Vol. 291, Issue 3, 1054-1059, December 1999

Interactive Role for Neurosteroids in Ethanol Enhancement of -Aminobutyric Acid-Gated Currents from Dissociated Substantia Nigra Reticulata Neurons¹

Hugh E. Criswell , Thomas J. McCown , Zhen Ming, Robert A. Mueller and George R. Breese

Departments of Psychiatry (H.E.C., T.J.M., G.R.B), Anesthesiology (H.E.C, G.R.B., Z.M., R.A.M.), and Pharmacology (G.R.B., R.A.M.), University of North Carolina Neurosciences Center (H.E.C., T.J.M., G.R.B.), The Bowles Center For Alcohol Studies (H.E.C., T.J.M., G.R.B), and The Gene Therapy Center (T.J.M.), School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Although previous in vivo electrophysiological studies demonstrated a consistent ethanol enhancement of -aminobutyric acid (GABA) responsiveness from substantia nigra reticulata (SNR) neurons, ethanol applied in vitro to dissociated neurons from the SNR had an inconsistent effect on GABA function. One source for the disparity between these contrasting in vivo and in vitro results could be an endogenous factor (acting on an auxiliary site on GABA_A receptors) that was not available to the isolated SNR neurons. Because neurosteroids are present in vivo and act on an auxiliary site, it was hypothesized that the presence of a neurosteroid was important for a consistent effect of ethanol on GABA responsiveness from neurons studied in vitro. Alone, the neurosteroid analog alphaxalone produced a significant, concentration-related enhancement of GABA responsiveness from isolated SNR neurons. In contrast to an inconsistent action of 100 mM ethanol on GABA responsiveness in the absence of alphaxalone, the presence of 30 and 100 nM alphaxalone resulted in the majority of isolated neurons responding to this ethanol level. At a concentration of alphaxalone as low as 30 nM, ethanol produced a robust concentration-related increase in GABA-gated currents from this cell type. The neurosteroid 3,5-tetrahydrodeoxycorticosterone (100 nM) also permitted a reliable concentration-dependent ethanol enhancement of responses to GABA from SNR cells, indicative that the effects of alphaxalone were not unique. This consistent neurosteroid-induced ethanol enhancement of GABA responsiveness from dissociated SNR neurons supports the view that neurosteroids may play a key role in the action of ethanol on postsynaptic GABA_A receptor function.