OPIOD ANTAGONISTS AND ETHANOL INDUCED DOPAMINE RELEASE

阿片拮抗剂和乙醇诱导多巴胺释放

• 批准号: 2693506
• 负责人: MICHAEL F STROMBERG
• 金额: $ 11.45万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2004-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2693506
• 关键词: alcoholic beverage consumption; craving; cues; dopamine; drug screening /evaluation; endogenous opioid; ethanol; histology; laboratory rat; microdialysis; naltrexone; narcotic antagonists; neuropharmacology; neurotransmitter transport; nucleus accumbens; oral administration; psychopharmacology; reinforcer; relapse /recurrence; serotonin

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.

酒精依赖康复患者保持戒酒是 难的。 通常，这些人经常对酒精进行采样 导致失控，导致旧病复发。 使用 纳曲酮作为心理社会治疗的药理学辅助剂 最近已证明该计划可以显着减少这些复发 率（O'Malley 等人，1992 年；Volpicelli 等人，1992 年）。 机制 纳曲酮通过何种方式实现这种效果尚不清楚，但一些 来自动物模型的证据表明，它可能通过阻止 乙醇诱导中脑边缘多巴胺的释放呈阳性 强化途径（Benjamin 等人，1992；Widdowson 和 Holman， 1992）。 这些途径与积极强化有关 许多滥用药物的特性，包括乙醇（Koob，1992）。 虽然初步证据表明内源性阿片类药物是一种潜在的药物 多巴胺强化途径的调节剂很有趣，很多 问题仍有待解答。 例如，它并不完全 明确特定类型的阿片受体有何贡献。 例如，如果 δ 拮抗作用是减少 过量饮酒，那么特定的δ拮抗剂会提供 在临床治疗酒精依赖方面具有优势。 这些 药物的副作用会更少，患者将能够获得 mu 激动剂缓解疼痛。本提案寻求培训 微透析，以便我可以继续我的研究 乙醇的神经药理学特性及其与 那些维持消费的强化特性。 具体来说， 微透析将允许评估细胞外水平 伏隔核中的多巴胺和血清素是由两者产生的 实验者急性注射乙醇，慢性自我注射 大鼠体内的乙醇。 它还将允许比较 themu 和 delta 选择性阿片拮抗剂、β-的有效性 Funaltrexamine 和 naltrindole，对于非选择性拮抗剂， 纳曲酮，对消费的行为测量和 神经化学措施。 因为药物的条件作用往往是 导致渴望增加并导致复发的原因 这些阿片类拮抗剂对细胞外多巴胺和血清素的影响 暴露于药物相关线索而产生的伏隔核将 也可以进行比较。 这项研究旨在增进我们的知识 阿片类拮抗剂如何帮助预防康复过程中的复发 酒精依赖患者。 此外，它还试图确定是否有其他 药物干预，例如 mu 或 delta 选择性 拮抗剂，比非选择性阿片类药物更有效 拮抗剂，纳曲酮。 此外，它将为我提供培训 微透析对于提高我的研究能力是必要的 与增强特性相关的神经药理学变化 乙醇。