Progesterone-metabolite prevents protein kinase C-dependent modulation of gamma-aminobutyric acid type A receptors in oxytocin neurons

Gonadal steroid feedback to oxytocin neurons during pregnancy is in part me diated via the neurosteroid allopregnanolone (3 alpha-OH-DHP), acting as al losteric modulator of postsynaptic gamma-aminobutyric acid type A (GABA(A)) receptors. We describe here a form of nongenomic progesterone signaling by showing that 3 alpha-OH-DHP not only potentiates GABA(A) receptor-channel activity but also prevents its modulation by protein kinase C (PKC). Applic ation of oxytocin or stimulation of PKC suppressed the postsynaptic GABA re sponses of oxytocin neurons in the absence, but not in the presence of 3 al pha-OH-DHP. This finding was true at the juvenile stage and during late pre gnancy, when the GABA(A) receptor is sensitive to 3 alpha-OH-DHP. In contra st, after parturition, when the GABA(A) receptors expressed by oxytocin neu rons are less sensitive to 3 alpha-OH-DHP, this neurosteroid no longer coun teracts PKC. The change in GABA(A)-receptor responsiveness to 3 alpha-OH-DH P helps to explain the onset of firing activity and thus the induction of o xytocin release at parturition.