RT Journal Article SR Electronic T1 Selective Antagonism of 5α-Reduced Neurosteroid Effects at GABAA Receptors JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1191 OP 1197 DO 10.1124/mol.65.5.1191 VO 65 IS 5 A1 Steven Mennerick A1 Yejun He A1 Xin Jiang A1 Brad D. Manion A1 Mingde Wang A1 Amanda Shute A1 Ann Benz A1 Alex S. Evers A1 Douglas F. Covey A1 Charles F. Zorumski YR 2004 UL http://molpharm.aspetjournals.org/content/65/5/1191.abstract AB Although neurosteroids have rapid effects on GABAA receptors, study of steroid actions at GABA receptors has been hampered by a lack of pharmacological antagonists. In this study, we report the synthesis and characterization of a steroid analog, (3α,5α)-17-phenylandrost-16-en-3-ol (17PA), that selectively antagonized neurosteroid potentiation of GABA responses. We examined 17PA using the α1β2γ2 subunit combination expressed in Xenopus laevis oocytes. 17PA had little or no effect on baseline GABA responses but antagonized both the response augmentation and the direct gating of GABA receptors by 5α-reduced potentiating steroids. The effect was selective for 5α-reduced potentiating steroids; 5β-reduced potentiators were only weakly affected. Likewise, 17PA did not affect barbiturate and benzodiazepine potentiation. 17PA acted primarily by shifting the concentration response for steroid potentiation to the right, suggesting the possibility of a competitive component to the antagonism. 17PA also antagonized 5α-reduced steroid potentiation and gating in hippocampal neurons and inhibited anesthetic actions in X. laevis tadpoles. Analogous to benzodiazepine site antagonists, the development of neurosteroid antagonists may help clarify the role of GABA-potentiating neurosteroids in health and disease.