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Ethanol Modulates the Interaction of the Endogenous Neurosteroid Allopregnanolone with the 122L GABA_A Receptor

Department of Anesthesiology, Washington University, St. Louis, Missouri

We have examined 122L GABA_A receptor modulation by the endogenous steroids allopregnanolone (35P), pregnenolone sulfate, and -estradiol in the absence and presence of ethanol. Coapplication of 0.1 to 1% (17-170 mM) ethanol influenced receptor modulation by 35P but not that by pregnenolone sulfate or -estradiol. One of the three kinetic effects evident in channel potentiation by 35P, prolongation of the longest-lived open time component (OT3), was affected by ethanol with the midpoint of its dose-response curve moved to lower steroid concentrations by 2 orders of magnitude without significantly affecting the maximal effect. Manipulations designed to affect the ability of 35P to prolong OT3 also affected OT3 prolongation in the presence of ethanol. A mutation to the 2 subunit, which reduces the ability of 35P to prolong OT3, also reduces the interaction between ethanol and 35P. And the presence of the competitive steroid antagonist (3,5)-17-phenylandrost-16-en-3-ol (17-PA) diminishes the positive interaction between ethanol and 35P on the GABA_A receptor. Together, the findings suggest that steroid interactions with the classic steroid binding site underlie the effect seen in the presence of ethanol, and that ethanol acts by increasing the affinity of 35P for the site. Tadpole behavioral assays showed that the presence of 35P at a concentration ineffective at causing changes in tadpole behavior shifted the ethanol dose-response curve for loss of righting reflex to lower concentrations and that this effect was neutralized by coapplication of 17-PA with 35P.

Address correspondence to: Gustav Akk, Department of Anesthesiology, Washington University in St Louis, Campus Box 8054, 660 S. Euclid Ave, St Louis, MO 63110. E-mail: akk{at}morpheus.wustl.edu

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