Tolerance to allopregnanolone with focus on the GABA‐A receptor

Abstract

Many studies have suggested a relationship between stress, sex steroids, and negative mental and mood changes in humans. The progesterone metabolite allopregnanolone is a potent endogenous ligand of the g-amino butyric acid -A (GABA-A) receptor, and the most discussed neuroactive steroid. Variations in the levels of neuroactive steroids that influence the activity of the GABA-A receptor cause a vulnerability to mental and emotional pathology. There are physiological conditions in which allopregnanolone production increases acutely (e.g. stress) or chronically (e.g. menstrual cycle, pregnancy), thus exposing the GABA-A receptor to high and continuous allopregnanolone concentrations. In such conditions, tolerance to allopregnanolone may develop. We have shown that both acute and chronic tolerances can develop to the effects of allopregnanolone. Following the development of acute allopregnanolone tolerance, there is a decrease in the abundance of the GABA-A receptor a4 subunit and the expression of the a4 subunit mRNA in the ventral-posteriomedial nucleus of the thalamus. Little is known about the mechanism behind allopregnanolone tolerance and its effects on assembly of the GABA-A receptor composition. The exact mechanism of the allopregnanolone tolerance phenomena remains unclear. The purpose of this review is to summarize certain aspects of current knowledge concerning allopregnanolone tolerance and changes in the GABA-A receptors. AbbreviationsCNS, central nervous system; EEG, electroencephalography; GABA-A, g-amino butyric acid -A; HRT, hormone replacement therapy; NMDA, N-methyl-D-aspartic acid; PMDD, premenstrual dysphoric disorder; PMS, premenstrual syndrome; SS, burst suppression of 1 s or more in the EEG (silent second); THDOC, tetrahydro-deoxycorticosterone; VPM, ventral-posteriomedial nucleus IntroductionThe development of tolerance to foreign compounds with effects in the central nervous system (CNS) is a common phenomenon. Whether tolerance can occur with endogenous substances and in specific disorders is less well known. The purpose of this review is to examine the possibility that chronic production of steroids active on the g-amino butyric acid -A (GABA-A) receptor may induce tolerance under certain conditions. In particular, inhibitory compounds working on the GABA-A receptor are known to induce tolerance. Well-known examples are benzodiazepines, barbiturates and alcohol, all of which enhance the inhibitory effect of GABA on the chloride ion flux through the GABA-A receptor (Allan et al., 1992;Pesold et al., 1997;Wallace et al., 2007). Endogenous GABA-A receptor agonists exist in the 3a-hydroxy metabolites of progesterone, testosterone and deoxycorticosterone, known as allopregnanolone, pregnanolone, androstanediol and tetrahydrodeoxycorticosterone (THDOC). These compounds are steroids and act as agonists at the GABA-A receptor, and hence are known as GABA steroids (Mellon and Griffin, 2002;Backstrom et al., 2003). The first evidence for the development of tolerance to chronic pregnanolone exposur...

Effects of Subchronic Finasteride Treatment and Withdrawal on Neuroactive Steroid Levels and Their Receptors in the Male Rat Brain

“…Data available in the literature indicate that THP treatment as well as its withdrawal (i.e., 24 h) transiently increases the expression of α4 subunit in the hippocampus [60]. A decrease of this GABA-A subunit has been reported after neonatal THP treatment [61] or following the development of acute THP tolerance [62]. Usually, the effect of THP on the expression of α4 subunit is associated with changes in the expression of δ subunit [60], which was not affected in our experimental model.…”

Low Serum Allopregnanolone Is Associated with Symptoms of Depression in Late Pregnancy

“…It is also obvious that depression and anxiety are at least as common during pregnancy as during other time points in a woman's fertile life [41], despite the anxiolytic and sedative levels of allopregnanolone. Given the possibility that a tolerance develops during several months of continuous increase [42], it is reasonable that only women with very high levels, or a steeper increase, would benefit from the protective effects of allopregnanolone during pregnancy. Insensitivity to other substances acting on the GABA A receptor, as well as tolerance to the anticonvulsive, learning-impairing, and anesthetic effects of allopregnanolone exposure have been demonstrated in rodent models [42].…”

“…Given the possibility that a tolerance develops during several months of continuous increase [42], it is reasonable that only women with very high levels, or a steeper increase, would benefit from the protective effects of allopregnanolone during pregnancy. Insensitivity to other substances acting on the GABA A receptor, as well as tolerance to the anticonvulsive, learning-impairing, and anesthetic effects of allopregnanolone exposure have been demonstrated in rodent models [42]. The GABA A receptor sensitivity to allopregnanolone may depend on receptor subunit composition, where the relative contributions of subunits α4 and δ have received most attention [43,44].…”

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