Implication of the endogenous opioid system in the genetic predisposition to alcoholism

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A number of studies have shown that genetic factors may control alcohol consumption and that the endogenous opioid system may mediate, at least in part, the reinforcing effects of alcohol. The major objective of our previous studies was to determine the effect of alcohol on the release of opioid peptides (endorphin, enkephalin and dynorphin peptides) in brain regions associated with the processes of reward and reinforcement. Our studies demonstrated that the effect of alcohol depended (a) on the amount of alcohol; (b) on the brain region; and (c) on the specific opioid peptide. In brief, it was observed that low to medium doses of alcohol increased the release of endorphins and enkephalins in brain regions involved in the processes of reward and reinforcement, while high doses increased the release of dynorphins. Based on the knowledge that endorphins and enkephalins mediate positive reinforcing effects, while dynorphins mediate aversive effects it may be proposed that low to medium amounts of alcohol are rewarding, while high amounts of alcohol are aversive to the animals. The first objective of the proposed studies is to provide an understanding of the significance of the ethanol induced changes on the release of opioid peptides on alcohol reinforcement. Thus, the impact of the ethanol induced changes on the release of opioid peptides will be determined by neutralizing the activity of the opioid peptides, through local application of their specific antisera in distinct brain regions, and estimating the changes in dopamine release (the release of which is increased by drugs of abuse) in relevant brain regions following an acute ethanol challenge. The second objective is to test the hypothesis that chronic alcohol consumption induces deficits in the opioid activity of the brain, which may maintain high alcohol consumption through the processes of negative reinforcement. Thus, the effect of chronic alcohol on the tissue content of opioid peptides, on their specific mRNAs, as well as on their extracellular levels in distinct brain regions will be determined. The proposed studies will enhance our understanding of the molecular mechanisms involved in the initiation and maintenance of high alcohol consumption.