Decreased immunoreactivity of the polypeptide precursor pro-opiomelanocortin (POMC) and the prohormone convertase pc1/3 after chronic ethanol exposure in Sprague-Dawley rats.

BACKGROUND:The melanocortin (MC) peptides and opioid peptide β-endorphin are cleaved from the polypeptide precursor pro-opiomelanocortin (POMC). POMC-derived peptides are generated by extensive posttranslational processing that involves several enzymes including prohormone convertase 1/3 and 2 (PC1/3 and PC2). Because ethanol (EtOH) decreases POMC mRNA levels, we determined whether the exposure to an EtOH-containing diet (ED) would significantly reduce central immunoreactivity (IR) of POMC, PC1/3, PC2, and β-endorphin. METHODS:Male Sprague-Dawley rats were given 18 days of access to a normal rodent chow or a control diet (CD), or short-term (4 days) or long-term (18 days) access to an ED. At the end of the study, rats were perfused with 4% paraformaldehyde, and their brains were sectioned into sets for processing with POMC, PC1/3, PC2, and β-endorphin IR. RESULTS:Rats exposed to an ED for 18 days (ED18) exhibited significant reductions of POMC and PC1/3 IR in the arcuate nucleus of the hypothalamus (Arc) relative to rats pair-fed a CD. On the other hand, rats exposed to an ED did not show any changes of central β-endorphin or PC2 IR relative to rats pair-fed a CD, regardless of length of exposure. Because there were no differences in body weights or caloric intake between the CD and ED groups, reductions of POMC and PC1/3 IR in ED-treated rats are best explained by EtOH exposure rather than altered energy balance. CONCLUSIONS:This study shows that EtOH site-specifically reduces POMC and PC1/3 IR in rat brain. These observations are consistent with EtOH-induced reductions of α-melanocyte-stimulating hormone (α-MSH) and POMC IR that were previously reported. As MC agonists have been shown to blunt EtOH intake in rodents, exogenous MC receptor agonists, as well as targets that may increase the synthesis of endogenous α-MSH (e.g., PC1/3), may have therapeutic value for treating alcohol abuse disorders and alcoholism.

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