We have developed a rat model in which chronic daily ethanol consumption/daily withdrawal induces hypothalamo-pituitary-adrenal (HPA), brain proopiomelanocortin (POMC) opioid, and behavioral (e.g., anxiety) changes persisting at least 4 weeks after stopping ethanol consumption. These interdependent neuronal, neuroendocrine, and behavioral changes have each been suggested to contribute to alcoholism, and together resemble the HPA+opioid+anxiety syndrome exhibited by abstinent alcoholics, so therapy to block or reverse them could contribute significantly to prevention or treatment of alcoholism. Chronic alcohol abuse also suppresses pineal melatonin secretion in both humans and rats, and plasma metatonin levels remain low during subsequent abstinence. Our preliminary studies suggest that restoration of normal plasma melatonin levels and patterns during and/or after chronic ethanol abuse may reverse some or all of the changes in the HPA+opioid+anxiety syndrome. Thus, our specific aims are to answer the following questions: (1) does melatonin therapy block, delay, or counteract effects of chronic daily ethanol consumption on ethanol dependence, the HPA/POMC axis, and interrelated neuroendocrine mechanisms?; (2) can melatonin therapy during and after ethanol withdrawal prevent HPA/POMC and behavioral changes during abstinence?; and (3) can melatonin therapy decrease elective self-administration of ethanol during chronic daily ethanol consumption, abstinence or repeated deprivation? These three specific aims will be addressed in corresponding studies in which nocturnal melatonin versus control treatments will be administered to rats in liquid diet during chronic daily episodes of ethanol consumption and withdrawal (Study 1), in liquid diet during and after withdrawal from chronic ethanol consumption (Study 2), and in water and ethanol solutions during free-choice drinking of ethanol and intervening deprivation periods (Study 3). Melatonin-induced changes will be assessed as behavioral (dependence, self-administration, sucrose preference, locomotor activity in a novel environment, anxiety-like behavior), endocrine (plasma corticosterone and ACTH levels, plasma corticosterone and ACTH responses to CRF and air-puff startle, plasma catecholamine responses to air-puff startle), and gene expression (forebrain and anterior pituitary POMC gene expression) responses characteristic of, consistent with, or contributing to alcohol abuse and/or relapse.
