1. Department of Neurobiology and Anatomy, Allegheny University of the Health Sciences, EPPI, 3200 Henry Avenue, Philadelphia, Pennsylvania 19129, USA
2. RIN Bioscience, Zeneca Pharmaceuticals, Zeneca Inc., Wilmington, Delaware 198505437, USA

Correspondence to: Sheryl S. Smith¹ Correspondence and requests for materials should be addressed to S.S.S. (e-mail: Email: smiths@auhs.edu).

The hormone progesterone is readily converted to 3-OH-5-pregnan-20-one (3,5-THP) in the brains of males and females¹,². In the brain, 3,5-THP acts like a sedative^{3, 4, 5}, decreasing anxiety and reducing seizure activity, by enhancing the function of GABA (-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 3,5-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 3,5-THP which enhance transcription of the gene encoding the 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 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.