Tolerance to allopregnanolone with focus on the GABA-A receptor.
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 γ-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 α4 subunit and the expression of the α4 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.
Turkmen
Sahruh
S
Department of Obstetrics & Gynaecology, Sundsvall County Hospital, Sweden. sahruh.turkmen@lvn.se
Backstrom
Torbjorn
T
Wahlstrom
Goran
G
Andreen
Lotta
L
Johansson
Inga-Maj
IM
D000818:Animals; D004361:Drug Tolerance; D005260:Female; D012739:Gonadal Steroid Hormones / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D011247:Pregnancy; D011280:Pregnanolone / Q000378:metabolism* / Q000494:pharmacology*; D011374:Progesterone / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D013315:Stress, Psychological; D013375:Substance Withdrawal Syndrome; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
D012739:Gonadal Steroid Hormones; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D011374:Progesterone; D005680:gamma-Aminobutyric Acid; D011280:Pregnanolone