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

The hormone progesterone is readily converted to 3 alpha-OH-5 alpha-pregnan-20-one (3 alpha,5 alpha-THP) in the brains of males and females(1,2), In the brain, 3 alpha,5 alpha-THP acts like a sedative(3-5), decreasing anxiety and reducing seizure activity, by enhancing the function of GABA (gamma-aminobutyric acid)(6-8), the brain's major inhibitory neurotransmitter, Symptoms of premenstrual syndrome (PMS), such as anxiety(9) and seizure(10,11) susceptibility, are associated with sharp declines in circulating levels of progesterone and, consequently, of levels of 3 alpha,5 alpha-THP in the brain. Abrupt discontinuation of use of sedatives such as benzodiazepines(12) and ethanol(13) 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 3 alpha,5 alpha-THP which enhance transcription of the gene encoding the alpha 4 subunit of the GABA(A) 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 alpha 4 gene transcript prevents these withdrawal properties. PMS symptoms may therefore be attributable, in part, to alterations in expression of GABA(A) receptor subunits as a result of progesterone withdrawal.