The Role of CLOCK in Ethanol-Related Behaviors

时钟在乙醇相关行为中的作用

基本信息

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
项目类别：
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

项目摘要

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与奖励和压力相关的神经元回路发生长期持续的变化。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)。几项研究表明，生物钟的分子成分在药物奖励和药物相关反应中发挥着关键作用。麦克隆等人。 (2005) 确定了昼夜节律运动输出周期 kaput (CLOCK) 基因在药物奖赏调节中的关键作用。 CLOCK 基因显性失活突变的小鼠（CLOCK 19 小鼠）表现出更高的可卡因敏感性和偏好。此外，这些小鼠表现出增强的运动活性、减少的焦虑样和抑郁样行为、在较低阈值下增加的颅内自我刺激（ICSS）以及VTA中的多巴胺能细胞活性增加（McClung等人，2005；Roybal等人）等，2007）。拟议的研究培训计划的目标是确定时钟在特定大脑区域中作为乙醇相关行为中介的作用。首先，我们将利用原位杂交技术确定长期酗酒如何调节大脑奖励和压力相关区域中 CLOCK 的表达水平。其次，我们将确定 CLOCK（CLOCK 19 小鼠）的显性失活突变如何影响操作性口服乙醇自我给药的测量。最后，我们将确定 VTA 中的 CLOCK 功能对于使用 RNAi 调节乙醇摄入和复发样饮酒行为是否重要。进一步检查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，因为许多正在康复的成瘾者表现出昼夜节律紊乱，这种紊乱在恢复过程中持续存在并导致复发。我对在分子和行为水平上进行酒精研究有着浓厚的兴趣。该培训计划的目标是为我提供使用尖端技术和方法、将数据转换为高知名度出版物的详细专业知识，并为我向独立过渡做好准备。我积极主动、勤奋并致力于推进酗酒的治疗。该计划与 UTSW 优秀的研究人员团队相结合，将使我能够实现本提案中概述的目标，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。 NRSA 申请的资助对我的成功起到了重要作用。公共健康相关性：拟议的工作将深入了解昼夜节律基因在饮酒和戒断慢性酗酒中的作用，这可能会导致药物渴望增加和复发。应用这些知识可以为停药期间的新治疗策略提供见解，从而降低复发率并改善治疗结果。