Alcohol exposure during the developmental period induces α-endorphin neuronal death and causes alteration in the opioid control of stress axis function

Proopiomelanocortin-producing neurons in the arcuate nucleus of the hypothalamus secrete β-endorphin (β-EP), which controls varieties of body functions including the feedback regulation of the CRH neuronal activity in the paraventricular nucleus of the hypothalamus. Whether ethanol exposure in developing rats induces β-EP neuronal death and alters their influence on CRH neurons in vivo has not been determined. We report here that binge-like ethanol exposures in newborn rats increased the number of apoptotic β-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 TGF-β1-linked apoptotic genes in β-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 β-EP neuronal perikarya in arcuate nuclei and in the number of β-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 challenge. The ethanol-treated animals also showed incompetent ability to respond to exogenous β-EP to alter the lipopolysaccharide-induced CRH mRNA levels. These data suggest that ethanol exposure during the developmental period causes β-EP neuronal death by cellular mechanisms involving the suppression of cyclic AMP production and activation of TGF-β1-linked apoptotic signaling and produces long-term structural and functional deficiency of β-EP neurons in the hypothalamus.