Allopregnanolone synthesis in cerebellar granule cells: Roles in regulation of GABA(A) receptor expression and function during progesterone treatment and withdrawal

Rat cerebellar granule cells were cultured for 5 days with progesterone, resulting in the conversion of progesterone to allopregnanolone, a potent and efficacious modulator of ?-aminobutyric acid (GABA) type-A receptors, as well as in decreases in the abundance of GABA(A)-receptor ?1, ?3, ?5, and ?2 subunit mRNAs. These effects were accompanied by decreases in the efficacies of diazepam and the ?-carboline DMCM with regard to modulation of GABA-evoked CI- currents. Withdrawal from such progesterone treatment resulted in a rapid and selective increase in the abundance of the GABA(A) ?4 subunit mRNA that was associated with a restoration of receptor sensitivity to the negative modulatory action of DMCM, a positive receptor response to flumazenil, and continued reduced responsiveness of receptors to diazepam. Prevention of allopregnanolone synthesis by the 5?-reductase inhibitor finasteride also prevented the changes in both GABAA receptor gene expression and receptor function elicited by progesterone treatment and withdrawal.