Preclinical Assessment of Deep Brain Stimulation for the Treatment of Alcoholism

深部脑刺激治疗酒精中毒的临床前评估

• 批准号: 8490764
• 负责人: ZACHARY Aaron RODD
• 金额: $ 21.89万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8490764
• 关键词: Abstinence; Alcohol consumption; Alcoholism; Alcohols; Animal Model; Area; Behavior; Biological; Brain region; Cocaine; Consumption; Data; Deep Brain Stimulation; Development; Devices; Disease; Drug Addiction; Ethanol; Frequencies; Gene Expression; Goals; Human; Intervention; Laboratories; Medial; Mediating; Mental Depression; Mental disorders; Neurosurgical Procedures; Nucleus Accumbens; Pharmaceutical Preparations; Pharmacological Treatment; Prefrontal Cortex; Procedures; Property; Psychological reinforcement; Radio; Rattus; Relapse; Research; Rodent; Self Administration; Site; System; Technology; Testing; Wireless Technology; alcoholism therapy; base; clinically relevant; compliance behavior; drinking; drug of abuse; neuroadaptation; neurochemistry; novel; pre-clinical; problem drinker; prototype; psychologic; public health relevance; treatment strategy

DESCRIPTION (provided by applicant): Attempts to develop efficacious pharmacotherapeutics for the treatment of alcoholism have, to date, not obtained this goal. Pharmacological treatment for alcoholism has been limited by efficacy of the compounds and lack of compliance by patients to employ the compounds. Recent human studies have indicated that a neurosurgical procedure, deep brain stimulation (DBS), is effective at reducing alcohol consumption in alcoholics with a co-morbid psychological treatment (e.g. depression). The study of neurosurgical treatment of alcoholism is a developing area of research, and findings obtained from detailed research examining the effects of DBS on alcohol consumption could augment the use of the procedure as a treatment for alcoholism, provide neuroanatomical information to illuminate the biological bases for the efficacy of DBS treatment, and/or allow for an integration of pharmacological and neurosurgical intervention for the treatment of alcoholism. The overall objectives of this proposal are to establish a wireless DBS treatment in rodents, determine the effects of DBS within the nucleus accumbens shell (AcbSh) on alcohol consumption in rats consuming pharmacologically relevant levels of EtOH, and to elucidate the biological consequences of DBS within the AcbSh and other brain regions. The nucleus accumbens shell (AcbSh) is a site where ethanol (EtOH; Engleman et al., 2009), cocaine (Rodd et al., 2005), and other drugs of abuse can produce reinforcing effects. The AcbSh is also a target site of DBS for the treatment of psychological disorders. Preliminary data indicate that our research group has developed a prototype wireless DBS system for use in rodents. In addition, direct DBS stimulation of the AcbSh selectively reduced EtOH consumption in alcohol-preferring (P) rats. The overarching hypotheses of the project are that; a) the development of a wireless DBS system is possible which would provide readily translatable technology for human DBS treatment, b) DBS within the AcbSh will be efficacious at reducing alcohol consumption, EtOH-seeking, and EtOH relapse drinking, and c) neuroadaptations produced by DBS within the AcbSh will provide targets for the development of pharmacotherapeutics for the treatment of alcoholism. The application will further develop the highly novel and clinically relevant wireless DBS system (Aim 1). In addition, the application will examine the effects of DBS within the AcbSh on multiple animal models of EtOH use in the P rat (Aim 2). To clarify the biological basis of the efficacy of DBS on EtOH consumption, the expression of genes within the AcbSh will be determined following DBS treatment and alterations in neurochemical levels within the medial prefrontal cortex (mPFC) will be determined during DBS treatment (Aim 3). This is a highly significant project that will provide important information on the development of wireless DBS, the efficacy of DBS treatment for alcoholism, and the biological consequences of DBS treatment within the AcbSh.

描述（由申请人提供）：迄今为止，开发用于治疗酒精中毒的有效药物治疗剂的尝试尚未实现这一目标。酒精中毒的药物治疗受到化合物的功效和患者缺乏使用化合物的依从性的限制。最近的人体研究表明，神经外科手术，脑深部电刺激（DBS），是有效的减少酒精消费与共病的心理治疗（如抑郁症）。酒精中毒的神经外科治疗研究是一个发展中的研究领域，从详细研究DBS对酒精消耗的影响中获得的发现可以增加该程序作为酒精中毒治疗的使用，提供神经解剖学信息以阐明DBS治疗疗效的生物学基础，和/或允许用于治疗酒精中毒的药理学和神经外科干预的整合。本提案的总体目标是在啮齿动物中建立无线DBS治疗，确定在消耗高相关水平EtOH的大鼠中，丘脑核壳（AcbSh）内DBS对酒精消耗的影响，并阐明AcbSh和其他脑区内DBS的生物学后果。核壳（AcbSh）是乙醇（EtOH; Engleman等人，2009）、可卡因（Rodd等人，2005），而其他滥用药物也会产生强化作用。AcbSh也是DBS治疗心理障碍的靶点。初步数据表明，我们的研究小组已经开发出一种原型无线DBS系统用于啮齿动物。此外，直接DBS刺激AcbSh选择性地减少了嗜酒精（P）大鼠的EtOH消耗。该项目的主要假设是：a）无线DBS系统的开发是可能的，其将提供用于人类DBS治疗的容易转换的技术，B）AcbSh内的DBS将有效地减少酒精消耗、EtOH寻求和EtOH复发性饮酒，以及c）DBS在AcbSh内产生的神经适应性将为开发用于治疗酒精中毒的药物治疗剂提供靶点。该应用将进一步开发高度新颖和临床相关的无线DBS系统（目标1）。此外，本申请将检查AcbSh内DBS对P大鼠使用EtOH的多个动物模型的影响（目的2）。为了阐明DBS对EtOH消耗有效性的生物学基础，将在DBS治疗后确定AcbSh内的基因表达，并在DBS治疗期间确定内侧前额叶皮质（mPFC）内神经化学水平的变化（目标3）。这是一个非常重要的项目，将提供有关无线DBS开发、DBS治疗酒精中毒的疗效以及AcbSh内DBS治疗的生物学后果的重要信息。