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The relation between changes in brain and plasma concentrations of neurosteroids and the function and structure of [Gamma]-aminobutyric acid type A ([GABA.sub.A]) receptors in the brain during pregnancy and after delivery was investigated in rats. In contrast with plasma, where all steroids increased in parallel, the kinetics of changes in the cerebrocortical concentrations of progesterone, allopregnanolone (AP), and allotetrahydrodeoxycorticosterone (THDOC) diverged during pregnancy. Progesterone was already maximally increased between days 10 and 15, whereas AP and allotetrahydrodeoxycorticosterone peaked around day 19. The stimulatory effect of muscimol on 36[Cl.sup.-] uptake by cerebrocortical membrane vesicles was decreased on days 15 and 19 of pregnancy and increased 2 days after delivery. Moreover, the expression in cerebral cortex and hippocampus of the mRNA encoding for [Gamma]2L [GABA.sub.A] receptor subunit decreased during pregnancy and had returned to control values 2 days after delivery. Also [Alpha]1,[Alpha]2, [Alpha]3, [Alpha]4, [Beta]1 [Beta]2,[Beta]3, and [Gamma]2S mRNAs were measured and failed to change during pregnancy. Subchronic administration of finasteride, a 5[Alpha]-reductase inhibitor, to pregnant rats reduced the concentrations of AP more in brain than in plasma as well as prevented the decreases in both the stimulatory effect of muscimol on 36[Cl.sup.-] uptake and the decrease of [Gamma]2L mRNA observed during pregnancy. These results indicate that the plasticity of [GABA.sub.A] receptors during pregnancy and after delivery is functionally related to fluctuations in endogenous brain concentrations of AP whose rate of synthesis/metabolism appears to differ in the brain, compared with plasma, in pregnant rats.

The effects of oral contraceptives (OCs) on neurosteroid concentrations were evaluated in female rats and women. In rats, ethynylestradiol and levonorgestrel (0.030 and 0.125 mg, respectively, subcutaneously) administered daily for 6 weeks reduced the concentrations of pregnenolone (−41%) progesterone (−74%) and allopregnanolone (−79%) in the cerebral cortex; the plasma concentrations of these steroids were also reduced but by smaller extents. OC administration for 3 months also reduced the serum concentrations of pregnenolone, progesterone and allopregnanolone in women. Chronic administration of OCs in rats increased the abundance of γ-aminobutyric acid type A (GABAA) receptor γ2L and γ2S subunit mRNAs and the relative protein in the cerebral cortex, while the amounts of various α and β subunit mRNAs were unaffected. Ovariectomy did not modify the effect of OCs administration on the concentrations of neurosteroids in the rat cerebral cortex (but not in the plasma) as well as on the GABAA receptor gene expression, suggesting a direct effect of OCs in brain. Finally, rats treated with OCs exhibited an anxiety-like behavior in the elevated plus-maze test. These results indicate that long-term treatment with OCs induced a persistent reduction in the concentrations of pregnenolone, progesterone and its GABAA receptor-active metabolite, allopregnanolone, both in rats and women. In rats this effect was associated with a plastic adaptation of GABAA receptor gene expression in the rat cerebral cortex. [Copyright &y& Elsevier]