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

一些研究表明，遗传因素可能控制酒精消费，内源性阿片系统可能至少部分介导酒精的强化作用。我们先前研究的主要目的是确定酒精对与奖赏和强化过程相关的脑区阿片肽（内啡肽、脑啡肽和强啡肽）释放的影响。 我们的研究表明，酒精的作用取决于（a）酒精的量;（B）大脑区域;（c）特定的阿片肽。简而言之，低到中等剂量的酒精增加了大脑中参与奖励和强化过程的内啡肽和脑啡肽的释放，而高剂量则增加了强啡肽的释放。 根据内啡肽和脑啡肽介导积极的强化作用，而强啡肽介导厌恶作用的知识，可以提出，低至中等量的酒精是有益的，而大量的酒精是厌恶的动物。 所提出的研究的第一个目的是提供对乙醇诱导的阿片肽释放的变化对酒精强化的意义的理解。因此，乙醇诱导的变化对阿片肽释放的影响将通过以下方式来确定：通过在不同脑区域中局部应用阿片肽的特异性抗血清来中和阿片肽的活性，并估计急性乙醇攻击后相关脑区域中多巴胺释放的变化（其释放因药物滥用而增加）。 第二个目的是检验慢性饮酒诱导大脑阿片活性缺陷的假设，这可能通过负强化过程维持高饮酒量。 因此，将确定慢性酒精对阿片肽的组织含量、其特异性mRNA以及其在不同脑区域中的细胞外水平的影响。 拟议的研究将提高我们对高酒精消费的启动和维持所涉及的分子机制的理解。

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.