γ-aminobutyric acid_A receptors mediate 3α-hydroxy-5α-pregnan-20-one-induced gonadotropin secretion

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