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

Abstract

Recently, we demonstrated a spinal GABA(A) receptor (GABA(A)R)-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(A)Rs-dependent inhibition of the induction of spinal reflex potentiation by actions through neurosteroid metabolites. Progesterone (5mg/kg, twice daily for 4 days) up-regulates the expression of GABA(A)R alpha2, alpha3, alpha4 and delta subunits, and is associated with attenuated repetitive stimulation-induced spinal reflex activity in ovariectomized rats. These changes were blocked by finasteride (50mg/kg, twice daily), an antagonist of neurosteroid synthesis from progesterone, but not by the progesterone receptor antagonist, RU486 (100mg/kg, twice daily). The induction of spinal reflex potentiation was attenuated after a short (30 min) intrathecal treatment with the neurosteroids, allopregnanolone (ALLOP, 10 microM, 10 microL) and 3 alpha,5 alpha-tetrahydrodeoxycorticosterone (THDOC, 10 microM, 10 microL). Acute intrathecal administration of the GABA(A)R antagonist, bicuculline (10 microM, 10 microL) reversed the inhibition produced by progesterone, THDOC and allopregnanolone. These results imply that progesterone-mediated effects on GABA(A)R expression and neural inhibition are regulated by neurosteroids synthesis rather than progesterone receptor activation.