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Synapsin 3: Involvement in Impulsivity and Drug Self-Administration

Synapsin 3：参与冲动和药物自我管理

基本信息

批准号：
8867197
负责人：
J. DAVID JENTSCH
金额：
$ 18.15万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2016-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8867197
关键词：
Alcohols Animal Model Architecture Behavior Behavioral Biological Biological Assay Biological Markers Brain Brain region Breeding Candidate Disease Gene Cells Chromosomes, Human, Pair 10 Cocaine Decision Making Dependence Dimensions Dopamine Dopamine D2 Receptor Down-Regulation Drug Addiction Drug Controls Drug abuse Drug usage Event Exhibits Exposure to Functional disorder Future Genes Genetic Genetic Recombination Genomics Health Human Impairment Impulsive Behavior Impulsivity Inbred Mouse Intravenous Lead Link Maps Measures Mediating Mind Modeling Molecular Analysis Molecular Genetics Mouse Strains Mus Nerve Nervous system structure Persons Pharmaceutical Preparations Phenotype Phosphoproteins Play Predisposition Presynaptic Terminals Prevention Prevention trial Procedures Psychopathology Publishing Quantitative Trait Loci Receptor Signaling Reporting Resolution Reversal Learning Rewards Risk Role Scanning Self Administration Series Signal Transduction Staging Substance Use Disorder Synapses Synapsin III Synapsins Testing Transgenic Mice Vesicle Withholding Treatment Work addiction alcohol use disorder base cognitive function cost dopaminergic neuron drug of abuse endophenotype executive function genome-wide linkage high risk interest neurochemistry neuromechanism neurotransmission novel receptor receptor binding response risk variant social trait transmission process

项目摘要

DESCRIPTION (provided by applicant): Difficulty suppressing or inhibiting pre-potent behaviors (one dimension of 'impulsivity' or impulsive behaviors) has been associated with elevated risk for drug and alcohol use disorders in humans and with heightened drug self-administration phenotypes in animal models. Recent work indicates that impulsive behaviors are linked to changes in dopamine D2 receptor- sensitive corticostriatal networks and that both are under the influence of as-of-yet unknown genetic mechanisms. We have used a genome-wide linkage approach in inbred mice to identify novel gene modulators of impulsivity, and we identified syn3, which encodes synapsin III, as a very high priority candidate gene. Subsequent to our published study, it was shown that syn3 controls the amplitude of dopamine release events, presumably through its localization and functions in dopaminergic nerve terminals. Based upon all this information, we now test the novel and high-risk hypothesis that syn3 expression within dopaminergic neurons influences: 1) dopamine release, 2) expression of post-synaptic D2-like receptors, 3) inhibitory control and 4) drug self-administration. Using a newly available conditional model that allows for brain-wide or dopamine neuron-specific deletion of syn3, we seek to experimentally test the role for this gene in these varied phenotypes, in turn establishing its key role in regulating a series of biological and behavioral endophenotypes for addiction. These high-risk studies offer an opportunity to establish the significance of a novel candidate risk gene for addictions, supporting more systematic multi-level studies in humans and animal models regarding synapsin III and its link to drug abuse susceptibility. These studies will also set the stage for in depth, mechanistic studies aimed at understanding how altered dopaminergic transmission causally influences impulse control and drug self-administration.

描述(由申请人提供)：抑制或抑制强效行为(冲动或冲动行为的一个维度)的困难与人类药物和酒精使用障碍的风险增加以及动物模型中药物自我给药表型的增加有关。最近的工作表明，冲动行为与多巴胺D2受体敏感的皮质纹状体网络的变化有关，两者都受到迄今尚不清楚的遗传机制的影响。我们已经在近交系小鼠中使用了全基因组连锁的方法来识别新的冲动基因调节器，我们发现编码突触素III的syn3是一个非常优先的候选基因。在我们发表的研究之后，我们发现Syn3可能通过其在多巴胺能神经末梢的定位和功能来控制多巴胺释放事件的幅度。基于所有这些信息，我们现在测试新的高风险假说，即在多巴胺能神经元中Syn3的表达影响：1)多巴胺释放，2)突触后D2样受体的表达，3)抑制控制和4)药物自身给药。使用一个新的条件模型，允许全脑或多巴胺神经元特异性缺失syn3，我们试图通过实验测试该基因在这些不同表型中的作用，进而确定它在调节一系列成瘾的生物和行为内表型中的关键作用。这些高风险研究为确定一种新的成瘾候选风险基因的重要性提供了机会，支持了在人类和动物模型中关于突触素III及其与药物滥用易感性的联系的更系统的多水平研究。这些研究还将为深入的、旨在了解多巴胺能传递变化如何影响冲动控制和药物自我给药的机制研究奠定基础。