Proopiomelanocortin producing neurons in the arcuate nucleus of the hypothalamus secrete -endorphin (-EP), which controls varieties of body functions including the feedback regulation of the corticotropin-releasing hormone (CRH) neuronal activity in the paraventricular nucleus of the hypothalamus. Whether ethanol exposure in developing rats induces -EP neuronal death and alters their influence on CRH neurons in vivo have not been determined. We report here that binge-like ethanol exposures in newborn rats increased the number of apoptotic -EP neurons in the arcuate nucleus of the hypothalamus. We also found that immediately after ethanol treatments there was a significant reduction in the expression of proopiomelanocortin and adenylyl cyclases mRNA and an increased expression of several transforming growth factor beta 1 (TGF-1)-linked apoptotic genes in -EP neurons isolated by Laser captured microdissection from arcuate nuclei of young rats. Several weeks after the ethanol treatment, we detected a reduction in the number of -EP neuronal perikarya in arcuate nuclei and in the number of -EP neuronal terminals in paraventricular nuclei of the hypothalamus in the treated rats. Additionally, these rats showed increased response of the hypothalamic CRH mRNA to the lipopolysaccharide (LPS) challenge. The ethanol-treated animals also showed incompetent ability to respond to exogenous -EP to alter the LPS-induced CRH mRNA levels. These data suggest that ethanol exposure during the developmental period causes -EP neuronal death by cellular mechanisms involving the suppression of cAMP production and activation of TGF-1-linked apoptotic signaling and produces long-term structural and functional deficiency of -EP neurons in the hypothalamus.