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The Journal of Neuroscience, May 1, 2002, 22(9):3366-3375

3-Hydroxypregnane Steroids Are Pregnenolone Sulfate-Like GABA_A Receptor Antagonists

Mingde Wang¹, Yejun He¹, Lawrence N. Eisenman⁵, Christopher Fields¹, Chun-Min Zeng³, Jose Mathews¹, Ann Benz¹, Tao Fu¹, Erik Zorumski¹, Joe Henry Steinbach², Douglas F. Covey³, Charles F. Zorumski^{1, 4}, and Steven Mennerick^{1, 4}

Departments of ¹ Psychiatry, ² Anesthesiology, ³ Molecular Biology and Pharmacology, ⁴ Anatomy and Neurobiology, and ⁵ Neurology, Washington University School of Medicine, St. Louis, Missouri 63110

Endogenous neurosteroids have rapid actions on ion channels, particularly GABA_A receptors, which are potentiated by nanomolar concentrations of 3-hydroxypregnane neurosteroids. Previous evidence suggests that 3-hydroxypregnane steroids may competitively antagonize potentiation induced by their 3 diastereomers. Because of the potential importance of antagonists as experimental and clinical tools, we characterized the functional effect of 3-hydroxysteroids. Although 3-hydroxysteroids reduced the potentiation induced by 3-hydroxysteroids, 3-hydroxysteroids acted noncompetitively with respect to potentiating steroids and inhibited the largest degrees of potentiation most effectively. Potentiation by high concentrations of barbiturates was also reduced by 3-hydroxysteroids. 3-Hydroxysteroids are also direct, noncompetitive GABA_A receptor antagonists. 3-Hydroxysteroids coapplied with GABA significantly inhibited responses to 15 µM GABA. The profile of block was similar to that exhibited by sulfated steroids, known blockers of GABA_A receptors. This direct, noncompetitive effect of 3-hydroxysteroids was sufficient to account for the apparent antagonism of potentiating steroids. Mutated receptors exhibiting decreased sensitivity to sulfated steroid block were insensitive to both the direct effects of 3-hydroxysteroids on GABA_A responses and the reduction of potentiating steroid effects. At concentrations that had little effect on GABAergic synaptic currents, 3-hydroxysteroids and low concentrations of sulfated steroids significantly reversed the potentiation of synaptic currents induced by 3-hydroxysteroids. We conclude that 3-hydroxypregnane steroids are not direct antagonists of potentiating steroids but rather are noncompetitive, likely state-dependent, blockers of GABA_A receptors. Nevertheless, these steroids may be useful functional blockers of potentiating steroids when used at concentrations that do not affect baseline neurotransmission.

Key words: neurosteroids; inhibitory postsynaptic current; GABA_A receptors; pregnenolone sulfate; anesthetic; hippocampal culture

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2293366-10$05.00/0

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