Prolonged ethanol (EtOH) exposure has been shown to be associated to neuroadaptive changes that involve alterations of GABAA receptor (GABAAR) gene expression and function. We recently focused our attention to the effects of chronic EtOH exposure on the expression of the GABAAR delta subunit in different populations of cultured rat neurons. GABAARs containing delta subunit are extrasynaptic, mediate tonic inhibition, and show a preferential sensitivity for the agonist THIP as well as neurosteroids and low concentrations of EtOH. Long-term (5 days) EtOH exposure and withdrawal differently altered delta subunit mRNA and peptide levels in hippocampal neurons and cerebellar granule cells. These EtOH-induced changes in delta subunit expression were associated to significant alterations in the efficacy of THIP and allopregnanolone, as measured by patch clamp recordings. These results indicate that the expression of the GABAAR delta subunit undergoes marked changes following long-term EtOH exposure and this may result in important alterations in tonic GABAergic inhibitory activity as well as neuronal excitability. We also recently found that, in isolated rat hippocampal slices, acute exposure to EtOH results in the stimulation of local synthesis of neurosteroids which is also associated to a potentiation of the GABAAR function in CA1 pyramidal neurons. These effects appear to be independent from steroid precursors pro- duced by peripheral organs as they occur also in the hippocampus of adrenalectomized-castrated rats. These findings suggest that EtOH may modulate GABAAR function through an increase in de novo brain syn- thesis of neurosteroids that is independent from the stimulation of the HPA axis.
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