That 3alpha-hydroxy-5alpha/beta-pregnane steroids (GABA steroids) have modulatory effects on the GABA-A receptor is well known. In behavioral studies in animals high exogenous dosages give concentrations not usually reached in the brain under physiological conditions. Animal and human studies show that GABA-A receptor-positive modulators like barbiturates, benzodiazepines, alcohol, and allopregnanolone have a bimodal effect. In pharmacological concentrations they are CNS depressants, anesthetic, antiepileptic, and anxiolytic. In low dosages and concentrations, reached endogenously, they can induce adverse emotional reactions in up to 20% of individuals. GABA steroids can also induce tolerance to themselves and similar substances, and rebound occurs at withdrawal. Menstrual cycle-linked disorders can be understood by the concept that they are caused by the action of endogenously produced GABA-steroids through three mechanisms: (a) direct action, (b) tolerance induction, and (c) withdrawal effect. Examples of symptoms and disorders caused by the direct action of GABA steroids are sedation, memory and learning disturbance, clumsiness, increased appetite, worsening of petit mal epilepsy, negative mood as tension, irritability and depression during hormone treatments, and the premenstrual dysphoric disorder (PMDD). A continuous exposure to GABA steroids causes tolerance, and women with PMDD are less sensitive to GABA-A modulators. A malfunctioning GABA-A receptor system is related to stress sensitivity, concentration difficulties, loss of impulse control, irritability, anxiety, and depression. An example of withdrawal effect is "catamenial epilepsy," when seizures increase during menstruation after the withdrawal of GABA steroids. Similar phenomena occur at stress since the adrenals produce GABA steroids during stress.

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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...