Preclinical Assessment of Deep Brain Stimulation for the Treatment of Alcoholism

描述（由申请人提供）：迄今为止，开发有效的酒精中毒药物治疗方法的尝试尚未达到这一目标。酒精中毒的药理学治疗受到化合物有效性和患者使用化合物缺乏依从性的限制。最近的人体研究表明，一种神经外科手术，深部脑刺激（DBS），可以有效地减少酗酒者的饮酒量，同时进行心理治疗（如抑郁症）。神经外科治疗酒精中毒的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扩大该程序作为酒精中毒治疗的使用，提供神经解剖学信息来阐明DBS治疗效果的生物学基础，和/或允许药物和神经外科干预治疗酒精中毒的整合。本提案的总体目标是在啮齿动物中建立无线DBS治疗，确定在服用药理学上相关水平的EtOH的大鼠中，伏隔核壳（AcbSh）内DBS对酒精消耗的影响，并阐明在AcbSh和其他脑区域内DBS的生物学后果。伏隔核壳（AcbSh）是乙醇（EtOH; Engleman et al., 2009）、可卡因（Rodd et al., 2005）和其他滥用药物可产生强化作用的部位。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用于啮齿动物的无线DBS系统原型。此外，直接DBS刺激AcbSh选择性地减少了嗜酒(P)大鼠的EtOH消耗。这个项目的首要假设是；a)无线DBS系统的开发是可能的，它将为人类DBS治疗提供易于转化的技术，b) AcbSh内的DBS将有效地减少酒精消耗，寻求EtOH和EtOH复发饮酒，c) AcbSh内DBS产生的神经适应性将为开发治疗酒精中毒的药物疗法提供目标。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（目标1）。此外，该申请将检查AcbSh内DBS对P大鼠使用EtOH的多种动物模型的影响（目的2）。为了阐明DBS对EtOH消耗效果的生物学基础，将在DBS治疗后测定AcbSh内基因的表达，并在DBS治疗期间测定内侧前额叶皮层（mPFC）内神经化学水平的变化（目的3）。这是一个非常重要的项目，将为无线DBS的发展、DBS治疗酒精中毒的疗效以及DBS治疗在AcbSh内的生物学后果提供重要信息。

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.