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First published on November 14, 2006; DOI: 10.1124/mol.106.029942

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Received for publication August 14, 2006.
Revised November 13, 2006.
Accepted for publication November 14, 2006.

Ethanol modulates the interaction of the endogenous neurosteroid allopregnanolone with the {alpha}1{beta}2{gamma}2L GABAA receptor

Gustav Akk 1*, Ping Li 1, Brad D Manion 1, Alex S Evers 1, Joseph H. Steinbach 1

1 Washington University School of Medicine

* Address correspondence to: E-mail: akk{at}morpheus.wustl.edu

Abstract

We have examined the {alpha}1{beta}2{gamma}2L GABAA receptor modulation by the endogenous steroids allopregnanolone (3{alpha}5{alpha}P), pregnenolone sulfate, and {beta}-estradiol in the absence and presence of ethanol. Coapplication of 0.1-1 % (17-170 mM) ethanol influenced receptor modulation by 3{alpha}5{alpha}P but not by pregnenolone sulfate or {beta}-estradiol. One of the three kinetic effects evident in channel potentiation by 3{alpha}5{alpha}P, 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 two orders of magnitude without significantly affecting the maximal effect. Manipulations designed to affect the ability of 3{alpha}5{alpha}P to prolong OT3 also affected OT3 prolongation in the presence of ethanol. A mutation to the {gamma}2 subunit, which reduces the ability of 3{alpha}5{alpha}P to prolong OT3, also reduces the interaction between ethanol and 3{alpha}5{alpha}P. And the presence of the competitive steroid antagonist, (3{alpha},5{alpha})-17-phenylandrost-16-en-3-ol (17-PA), diminishes the positive interaction between ethanol and 3{alpha}5{alpha}P on the GABAA 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 3{alpha}5{alpha}P for the site. Tadpole behavioral assays showed that the presence of 3{alpha}5{alpha}P 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 3{alpha}5{alpha}P.


Key words: GABAA, GABAC, Sex hormones, Alcohols


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