PROGESTERONE RECEPTOR-MEDIATED EFFECTS OF NEUROACTIVE STEROIDS

Several 3alpha-hydroxysteroids accumulate in the brain after local syn thesis or after metabolization of steroids that are provided by the ad renals. The 3alpha-hydroxy ring A-reduced pregnane steroids allopregna nolone and tetrahydrodeoxycorticosterone are believed not to interact with intracellular receptors, but enhance GABA-mediated chloride curre nts. The present study shows that these neuroactive steroids can regul ate gene expression via the progesterone receptor. The induction of DN A binding and transcriptional activation of the progesterone receptor requires intracellular oxidation of the neuroactive steroids into prog esterone receptor active 5alpha-pregnane steroids. Thus, at physiologi cal concentrations, these neuroactive steroids regulate neuronal funct ion through their effects on both transmitter-gated ion channels and s teroid receptor-regulated gene expression.