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）：迄今为止还没有实现这一目标，试图开发有效的药物治疗酗酒的药物治疗。酒精中毒的药理学治疗受到化合物的功效和患者缺乏使用这些化合物的依从性的限制。最近的人类研究表明，神经外科手术，深脑刺激（DBS）可有效减少与心理治疗（例如抑郁症）的酒精中毒的饮酒。对酒精中毒的神经外科治疗的研究是一个正在发展的研究领域，从检查DBS对酒精消耗的影响获得的发现可能会增加该程序作为酒精中毒的治疗方法，从而提供神经解剖学信息，以照亮神经解剖学，以使生物学基础对DBS治疗，或者允许对酒精饮料的综合治疗疗法进行治疗。该提案的总体目标是在啮齿动物中建立无线DBS处理，确定DBS伏伏核壳中DBS（ACBSH）对消耗ETOH的药理相关水平的大鼠饮酒的影响，并阐明ACBSH和其他大脑区域内DBS的生物学后果。伏隔核壳（ACBSH）是乙醇（Etoh; Engleman等，2009），可卡因（Rodd等，2005）的部位，其他滥用药物可以产生增强作用。 ACBSH也是用于治疗心理疾病的DBS的目标部位。初步数据表明，我们的研究小组已经开发了一种用于啮齿动物的原型无线DBS系统。此外，直接对ACBSH的直接DBS刺激有选择地降低了饮酒的大鼠（P）大鼠的ETOH消耗。该项目的总体假设是； a）可以开发无线DBS系统，可以为人类DBS处理提供容易翻译的技术，b）ACBSH内的DBS将有效地减少饮酒，寻求EtOH，寻求ETOH，ETOH复发饮酒，以及C）DBS在ACBSH中产生的DBS神经适应性，为ACBSH内的靶标提供了药物治疗的靶标，可以为酒精饮料提供了治疗。该应用程序将进一步开发高度新颖和临床相关的无线DBS系统（AIM 1）。此外，该应用将检查ACBSH中DBS对P大鼠多种动物使用的多种动物模型的影响（AIM 2）。为了阐明DBS对ETOH消耗的疗效的生物学基础，将在DBS治疗后确定ACBSH中基因的表达，并在DBS治疗期间确定内侧前额叶皮层（MPFC）内神经化学水平的改变（AIM 3）。这是一个非常重要的项目，它将提供有关无线DBS开发的重要信息，DBS治疗对酒精中毒的疗效以及ACBSH中DBS治疗的生物学后果。