Preclinical Assessment of Deep Brain Stimulation for the Treatment of Alcoholism

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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.