The Role of CLOCK in Ethanol-Related Behaviors

时钟在乙醇相关行为中的作用

• 批准号: 8129251
• 负责人: Angela Renee Ozburn
• 金额: $ 5.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8129251
• 关键词: Affect; Alcohol abuse; Alcohol consumption; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Anxiety; Behavior; Behavioral; Brain; Brain region; Breeding; Cell Nucleus; Chronic; Circadian Rhythms; Cocaine; Consumption; Data; Dominant-Negative Mutation; Dopaminergic Cell; Dose; Drug abuse; Ethanol; Exhibits; Exposure to; Extinction (Psychology); Feedback; Funding; Gene Expression; Genes; Goals; Hormonal; Hour; In Situ Hybridization; Incentives; Knowledge; Measures; Mediator of activation protein; Mental Depression; Molecular; Motivation; Motor Activity; Mus; National Research Service Awards; Nucleus Accumbens; Oral; Output; Pattern; Pharmaceutical Preparations; Phenotype; Physiology; Publications; RNA Interference; Recovery; Regulation; Relapse; Research; Research Personnel; Research Training; Rewards; Role; Self Administration; Self Stimulation; Stress; Techniques; Testing; Tissues; Training; Treatment outcome; Ventral Tegmental Area; Wild Type Mouse; Withdrawal; Work; alcohol abuse therapy; alcohol behavior; alcohol effect; alcohol relapse; alcohol research; alcohol reward; alcohol seeking behavior; alcoholism therapy; base; binge drinking; career; chronic alcohol ingestion; circadian pacemaker; cohort; craving; deprivation; drinking behavior; drug craving; drug of abuse; drug relapse; drug reward; drug withdrawal; improved; insight; interest; knock-down; neuronal circuitry; preference; putamen; response; small hairpin RNA; success; suprachiasmatic nucleus; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): Repeated exposure to drugs of abuse leads to long lasting changes in reward- and stress-related neuronal circuitry. Important components of this circuitry include the caudate-putamen, nucleus accumbens, central nucleus of the amygdala, and the ventral tegmental area (VTA). Several studies have suggested a role for molecular components of the circadian clock as key players in drug reward and drug-associated responses. McClung et al. (2005) identified a key role for the circadian locomotor output cycles kaput (CLOCK) gene in the regulation of drug reward. Mice bearing a dominant negative mutation in the CLOCK gene (CLOCK 19 mice) exhibit increased cocaine sensitivity and preference. Furthermore, these mice exhibit increased locomotor activity, reduced anxiety-like and depression-like behavior, increased intracranial self-stimulation (ICSS) at a lower threshold, and increased dopaminergic cell activity in the VTA (McClung et al., 2005; Roybal et al., 2007). The goal of the proposed research training plan is to identify the role of CLOCK in specific brain regions as a mediator of ethanol-related behavior. First, we will determine how chronic binge ethanol consumption regulates expression levels of CLOCK in reward- and stress-related regions of the brain using in situ hybridization. Second, we will determine how a dominant negative mutation of CLOCK (CLOCK 19 mice) affects measures of operant oral ethanol self-administration. Finally, we will determine if CLOCK function in the VTA is important in modulating ethanol intake and relapse-like drinking behavior using RNAi. Further examination of the role of circadian genes in alcohol-related behaviors will have exciting translational significance for treatment, as many recovering addicts exhibit circadian disruptions that persist in recovery and contribute to relapse. I have a strong interest to perform alcohol research at the molecular and behavioral levels. The goal of this training plan is to provide me with detailed expertise in the use of cutting edge techniques and approaches, conversion of data into high-visibility publications, and prepare me for a transition to independence. I am motivated, diligent, and dedicated to advancing the treatment of alcoholism. This plan, combined with the excellent group of researchers at UTSW will allow me to obtain my goals outlined in this proposal, as well as prepare me for a successful independent research career in the alcohol and drug abuse field. The funding of this NRSA application is instrumental in my success. PUBLIC HEALTH RELEVANCE: The proposed work will provide insights into the role of circadian genes in alcohol consumption and withdrawal from chronic binge-drinking, which may contribute to increased drug craving and relapse. Application of this knowledge may provide insights into new treatment strategies during drug withdrawal thereby decreasing the relapse rate and improving treatment outcomes.

描述（由申请人提供）：反复接触滥用药物会导致奖赏和压力相关神经回路的长期变化。该回路的重要组成部分包括尾壳核、伏隔核、杏仁核中央核和腹侧被盖区（VTA）。一些研究表明，生物钟的分子成分在药物奖励和药物相关反应中起着关键作用。McClung等人（2005）确定了昼夜运动输出周期（CLOCK）基因在药物奖励调节中的关键作用。携带CLOCK基因显性负突变的小鼠（CLOCK 19小鼠）表现出增加的可卡因敏感性和偏好。此外，这些小鼠表现出运动活动增加，焦虑和抑郁样行为减少，低阈值下颅内自我刺激（ICSS）增加，VTA多巴胺能细胞活性增加（McClung et al., 2005; Roybal et al., 2007）。提出的研究训练计划的目标是确定时钟在特定大脑区域作为酒精相关行为的中介的作用。首先，我们将利用原位杂交技术确定慢性酒精暴饮如何调节大脑奖励和压力相关区域的CLOCK表达水平。其次，我们将确定CLOCK （CLOCK 19小鼠）的显性负突变如何影响操作性口服乙醇自我给药的测量。最后，我们将利用RNAi确定VTA中的CLOCK功能在调节乙醇摄入量和复发样饮酒行为中是否重要。进一步研究昼夜节律基因在酒精相关行为中的作用将对治疗具有令人兴奋的转化意义，因为许多康复中的成瘾者表现出在康复过程中持续存在的昼夜节律中断，并导致复发。我对在分子和行为水平上进行酒精研究有浓厚的兴趣。这个培训计划的目标是为我提供使用尖端技术和方法的详细专业知识，将数据转化为高知名度的出版物，并为我向独立过渡做好准备。我有上进心，勤奋，致力于推动酒精中毒的治疗。这个计划，加上UTSW优秀的研究团队，将使我能够实现我在提案中概述的目标，并为我在酒精和药物滥用领域成功的独立研究生涯做好准备。这次NRSA申请的资助对我的成功起了重要作用。