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: 6163727
• 负责人: MICHAEL F STROMBERG
• 金额: $ 11.46万
• 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/6163727
• 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.

在酒精依赖康复患者中保持戒酒是 很难。通常，这些人经常对酒精进行采样 导致失控，加速复发。对.的使用 纳曲酮作为心理社会治疗的药理辅助剂 最近的研究表明，该计划可以显著减少这种复发 Rate(O‘Malley等人，1992；Volpicelli等人，1992)。这一机制 目前尚不清楚纳曲酮是通过什么途径达到这种效果的，但一些 来自动物模型的证据表明，它可能通过预防 乙醇诱导中脑边缘阳性神经元多巴胺的释放 增强途径(Benjamin等人，1992；Widdowson和Holman， (1992年)。这些途径与积极的强化有关。 许多滥用药物的特性，包括乙醇(Koob，1992)。 虽然最初的证据表明内源性阿片类药物是潜在的 多巴胺强化通路的调节器很有趣，有很多 问题仍有待回答。例如，它并不完全 明确特定类型的阿片受体有什么贡献。 例如，如果三角洲对抗是减少 过量饮酒，那么特定的三角洲拮抗剂就会提供 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 MU激动剂的止痛作用。该提案寻求在以下方面进行培训 这样我就可以继续我的研究 乙醇的神经药理学特性及其与神经毒性的关系 这些强化了维持消费的属性。具体来说， 微透析将使评估细胞外水平成为可能 伏核中的多巴胺和5-羟色胺 实验者给予急性乙醇和慢性自我给药 乙醇对大鼠的影响。它还将允许比较 Temu和Delta选择性阿片类拮抗剂的疗效 对非选择性拮抗剂呋喃曲克明和纳曲啶， 纳曲酮，在消费的行为指标和 神经化学指标。因为条件性药物效应通常 对导致复发的渴望的增加负责，其影响 阿片类拮抗剂对神经细胞外多巴胺和5-羟色胺的影响 通过接触药物相关线索产生的伏隔核会 也可以拿来比较。这项研究旨在增进我们的知识 阿片类拮抗剂如何在康复过程中帮助防止复发 酒精依赖患者。此外，它还试图确定是否还有其他 药物干预，如选择性的MU或Delta 拮抗剂，将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 在微透析方面有必要提高我的研究能力 与补肾益气作用相关的神经药理学变化 乙醇。