PT  - JOURNAL ARTICLE
AU  - Steven Mennerick
AU  - Yejun He
AU  - Xin Jiang
AU  - Brad D. Manion
AU  - Mingde Wang
AU  - Amanda Shute
AU  - Ann Benz
AU  - Alex S. Evers
AU  - Douglas F. Covey
AU  - Charles F. Zorumski
TI  - Selective Antagonism of 5α-Reduced Neurosteroid Effects at GABA<sub>A</sub> Receptors
AID  - 10.1124/mol.65.5.1191
DP  - 2004 May 01
TA  - Molecular Pharmacology
PG  - 1191--1197
VI  - 65
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/65/5/1191.short
4100  - http://molpharm.aspetjournals.org/content/65/5/1191.full
SO  - Mol Pharmacol2004 May 01; 65
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.