Changes in expression of the delta subunit of the GABAA receptor and in receptor function induced by progesterone exposure and whitdrawal.

Type A receptors for GABA (GABAA receptors) that contain the ? subunit are located predominantly at extrasynaptic sites and are implicated in modulation of neuronal excitability through tonic inhibition. We have examined the effects of chronic exposure to and subsequent withdrawal of progesterone or the progesterone metabolite 3?-hydroxy-5?-pregnan-20-one (3?,5?-THPROG) on expression of the ? subunit of GABAA receptors and on receptor function in cultured rat hippocampal neurons. Progesterone treatment for 1 day increased the amounts of both ? subunit mRNA and protein, whereas such treatment for 6 days induced marked decreases in the abundance of both the mRNA and protein. Subsequent progesterone withdrawal up-regulated expression of the ? subunit, which was significantly increased at 9-12 h after withdrawal. These effects of progesterone were mimicked by 3?,5?-THPROG and blocked by the 5?-reductase inhibitor finasteride. They were also accompanied by parallel changes in the function of GABAA receptors in hippocampal neurons. These results show that chronic exposure to and withdrawal of progesterone induce differential effects on both expression of the ? subunit of GABAA receptors and receptor function that are mediated by 3?,5?-THPROG. They are consistent with the notion that this progesterone metabolite plays a key physiological role in modulation of GABAergic synapses.