Mechanism of Disulfiram-Induced Cocaine Abstinence

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强化作用有关。虽然这一途径和DA信号通路是这一领域研究的重点，但也清楚的是，去甲肾上腺素(NE)通过与多巴胺能系统的相互作用，在调节动物模型对药物滥用的神经化学和行为反应中发挥着重要作用。多巴胺(Beta-羟基酶，DBH)酶在去甲肾上腺素的细胞中将DA转化为NE，从而控制大脑中NE和DA的丰度。人类的遗传和药理学数据支持DBH在调节精神刺激剂相关行为方面的重要作用。首先，人类DBH基因的一个常见多态是DBH酶活性的关键决定因素，似乎影响对可卡因的行为和认知反应。其次，DBH抑制剂双硫兰(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。 这项建议的目的是确定DBH活性对儿茶酚胺神经化学和可卡因相关行为的影响，包括敏化、奖赏、厌恶和复发，并了解为什么双硫仑给药会导致依赖人类的可卡因戒断。这将通过结合遗传学(DBH基因敲除小鼠)和药理学(双硫兰)来实现。完成这项提案中的目标将有助于我们理解去甲肾上腺素和多巴胺能系统之间的相互作用如何影响药物成瘾和双硫仑诱导的可卡因戒断的机制，并将为精神刺激性依赖提供新的治疗方法。

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