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NEUROPHARMACOLOGY
Subunit of 
-Aminobutyric Acid Type A Receptors Does Not Confer Sensitivity to Low Concentrations of Ethanol
Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas (C.M.B., R.A.H.); Department of Electrophysiology, H. Lundbeck A/S, Valby, Denmark (S.S., B.E.); Neuroscience Institute, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, Dundee University, Dundee, United Kingdom (M.B.H., D.B., J.J.L.); and Department of Molecular and Cellular Neuroscience, Merck Sharp & Dohme Research Laboratories, The Neuroscience Research Centre, Harlow, United Kingdom (G.M., K.A.W.)
GABAA receptors (GABAARs) are usually formed by 
, 
, and 
or 
subunits. Recently, -containing GABAARs expressed in Xenopus oocytes were found to be sensitive to low concentrations of ethanol (1–3 mM). Our objective was to replicate and extend the study of the effect of ethanol on the function of 43 GABAARs. We independently conducted three studies in two systems: rat and human GABAARs expressed in Xenopus oocytes, studied through two-electrode voltage clamp; and human GABAARs stably expressed in the fibroblast L(tk–) cell line, studied through patch-clamp electrophysiology. In all cases, 43 GABAARs were only sensitive to high concentrations of ethanol (100 mM in oocytes, 300 mM in the cell line). Expression of the subunit in oocytes was assessed through the magnitude of the maximal GABA currents and sensitivity to zinc. Of the three rat combinations studied, 43 was the most sensitive to ethanol, isoflurane, and 5-pregnan-3,21-diol-20-one (THDOC); 43 and 432S were very similar in most aspects, but 43 was more sensitive to GABA, THDOC, and lanthanum than 432S GABAARs. Ethanol at 30 mM did not affect tonic GABA-mediated currents in dentate gyrus reported to be mediated by GABAARs incorporating 4 and subunits. We have not been able to replicate the sensitivity of 43 GABAARs to low concentrations of ethanol in four different laboratories in independent studies. This suggests that as yet unidentified factors may play a critical role in the ethanol effects on -containing GABAARs.
Address correspondence to: Dr. R. Adron Harris, The University of Texas at Austin, Waggoner Center for Alcohol and Addiction Research, 1 University Station A4800, Austin, TX 78712-0159. E-mail: harris{at}mail.utexas.edu
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