Mechanism of Disulfiram-Induced Cocaine Abstinence

双硫仑诱导可卡因戒断的机制

• 批准号: 7587415
• 负责人: DAVID WEINSHENKER
• 金额: $ 32.62万
• 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 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7587415
• 关键词: Abstinence; Affinity; Alleles; Animal Model; Animals; Area; Attenuated; Behavior; Behavioral; Binding; Brain; Catecholamines; Cells; Cocaine; Cocaine Dependence; Corpus striatum structure; Data; Development; Disulfiram; Dopamine; Dopamine D2 Receptor; Drug Addiction; Drug Psychoses; Employee Strikes; Enzymes; Equilibrium; Extinction (Psychology); Genes; Genetic; Genetic Polymorphism; Genotype; Human; Intake; Knockout Mice; Lead; Maintenance; Mediating; Microdialysis; Mixed Function Oxygenases; Modeling; Mus; Neurons; Norepinephrine; Pathway interactions; Pharmacology; Phenotype; Play; Production; Property; Psychostimulant dependence; Rattus; Relapse; Research; Rewards; Rodent; Role; Self Administration; Signal Transduction; System; Testing; behavior influence; drug craving; drug of abuse; effective therapy; improved; in vivo; inhibitor/antagonist; mesolimbic system; neurochemistry; noradrenergic; novel; pre-clinical; preference; psychostimulant; radioligand; response

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.

中脑边缘多巴胺(DA)系统主要参与了 滥用药物。虽然这条通路和DA信号是这一领域大多数研究的焦点，但它也是 明确去甲肾上腺素(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滥用药物的神经化学和行为反应。这种酶 多巴胺(3-羟基酶，DBH)在去甲肾上腺素的细胞中将DA转化为NE，从而控制 去甲肾上腺素和多巴胺在大脑中。人类的遗传和药理学数据支持了 DBH在调节精神刺激剂相关行为中的作用首先，人类Dbh基因的一种常见的多态 基因是胸径酶活性的关键决定因素，并似乎影响行为和认知 对可卡因的反应。其次，DBH抑制剂双硫兰(Antabuse)已显示出作为一种 治疗可卡因依赖，但其作用机制尚不清楚。 这项建议的目的是确定DBH活性对儿茶酚胺的影响 神经化学和可卡因相关行为，包括敏感化、奖赏、厌恶和复发，以及 了解为什么服用双硫兰会导致依赖人类的可卡因戒断。这将是 通过结合使用遗传学(DBH基因敲除小鼠)和药理学(双硫兰)来完成。 完成这一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对药物成瘾的影响及双硫仑的作用机制 诱导可卡因戒断，并将为精神刺激性依赖提供新的治疗方法。

项目成果

Genetic or pharmacological blockade of noradrenaline synthesis enhances the neurochemical, behavioral, and neurotoxic effects of methamphetamine.

去甲肾上腺素合成的遗传或药理学阻断会增强甲基苯丙胺的神经化学、行为和神经毒性作用。

• DOI: 10.1111/j.1471-4159.2007.05145.x
• 发表时间: 2008
• 期刊: Journal of neurochemistry
• 影响因子: 4.7
• 作者: Weinshenker,David;Ferrucci,Michela;Busceti,CarlaL;Biagioni,Francesca;Lazzeri,Gloria;Liles,LCameron;Lenzi,Paola;Pasquali,Livia;Murri,Luigi;Paparelli,Antonio;Fornai,Francesco
• 通讯作者: Fornai,Francesco