Alcohol exposure during the developmental period induces beta-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 beta-endorphin (beta-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 beta-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 beta-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-beta1-linked apoptotic genes in beta-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 beta-EP neuronal perikarya in arcuate nuclei and in the number of beta-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 beta-EP to alter the lipopolysaccharide-induced CRH mRNA levels. These data suggest that ethanol exposure during the developmental period causes beta-EP neuronal death by cellular mechanisms involving the suppression of cyclic AMP production and activation of TGF-beta1-linked apoptotic signaling and produces long-term structural and functional deficiency of beta-EP neurons in the hypothalamus.
Sarkar
Dipak K
DK
Endocrinology Program, Rutgers-The State University of New Jersey, 84 Lipman Drive, New Brunswick, NJ 08901, USA. sarkar@aesop.rutgers.edu
Kuhn
Peter
P
Marano
Jasson
J
Chen
Cuiping
C
Boyadjieva
Nadka
N
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D007031:Hypothalamus / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000502:physiology; D017729:Presynaptic Terminals / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological / Q000503:physiopathology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D001615:beta-Endorphin / Q000378:metabolism* / Q000502:physiology
D051017:Apoptosis Regulatory Proteins; D053773:Transforming Growth Factor beta1; D000431:Ethanol; D001615:beta-Endorphin; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP