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 (HP) 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 (ACTH) was blunted by the intracerebroventricular (icv) injection of a cell-permeable peptide that inhibits NF-B translocation. Alcohol also increased hypothalamic IB mRNA levels, a factor that regulates NF-B protein activation and the activity of NF-B DNA binding, and whose expression are thought to reflect NF-B activity. This response, which was not accompanied by detectable changes in brain levels of pro-inflammatory 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 if 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 I-B transcripts. As 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 HP axis activity that involves independent roles of corticosterone and CRF.