Neurosteroids, GABA(A) receptors, and ethanol dependence

Changes in the expression of type A receptors for gamma-aminobutyric acid (GABA) represent one of the mechanisms implicated in the development of tolerance to and dependence on ethanol. The impact of such changes on the function and pharmacological sensitivity of GABA(A) receptors (GABA(A)Rs) has remained unclear, however. Certain behavioral and electrophysiological actions of ethanol are mediated by an increase in the concentration of neuroactive steroids in the brain that results from stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. Such steroids include potent modulators of GABA(A)R function. We have investigated the effect of ethanol exposure and withdrawal on subunit expression and receptor function evaluated by subunit selective compounds, as well as the effects of short-term exposure to ethanol on both neurosteroid synthesis and GABA(A)R function, in isolated neurons and brain tissue. Chronic treatment with and subsequent withdrawal from ethanol alter the expression of genes for specific GABA(A)R subunits in cultured rat neurons, and these changes are associated with alterations in receptor function and pharmacological sensitivity to neurosteroids, zaleplon, and flumazenil. Acute ethanol exposure increases the amount of 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) in hippocampal slices by a local action independent of the activity of the HPA axis. This effect of ethanol was associated with an increased amplitude of GABA(A)R-mediated miniature inhibitory postsynaptic currents recorded from CA1 pyramidal neurons in such slices. Chronic ethanol exposure elicits changes in the subunit composition of GABA(A)Rs, which, in turn, likely contribute to changes in receptor function associated with the altered pharmacological and behavioral sensitivity characteristic of ethanol tolerance and dependence. Ethanol may also modulate GABA(A)R function by increasing the de novo synthesis of neurosteroids in the brain in a manner independent of the HPA axis. This latter mechanism may play an important role in the central effects of ethanol.