Gamma-aminobutyric acidA receptors mediate 3 alpha-hydroxy-5 alpha-pregnan-20-one-induced gonadotropin secretion.

3 alpha-Hydroxy-5 alpha-pregnan-20-one (3 alpha, 5 alpha-THP), can selectively release LH in estrogen-primed ovariectomized rats. This progesterone metabolite does not bind to the progesterone receptor. Recently, 3 alpha,5 alpha-THP has been reported to be a potent modulator of the gamma-aminobutyric acidA (GABAA) receptor in the brain. Therefore, the purpose of this study was to determine whether 3 alpha,5 alpha-THP's effect on gonadotropin secretion is GABAA receptor mediated. Ovariectomized immature rats were primed for 2 days with estradiol (2 micrograms/rat.day). On the morning of the third day, 3 alpha,5 alpha-THP was administered either with or without prior treatment with progesterone receptor antagonist (RU486) or the GABAA receptor antagonist picrotoxin. When 3 alpha,5 alpha-THP was administered alone, a dose-related effect on LH and FSH release was observed. The 0.8 mg/kg BW dose of 3 alpha,5 alpha-THP stimulated both LH and FSH release, whereas the 1.6 mg/kg BW dose released only LH. The GABAA receptor antagonist picrotoxin had no significant effect on LH or FSH secretion. However, administration of picrotoxin 30 min before 0.8 mg/kg BW 3 alpha,5 alpha-THP resulted in antagonism of 3 alpha,5 alpha-THP's ability to release LH and FSH. The effects of 1.6 mg/kg BW 3 alpha,5 alpha-THP on serum LH were also blocked by picrotoxin. Picrotoxin was ineffective in altering the gonadotropin-stimulating response of progesterone and deoxycorticosterone. These steroids do not bind to the GABAA receptor. The progesterone receptor antagonist RU486 administered alone had no effect on serum LH or FSH levels. When RU486 was administered before 3 alpha,5 alpha-THP treatment, it was ineffective in blocking 3 alpha,5 alpha-THP's ability to release LH. These studies indicate that the GABAA receptor is responsible for mediating 3 alpha,5 alpha-THP-induced gonadotropin secretion.