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

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

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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奖励和压力相关的神经元电路的持久变化。该电路的重要组成部分包括尾状药物，伏隔核，杏仁核的中央核和腹侧盖区（VTA）。几项研究表明，昼夜节律的分子成分是药物奖励和与药物相关的反应中的关键参与者。 McClung等。（2005年）确定了昼夜节律输出周期Kaput（时钟）基因在药物奖励调节中的关键作用。时钟基因（时钟19只小鼠）中具有显性阴性突变的小鼠表现出可卡因的敏感性和偏好。此外，这些小鼠表现出增加的运动活性，焦虑样和抑郁症的行为降低，在较低阈值下增加颅内自我刺激（ICS），并增加了VTA中多巴胺能细胞的活性（McClung等人，2005年； Roybal等人； Roybal等； Roybal等人，2007年）。拟议的研究培训计划的目的是确定时钟在特定的大脑区域中的作用，作为乙醇相关行为的中介。首先，我们将使用原位杂交来确定如何调节大脑奖励和压力相关区域中时钟的表达水平。其次，我们将确定时钟（时钟19只小鼠）的主要负突变如何影响手术口服乙醇自我给药的度量。最后，我们将确定VTA中的时钟功能对于使用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翻译意义，因为许多康复的瘾君子表现出昼夜节律破坏，这些破坏持续恢复并有助于复发。我对在分子和行为水平进行酒精研究有浓厚的兴趣。该培训计划的目的是为我提供尖端技术和方法，数据转换为高可见性出版物的详细专业知识，并为我做好过渡到独立性的准备。我有动力，勤奋和致力于推进酒精中毒的治疗。该计划加上UTSW的优秀研究人员将使我能够获得本提案中概述的目标，并为我为酒精和药物滥用领域的成功独立研究事业做好准备。此NRSA应用程序的资金有助于我的成功。公共卫生相关性：拟议的工作将提供有关昼夜节律基因在饮酒中的作用和退出慢性暴饮暴食的作用的见解，这可能有助于增加毒品的渴望和复发。这些知识的应用可能会在药物提取期间对新的治疗策略提供见解，从而降低复发率并改善治疗结果。