Preclinical Assessment of Deep Brain Stimulation for the Treatment of Alcoholism

描述(由申请人提供)：到目前为止，开发治疗酒精中毒的有效药物疗法的尝试尚未达到这一目标。酒精中毒的药物治疗一直受到这些化合物的疗效和患者使用这些化合物的依从性的限制。最近的人类研究表明，一种名为脑深部刺激(DBS)的神经外科手术在减少酗酒者饮酒方面是有效的，并伴有心理治疗(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DBS对酒精消费影响的详细研究中获得的结果可能会增加DBS作为酒精中毒治疗程序的使用，提供神经解剖学信息来阐明DBS治疗有效性的生物学基础，和/或允许将药理学和神经外科干预结合起来治疗酒精中毒。这项建议的总体目标是在啮齿动物身上建立一种无线DBS治疗方法，确定伏隔核壳内DBS(AcbSh)对饮用药理上相关水平的乙醇的大鼠酒精消费的影响，并阐明DBS在AcbSh和其他脑区的生物学后果。伏隔核外壳(AcbSh)是乙醇(Etoh；Engeman等人，2009)、可卡因(Rodd等人，2005)和其他滥用药物可以产生增强作用的部位。AcbSh也是星展银行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用于啮齿动物的无线DBS系统原型。此外，DBS直接刺激AcbSh选择性地减少了酒精偏爱(P)大鼠的乙醇消耗量。该项目的主要假设是：a)无线DBS系统的开发将为人类DBS治疗提供容易翻译的技术，b)AcbSh内的DBS将有效地减少酒精消耗、寻求酒精和复发饮酒，以及c)由AcbSh内的DBS产生的神经适应将为治疗酒精中毒的药物疗法的开发提供靶点。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，该应用程序将检查AcbSh内的DBS对P鼠使用乙醇的多种动物模型的影响(目标2)。为了阐明DBS对乙醇消耗的疗效的生物学基础，将在DBS治疗后测定AcbSh内基因的表达，并将在DBS治疗期间测定内侧前额叶皮质(MPFC)神经化学水平的变化(目标3)。这是一个非常有意义的项目，将提供关于无线DBS的发展、DBS治疗酒精中毒的疗效以及在AcbSh内治疗DBS的生物学后果的重要信息。

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.