Mechanism of Disulfiram-Induced Cocaine Abstinence

中脑边缘多巴胺（DA）系统主要涉及以下增强效应： 滥用药物。虽然这一途径和DA信号是这一领域大多数研究的焦点，但它也是 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 在动物模型中调节对药物滥用的神经化学和行为反应。酶 多巴胺β-羟化酶（DBH）在去甲肾上腺素能细胞中将DA转化为NE，从而控制多巴胺β-羟化酶的丰度。 NE和DA都在大脑中。人类的遗传和药理学数据支持以下方面的重要作用： DBH在调节精神兴奋剂相关行为中的作用首先，人类Dbh中的常见多态性 基因是DBH酶活性的关键决定因素，并且似乎影响行为和认知 对可卡因的反应第二，DBH抑制剂双硫仑（Antabuse）已显示出惊人的前景， 治疗可卡因依赖，但其作用机制尚不清楚。 本建议的目的是确定DBH活性对儿茶酚胺的影响 神经化学和可卡因相关行为，包括敏化，奖励，厌恶和复发，以及 理解为什么双硫仑给药会导致依赖者戒除可卡因。这将是 通过使用遗传学（Dbh敲除小鼠）和药理学（双硫仑）的组合来完成。 完成本提案中的目标将有助于我们理解 去甲肾上腺素能和多巴胺能系统影响药物成瘾和双硫仑的机制- 诱导可卡因戒断，并将提出新的治疗精神兴奋剂依赖。

The mesolimbic dopamine (DA) system has been primarily implicated in the reinforcing effects of drugs of abuse. While this pathwayand 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 (3-hydroxylase(DBH) converts DA to NE in noradrenegic cells, thus controlling the abundanceof 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 humanDbh gene is a critical determinant of DBH enzymatic activity and appears to influence behavioral andcognitive 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 DBHactivity 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 proposalwill contribute to our understanding of how the interaction between noradrenergic and dopaminergic systemsinfluences drug addiction and the mechanism of disulfiram- induced cocaine abstinence, and will suggest novel treatments for psychostimulant dependence.