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Role Played by Hypothalamic Nuclear Factor-B in Alcohol-Mediated Activation of the Rat Hypothalamic-Pituitary-Adrenal Axis

The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037

Address all correspondence and requests for reprints to: Catherine Rivier, Ph.D., The Salk Institute, 10010 North Torrey Pines Road, La Jolla, California 92037. E-mail: crivier{at}salk.edu.

The DNA binding protein nuclear factor-B (NF-B) is a transcription factor translocated from the cytosol to the nucleus in response to stressors. Here we determined whether the known ability of alcohol to activate the hypothalamic-pituitary axis was mediated by NF-B, tested the hypothesis that this phenomenon was accompanied by increased hypothalamic NF-B transcripts, and investigated some of the mechanisms involved in this response. We found that alcohol-induced increase in plasma ACTH was blunted by the intracerebroventricular (icv) injection of a cell-permeable peptide that inhibits NF-B translocation. Alcohol also increased hypothalamic inhibitory factor B (IB) mRNA levels, a factor that regulates NF-B protein activation and the activity of NF-B DNA binding and whose expression is thought to reflect NF-B activity. This response, which was not accompanied by detectable changes in brain levels of proinflammatory cytokines, was partially retained in adrenalectomized/corticosterone-replaced rats. The icv injection of corticotropin-releasing factor (CRF), a hypothalamic peptide that is released by alcohol and mediates its influence on ACTH secretion, also stimulated hypothalamic IB transcription. We therefore determined whether brain CRF played a role in the influence of alcohol on NF-B signaling pathways. Indeed, the icv injection of the CRF antagonist -helCRF_9–41 decreased alcohol-induced hypothalamic IB transcripts. Because this antagonist did not alter corticosterone levels, our data suggest that the role played by CRF was not modulated by this steroid. Collectively, our results provide evidence for a functional interaction between alcohol and NF-B-dependent pathway in stimulating the rat hypothalamic-pituitary axis activity that involves independent roles of corticosterone and CRF.