OPIOD ANTAGONISTS AND ETHANOL INDUCED DOPAMINE RELEASE

酒精依赖康复者保持戒酒， 难 通常，这些人的酒精样本经常 会导致失控从而导致复发 使用 纳洛酮作为心理社会治疗的药物辅助剂 最近的一项研究表明，该计划可以显著减少这些复发 比率（O 'Malley等人，1992; Volpicelli等人，1992年）。 机制 纳洛酮是如何达到这种效果的尚不清楚，但一些 来自动物模型的证据表明，它可能是通过阻止 乙醇诱导的中脑边缘核多巴胺释放 增强途径（Benjamin等人，1992年; Widdowson和Holman， 1992年）。 这些途径与积极强化 包括乙醇在内的许多滥用药物的特性（Koob，1992）。 虽然最初的证据表明内源性阿片类药物可能是 多巴胺强化途径的调节剂是有趣的，许多 问题仍有待解答。 例如，它不完全是 明确特定类型的阿片受体的作用。 例如，如果δ拮抗作用是降低 过量饮酒，那么特定的δ拮抗剂将提供 在酒精依赖的临床治疗中具有优势。 这些 药物的副作用会更少，患者将能够获得 μ激动剂的疼痛缓解。这项建议寻求培训， 微透析，这样我就可以继续研究 乙醇的神经药理学特性以及这些特性与 这些增强的属性维持消费。 具体地说， 微透析将允许评估细胞外水平的 多巴胺和5-羟色胺在丘脑核中的作用， 实验者给予急性乙醇和慢性自我给药 酒精在老鼠身上 它还将允许比较 μ和δ选择性阿片拮抗剂，β- 对非选择性拮抗剂， 纳洛酮，对消费行为和 神经化学指标 因为条件性药物作用通常 负责增加渴望，导致复发， 这些阿片类拮抗剂对细胞外多巴胺和血清素的作用， 通过暴露于药物相关线索而产生的丘脑核将 也可以比较。 这项研究旨在增进我们对 阿片类药物拮抗剂如何帮助防止复发， 酒精依赖患者 此外，它还试图确定其他 药理学干预，如mu或delta选择性 拮抗剂，将比非选择性阿片类药物更有效 拮抗剂，纳洛酮。 此外，它将为我提供培训， 在微透析技术中， 神经药理学的变化有关的强化性能 乙醇

Maintaining abstinence in recovering alcohol dependent patients is difficult. Often, sampling of alcohol by these individuals frequently leads to a loss of control that precipitates a relapse. The use of naltrexone as a pharmacological adjunct to the psychosocial treatment program has recently been shown to significantly reduce these relapse rates (O'Malley et al., 1992; Volpicelli et al., 1992). The mechanism by which naltrexone achieves this effect remains unclear, but some evidence from animal models suggests that it may do so by preventing the ethanol-induced release of dopamine in the mesolimbic positive reinforcing pathways (Benjamin et al., 1992; Widdowson and Holman, 1992). These pathways have been implicated in the positive reinforcing properties of many drugs of abuse, including ethanol (Koob, 1992). While the initial evidence implicating endogenous opioids as a potential modulator of dopamine reinforcement pathways is interesting, many questions remain to be answered. For example, it is not completely clear what contribution is made by specific types of opioid receptors. If, for example, delta antagonism is the critical factor in reducing excessive alcohol drinking, then specific delta antagonists would offer an advantage in the clinical treatment of alcohol dependence. These drugs would have fewer side effects and patients would be able to obtain pain relief from mu agonists. This proposal seeks training in microdialysis so that I can continue my investigation of the neuropharmacological properties of ethanol and how these may relate to those reinforcing properties that maintain consumption. Specifically, microdialysis will permit the assessment of extracellular levels of dopamine and serotonin in the nucleus accumbens resulting from both experimenter administered acute ethanol and chronic self-administered ethanol in rats. It will also allow for the comparison of the effectiveness of themu and delta selective opioid antagonists, beta- funaltrexamine and naltrindole, to the nonselective antagonist, naltrexone, on both the behavioral measure of consumption and the neurochemical measures. Because conditioned drug effects are often responsible for increases in craving that lead to relapse, the effects of these opioid antagonists on extracellular dopamine and serotonin in the nucleus accumbens produced by exposure to drug associated cues will also be compared. This research is designed to advance our knowledge of how opioid antagonists help protect against relapse in recovering alcohol dependent patients. In addition, it seeks to determine if other pharmacological interventions, such as a mu or delta selective antagonist, would be more effective than the nonselective opioid antagonist, naltrexone. Further, it will provide me with the training in microdialysis necessary to advance my ability to study the neuropharmacological changes related to the reinforcing properties of ethanol.