Neuroactive steroids inhibit spinal reflex potentiation by selectively enhancing specific spinal GABA_A receptor subtypes

Recently, we demonstrated a spinal GABA_A receptor (GABA_AR)-dependent inhibition on the induction of repetitive stimulation-induced spinal reflex potentiation. However, it remains unclear whether steroid hormones modulate such an inhibition. Here, we show that progesterone is capable of producing GABA_ARs-dependent inhibition of the induction of spinal reflex potentiation by actions through neurosteroid metabolites. Progesterone (5 mg/kg, twice daily for 4 days) up-regulates the expression of GABA_AR α2, α3, α4 and δ subunits, and is associated with attenuated repetitive stimulation-induced spinal reflex activity in ovariectomized rats. These changes were blocked by finasteride (50 mg/kg, twice daily), an antagonist of neurosteroid synthesis from progesterone, but not by the progesterone receptor antagonist, RU486 (100 mg/kg, twice daily). The induction of spinal reflex potentiation was attenuated after a short (30 min) intrathecal treatment with the neurosteroids, allopregnanolone (ALLOP, 10 μM, 10 μL) and 3α,5α-tetrahydrodeoxycorticosterone (THDOC, 10 μM, 10 μL). Acute intrathecal administration of the GABA_AR antagonist, bicuculline (10 μM, 10 μL) reversed the inhibition produced by progesterone, THDOC and allopregnanolone. These results imply that progesterone-mediated effects on GABA_AR expression and neural inhibition are regulated by neurosteroids synthesis rather than progesterone receptor activation.