title: Selective antagonism of 5alpha-reduced neurosteroid effects at GABA(A) receptors.
abstract: 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.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA. menneris@psychiatry.wustl.edu
authors.forename: Steven
authors.initials: S
authors.lastname: Mennerick
authors.forename: Yejun
authors.initials: Y
authors.lastname: He
authors.forename: Xin
authors.initials: X
authors.lastname: Jiang
authors.forename: Brad D
authors.initials: BD
authors.lastname: Manion
authors.forename: Mingde
authors.initials: M
authors.lastname: Wang
authors.forename: Amanda
authors.initials: A
authors.lastname: Shute
authors.forename: Ann
authors.initials: A
authors.lastname: Benz
authors.forename: Alex S
authors.initials: AS
authors.lastname: Evers
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Covey
authors.forename: Charles F
authors.initials: CF
authors.lastname: Zorumski
mesh_terms: D000737:Androstenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D004357:Drug Synergism; D018756:GABA Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists; D006624:Hippocampus / Q000166:cytology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: C485374:17-phenylandrost-16-en-3-ol; D000737:Androstenols; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D013256:Steroids