Role of brain allopregnanolone in the plasticity of γ-aminobutyric acid type A receptor in rat brain during pregnancy and after delivery

TLDR

The study examined how neurosteroid levels in brain and plasma affect GABA A receptor function and structure during pregnancy and postpartum in rats. The authors used subchronic finasteride to inhibit 5α‑reductase, lowering brain allopregnanolone and preventing pregnancy‑related reductions in muscimol‑stimulated chloride uptake and γ2L subunit mRNA. Pregnancy produced divergent brain steroid kinetics, decreased muscimol‑stimulated chloride uptake and γ2L mRNA, while finasteride blocked these changes, indicating that GABA A receptor plasticity is linked to brain allopregnanolone levels.

Abstract

The relation between changes in brain and plasma concentrations of neurosteroids and the function and structure of γ-aminobutyric acid type A (GABA 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 − 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 γ2L GABA A receptor subunit decreased during pregnancy and had returned to control values 2 days after delivery. Also α1,α2, α3, α4, β1, β2, β3, and γ2S mRNAs were measured and failed to change during pregnancy. Subchronic administration of finasteride, a 5α-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 − uptake and the decrease of γ2L mRNA observed during pregnancy. These results indicate that the plasticity of GABA 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.