期刊
BRITISH JOURNAL OF PHARMACOLOGY
卷 162, 期 2, 页码 311-327出版社
WILEY
DOI: 10.1111/j.1476-5381.2010.01059.x
关键词
allopregnanolone; GABA-A receptor; tolerance; silent second; mRNA; neurosteroid
资金
- Swedish Medical Research Council [4X-11198]
- Umea sjukvard, spjutspetsanslag, Visare Norr Norra Regionen
- EU
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 gamma-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 alpha 4 subunit and the expression of the alpha 4 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.
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