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

[Amanita Research]

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

Abstract: The relation between changes in brain and plasma concentrations of neurosteroids and the function and structure of γ-aminobutyric acid type A (GABAA) 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 36Cl− 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 GABAA 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 36Cl− uptake and the decrease of γ2L mRNA observed during pregnancy. These results indicate that the plasticity of GABAA 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.

An important feature of γ-aminobutyric acid type A (GABAA) receptors in rat brain is their plasticity in response to exposure to brief or long-lasting physiological stimuli or to long-term pharmacological treatments. The kinetic characteristics of the various binding sites located on the GABAA receptor, as well as the density and function of these receptors in different areas of the rat brain, are affected by acute stressful stimuli (handling, foot shock, swimming), postnatal development, aging, kindling, and long-term administration of anxiolytic, hypnotic, or anticonvulsant drugs (1–6). Although recent studies have suggested that some of these changes may be mediated at the level of expression of receptor subunit genes (7–10), the chemical or molecular events that underlie such rapid, short-term, or persistent changes in the density and affinity of binding sites associated with GABAA receptors, as well as in the function of the receptor complex, remain to be characterized.

Neurosteroids accumulate in the mammalian brain in a manner that is, at least in part, independent of the peripheral tissues (adrenal glands and gonads) that synthesize these compounds (11). Systemic administration of progesterone or its metabolites 3α-hydroxy-5α-pregnan-20-one (allopregnanolone, AP) and 3α,21-dihydroxy-5α-pregnan-20-one (allotetrahydrodeoxycorticosterone, THDOC) induces anxiolytic, hypnotic, or anticonvulsant effects (for review see ref. 12) by enhancing the function of GABAA receptors (12, 13). These observations suggest that endogenous variations in the plasma and brain concentrations of these compounds induced by physiological, pharmacological, or pathological conditions might play an important role in modulation of neuronal excitability; such modulation, in turn, might result in alterations in such characteristics as emotional state, sleep pattern, and seizure threshold. Indeed, several studies have indicated that these neuroactive steroids may play a physiological role in aggression, epilepsy, and premenstrual syndrome (14–16). Consistent with these data, changes in the plasma and brain concentrations of neuroactive steroids elicited either by physiological conditions (17, 18) or by pharmacological treatments (12, 19, 20) have been associated with alterations in the behavioral and neurochemical responses linked to central GABAA receptors.

To clarify the role of the rapid effects of these neuroactive steroids on the GABAA receptor complex in the physiological modulation of receptor activity, we now have evaluated the possible functional relation between the plasticity of GABAA receptors and the changes in plasma and brain concentrations of progesterone, AP, and THDOC during pregnancy and after delivery in rats. Furthermore, we examined whether administration of finasteride, a selective blocker of 5α-reductase (21), at a dose that markedly reduces the concentrations of AP and THDOC in plasma and brain was able to reverse the changes in GABAA receptor function and structure elicited by pregnancy.

https://www.pnas.org/content/95/22/13284