthermore, in hippocampal slices of SI mice we also observed a marked reduction of both cellular excitability and long term potentiation (LTP) in pyramidal neurons of the CA1 hippocampal sub-region, effects that were prevented by the long term treatment of SI mice with the neuroactive steroid precursor progesterone. In this article, we summarize some of our recent findings on the effects of SI in C57BL/6J mice on voluntary EtOH intake, regulation of GABA_ARs gene expression and function and hippocampal long term synaptic plasticity.