GABAA receptor α4 subunit suppression prevents withdrawal properties of an endogenous steroid

Sheryl S. Smith (), Qi Hua Gong, Fu-Chun Hsu, Ronald S. Markowitz, J. M. H. ffrench-Mullen and Xinshe Li
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Sheryl S. Smith: Allegheny University of the Health Sciences, EPPI
Qi Hua Gong: Allegheny University of the Health Sciences, EPPI
Fu-Chun Hsu: Allegheny University of the Health Sciences, EPPI
Ronald S. Markowitz: Allegheny University of the Health Sciences, EPPI
J. M. H. ffrench-Mullen: RIN Bioscience, Zeneca Pharmaceuticals, Zeneca Inc.
Xinshe Li: Allegheny University of the Health Sciences, EPPI

Nature, 1998, vol. 392, issue 6679, 926-929

Abstract: Abstract The hormone progesterone is readily converted to 3α-OH-5α-pregnan-20-one (3α,5α-THP) in the brains of males and females1,2. In the brain, 3α,5α-THP acts like a sedative3,4,5, decreasing anxiety and reducing seizure activity, by enhancing the function of GABA (γ-aminobutyric acid)6,7,8, the brain's major inhibitory neurotransmitter. Symptoms of premenstrual syndrome (PMS), such as anxiety9 and seizure10,11 susceptibility, are associated with sharp declines in circulating levels of progesterone and, consequently, of levels of 3α,5α-THP in the brain. Abrupt discontinuation of use of sedatives such as benzodiazepines12 and ethanol13 can also produce PMS-like withdrawal symptoms. Here we report a progesterone-withdrawal paradigm, designed to mimic PMS and post-partum syndrome in a rat model. In this model, withdrawal of progesterone leads to increased seizure susceptibility and insensitivity to benzodiazepine sedatives through an effect on gene transcription. Specifically, this effect was due to reduced levels of 3α,5α-THP which enhance transcription of the gene encoding the α4 subunit of the GABAA receptor. We also find that increased susceptibility to seizure after progesterone withdrawal is due to a sixfold decrease in the decay time for GABA currents and consequent decreased inhibitory function. Blockade of the α4 gene transcript prevents these withdrawal properties. PMS symptoms may therefore be attributable, in part, to alterations in expression of GABAA receptor subunits as a result of progesterone withdrawal.

Date: 1998
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DOI: 10.1038/31948

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