Mechanism of Disulfiram-Induced Cocaine Abstinence

双硫仑诱导可卡因戒断的机制

• 批准号: 7033268
• 负责人: DAVID WEINSHENKER
• 金额: $ 34.43万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-10 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7033268
• 关键词: behavior test; behavioral /social science research tag; cocaine; disulfiram; dopamine; dopamine beta monooxygenase; drug /alcohol abstinence; drug habituation; enzyme activity; enzyme inhibitors; genetically modified animals; genotype; laboratory mouse; laboratory rat; microdialysis; neurochemistry; neuropharmacology; norepinephrine; radiotracer; reinforcer; relapse /recurrence; self medication; substance abuse related behavior

DESCRIPTION (provided by applicant): The mesolimbic dopamine (DA) system has been primarily implicated in the reinforcing effects of drugs of abuse. While this pathway and DA signaling are the focus of most research in this area, it is also clear that norepinephrine (NE), via interactions with the dopaminergic system, plays an important role in modulating the neurochemical and behavioral responses to drugs of abuse in animal models. The enzyme dopamine (Beta-hydroxylase (DBH) converts DA to NE in noradrenegic cells, thus controlling the abundance of both NE and DA in the brain. Genetic and pharmacological data in humans support an important role for DBH in modulating psychostimulant-related behaviors. First, a common polymorphism in the human Dbh gene is a critical determinant of DBH enzymatic activity and appears to influence behavioral and cognitive responses to cocaine. Second, the DBH inhibitor disulfiram (Antabuse) has shown striking promise as a treatment for cocaine dependence, yet its mechanism of action is unknown. The objective of this proposal is to determine the influence of DBH activity on catecholamine neurochemistry and cocaine-related behaviors, including sensitization, reward, aversion, and relapse, and to understand why disulfiram administration results in cocaine abstinence in dependent humans. This will be accomplished by using a combination of genetics (Dbh knockout mice), and pharmacology (disulfiram). Completion of the aims in this proposal will contribute to our understanding of how the interaction between noradrenergic and dopaminergic systems influences drug addiction and the mechanism of disulfiram- induced cocaine abstinence, and will suggest novel treatments for psychostimulant dependence

描述（由申请人提供）：中脑边缘多巴胺（DA）系统主要与滥用药物的增强作用有关。虽然该通路和 DA 信号传导是该领域大多数研究的焦点，但也很明显，去甲肾上腺素 (NE) 通过与多巴胺能系统的相互作用，在调节动物对滥用药物的神经化学和行为反应中发挥着重要作用。模型。多巴胺酶（β-羟化酶 (DBH)）在去甲肾上腺素能细胞中将 DA 转化为 NE，从而控制大脑中 NE 和 DA 的丰度。人类遗传和药理学数据支持 DBH 在调节精神兴奋剂相关行为中发挥重要作用。首先，人类 Dbh 基因中常见的多态性是 DBH 酶活性的关键决定因素，并且似乎会影响对可卡因的行为和认知反应。抑制剂双硫仑（Antabuse）在治疗可卡因依赖方面显示出惊人的前景，但其作用机制尚不清楚。 该提案的目的是确定 DBH 活性对儿茶酚胺神经化学和可卡因相关行为（包括敏化、奖赏、厌恶和复发）的影响，并了解为什么双硫仑给药会导致可卡因依赖者戒断。这将通过结合遗传学（Dbh 敲除小鼠）和药理学（双硫仑）来实现。完成本提案中的目标将有助于我们了解去甲肾上腺素能系统和多巴胺能系统之间的相互作用如何影响药物成瘾以及双硫仑诱导的可卡因戒断机制，并将为精神兴奋剂依赖提出新的治疗方法