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Tolerance to allopregnanolone with focus on the GABA-A receptor
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Department of Obstetrics & Gynaecology, Sundsvall County Hospital, Sundsvall, Sweden.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Department of Obstetrics & Gynaecology, Sundsvall County Hospital, Sundsvall, Sweden.
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2011 (English)In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 162, no 2, 311-327 p.Article in journal (Refereed) Published
Abstract [en]

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 (VPM) 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.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2011. Vol. 162, no 2, 311-327 p.
Keyword [en]
Allopregnanolone, GABA-A receptor, tolerance, silent second, mRNA, neurosteroid
National Category
Pharmaceutical Sciences Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:umu:diva-36798DOI: 10.1111/j.1476-5381.2010.01059.xISI: 000285305900001PubMedID: 20883478OAI: oai:DiVA.org:umu-36798DiVA: diva2:356363
Available from: 2010-10-12 Created: 2010-10-12 Last updated: 2015-06-15Bibliographically approved

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Turkmen, SahruhBäckström, TorbjörnWahlström, GöranAndréen, LottaJohansson, Inga-Maj

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