Chronic daily ethanol and withdrawal: 3. Forebrain pro-opiomelanocortin gene expression and implications for dependence, relapse, and deprivation effect

Background: Although forebrain pro-opiomelanocortin (POMC)-producing neurons seem to mediate or modulate many responses to ethanol consumption, changes in activity of this opiomelanocortinergic system in response to chronic ethanol consumption, withdrawal, and subsequent abstinence remain unresolved. Methods: We investigated the effects of chronic daily ethanol consumption, withdrawal, and subsequent abstinence on adult male Sprague-Dawley rat forebrain opiomelanocortinergic activity as reflected by changes in hypothalamic POMC messenger RNA (mRNA) content by using a well characterized liquid diet model that we have previously demonstrated to accurately simulate not only daily oral ethanol consumption quantity and pattern, but also both neuroendocrine and behavioral changes characteristic of actively drinking and subsequently abstinent alcoholics. Results: After 7 weeks of daily ethanol consumption at night and withdrawal during the day, evening mediobasal hypothalamus POMC mRNA concentrations were suppressed versus both ad libitum-fed and pair-fed controls. Morning POMC mRNA concentrations were also suppressed versus ad libitum-fed controls and tended to be decreased versus pair-fed controls. Three weeks after gradual removal of ethanol from the diet, mediobasal hypothalamus POMC mRNA concentrations were increased relative to ad libitum-fed and pair-fed controls. Plasma concentrations of corticosterone, testosterone, and leptin were also altered by the daily ethanol/withdrawal treatment and by subsequent abstinence. Conclusions: Because each of these hormones has been demonstrated to modify forebrain POMC gene expression under some conditions, the overall changes in forebrain opiomelanocortinergic regulation in response to chronic daily ethanol/withdrawal and subsequent abstinence probably reflect, at least in part, regulation by multiple endocrine mechanisms, together with responses to stress, development of tolerance during chronic daily ethanol consumption, and rebound of function after termination of this consumption. Overall, the demonstrated changes in forebrain POMC gene expression are consistent with significant roles for forebrain opiomelanocortinergic regulation in mediating alcohol dependence, propensity to relapse, and the alcohol deprivation effect.