期刊
JOURNAL OF NEUROCHEMISTRY
卷 115, 期 1, 页码 142-152出版社
WILEY
DOI: 10.1111/j.1471-4159.2010.06904.x
关键词
ACTH; adrenal; brain; ethanol; GABA; neuroactive steroid
资金
- [R37-AA10564]
- [T32-AA007573]
P>Acute ethanol administration increases potent GABAergic neuroactive steroids, specifically (3 alpha,5 alpha)-3-hydroxypregnan-20-one (3 alpha,5 alpha-THP) and (3 alpha,5 alpha)-3,21-dihydroxypregnan-20-one. In addition, neuroactive steroids contribute to ethanol actions. Chronic ethanol exposure results in tolerance to many effects of ethanol, including ethanol-induced increases in neuroactive steroid levels. To determine the mechanisms of tolerance to ethanol-induced increases in neuroactive steroids, we investigated critical signaling molecules that are required for acute ethanol effects. Male Sprague-Dawley rats were administered ethanol via liquid diet for 2 weeks and steroid levels, adrenocorticotrophic hormone (ACTH) and adrenal steroidogenic acute regulatory (StAR) protein expression were measured. Chronic ethanol exposure elicits tolerance to ethanol-induced elevation of serum ACTH and the steroids pregnenolone and progesterone. Surprisingly, chronic ethanol exposure does not result in tolerance to ethanol-induced increases in adrenal StAR protein. However, ethanol-induced StAR phosphorylation is decreased when compared to acute ethanol administration. A separate group of rats exposed to chronic ethanol diet were subsequently challenged with ethanol (2 g/kg) and exhibited a blunted elevation of serum ACTH and progesterone as well as cerebral cortical and hippocampal 3 alpha,5 alpha-THP. Administration of ACTH with the ethanol challenge restored the elevation of serum ACTH and progesterone as well as cerebral cortical 3 alpha,5 alpha-THP levels to those observed in ethanol-naive rats. Thus, chronic ethanol exposure disrupts ACTH release, which results in tolerance to ethanol-induced increases in neuroactive steroid levels. Loss of the ethanol-induced increases in neuroactive steroids may contribute to behavioral tolerance to ethanol and influence the progression towards alcoholism.
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