GABA(A) RECEPTOR ALPHA-4 SUBUNIT SUPPRESSION PREVENTS WITHDRAWAL PROPERTIES OF AN ENDOGENOUS STEROID

The hormone progesterone is readily converted to 3 alpha-OH-5 alpha-pr egnan-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), dec reasing anxiety and reducing seizure activity, by enhancing the functi on of GABA (gamma-aminobutyric acid)(6-8), the brain's major inhibitor y neurotransmitter, Symptoms of premenstrual syndrome (PMS), such as a nxiety(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-wi thdrawal paradigm, designed to mimic PMS and post-partum syndrome in a rat model. In this model, withdrawal of progesterone leads to increas ed seizure susceptibility and insensitivity to benzodiazepine sedative s through an effect on gene transcription. Specifically, this effect w as due to reduced levels of 3 alpha,5 alpha-THP which enhance transcri ption of the gene encoding the alpha 4 subunit of the GABA(A) receptor . We also find that increased susceptibility to seizure after progeste rone withdrawal is due to a sixfold decrease in the decay time for GAB A currents and consequent decreased inhibitory function. Blockade of t he alpha 4 gene transcript prevents these withdrawal properties. PMS s ymptoms may therefore be attributable, in part, to alterations in expr ession of GABA(A) receptor subunits as a result of progesterone withdr awal.