Our hypothesis is that ethanol ingestion produces changes in activity of the forebrain opiomelanocortinergic neuronal system, which we suggest mediates some effects of alcohol on neuroendocrine regulation and behavioral mechanisms. This neuronal system originates in the mediobasohypothalamus (MBH) and primarily innervates the limbic system, where beta-endorphin (beta END) and co-secreted opiomelanocortins have been proposed to modulate on mediate the activity of a remarkable variety of brain functions, including positive reinforcement, psychomotor stimulation, thermoregulation, analgesia, eating/drinking, sexual behavior, pituitary function, attention and mood. Since alcohol likely increases both dopaminergic and corticotropin-releasing factor (CRF) neurosecretion within the MBH, and both dopamineric and CRF stimulation increase MBH beta END secretion the effect of alcohol on this endogenous opioid system may be indirect. Accordingly, the effects of acute, repeated and chronic treatment of adult male rats with alcohol, as well as withdrawal from chronic alcohol treatment, will be determined with respect to forebrain opiomelanocortinergic as well as hypothalamic CRF and tuberoinfundibular dopaminergic neuronal activity. Changes in MBH proopiomelanocortin (POMC, the precursor peptide for beta END and other opiomelanocortin peptides) gene expression (i.e. POMC mRNA content, determined by ribonuclease protection assay), considered together with changes in POMC-derived peptide (e.g. beta END, alpha MSH) concentrations (determined by radioimmunoassay, RIA) in the MBH as well as in projection sites of the opiomelanocortinergic system which are involved in neuroendocrine and reward response (e.g. medial forebrain bundle/lateral hypothalamus, nucleus accumbens, medial preoptic area, ventral tegmental areas), will be used to estimate forebrain opiomelanocortinergic activity. Changes in MBH tyrosine hydroxylase (TH, rate limiting enzyme in dopamine synthesis) and paraventricular proCRF mRNA contents will provide indices of TH and CRF syntheses and thus tuberoinfundibular dopaminergic and hypothalamic CRF secretory activity, respectively. Changes in plasma luteinizing hormone, prolactin, corticosterone and testosterone concentrations (RIA) will provide indices of pituitary, adrenal and gonadal function. Using the rat as a model, our studies will evaluate: 1) how acute, repeated and chronic in vivo administration of ethanol changes forebrain opiomelanocortinergic activity, 2) how withdrawal from chronic administration of alcohol alters forebrain opiomelanocortinergic activity, 3) whether alcohol-induced changes in brain opiomelanocortinergic activity are correlated with and thus probably functionally related to changes in tuberoinfundibular dopaminergic and/or hypothalamic CRF-secretory activity, and 4) the roles of MBH beta-endorphinergic, dopaminergic and CRF-secretory activity in the effects of alcohol on neuroendocrine regulation of pituitary, adrenal and gonadal function.
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