Selective antagonism of 5alpha-reduced neurosteroid effects at GABA(A) receptors

Mennerick, StevenDepartment of Psychiatry, Washington University School of Medicine, St. Louis, Missouri (author)

Although neurosteroids have rapid effects on GABA(A) 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, (3alpha,5alpha)-17-phenylandrost-16-en-3-ol (17PA), that selectively antagonized neurosteroid potentiation of GABA responses. We examined 17PA using the alpha1beta2gamma2 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 5alpha-reduced potentiating steroids. The effect was selective for 5alpha-reduced potentiating steroids; 5beta-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 5alpha-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.

He, YejunDepartment of Psychiatry, Washington University School of Medicine, St. Louis, Missouri (author)
Jiang, XinDepartment of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri (author)
Manion, Brad DDepartment of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri (author)
Wang, MingdeDepartment of Psychiatry, Washington University School of Medicine, St. Louis, Missouri(Swepub:umu)miwa0010 (author)
Shute, AmandaDepartment of Psychiatry, Washington University School of Medicine, St. Louis, Missouri (author)
Benz, AnnDepartment of Psychiatry, Washington University School of Medicine, St. Louis, Missouri (author)
Evers, Alex SDepartment of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri (author)
Covey, Douglas FDepartment of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri (author)
Zorumski, Charles FDepartment of Psychiatry, Washington University School of Medicine, St. Louis, Missouri (author)
Department of Psychiatry, Washington University School of Medicine, St. Louis, MissouriDepartment of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri (creator_code:org_t)

In:Molecular Pharmacology: American Society for Pharmacology & Experimental Therapeutics (ASPET)65:5, s. 1191-11970026-895X1521-0111

By the author/editor: Mennerick, Steve ...; He, Yejun; Jiang, Xin; Manion, Brad D; Wang, Mingde; Shute, Amanda; show more...; Benz, Ann; Evers, Alex S; Covey, Douglas F; Zorumski, Charle ...; show less...

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