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Role and regulation of class IIa HDACs in cocaine addiction

IIa 类 HDAC 在可卡因成瘾中的作用和调节

基本信息

批准号：
8575636
负责人：
Christopher W Cowan
金额：
$ 40.03万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8575636
关键词：
Acute Adult Animals Behavior Behavioral Behavioral Model Biological Assay Brain Cell Nucleus Chromatin Chronic Cocaine Cocaine Dependence Complement Complex Cyclic AMP Data Development Drug Addiction Drug abuse Drug usage Enzymes Epigenetic Process Face Future Gene Delivery Gene Expression Gene Expression Regulation Generations Goals Grant HDAC4 gene HDAC5 gene Histones Human Individual Intake Intravenous Investments Knockout Mice Measures Mediating Metric Modeling Molecular Motivation Mus Mutant Strains Mice Neurons Nuclear Nuclear Export Nuclear Import Pattern Pharmaceutical Preparations Phosphorylation Phosphorylation Site Process Protein Dephosphorylation Publishing Rattus Reagent Regulation Research Rewards Role Self Administration Series Signal Transduction Site Symptoms Techniques Testing Therapeutic Viral Viral Vector Work addiction adverse outcome cocaine exposure conditioning drug craving drug of abuse drug relapse drug seeking behavior experience human disease in vivo insight mutant new therapeutic target novel overexpression prevent public health relevance recombinant virus recombinase response therapeutic development tool

项目摘要

DESCRIPTION (provided by applicant): Identifying key molecules that modulate drug experience-induced brain reward plasticity remains an important goal of current drug abuse research. We recently identified a novel regulatory mechanism by which cocaine stimulates the transient dephosphorylation of HDAC5 at S279, which induces nuclear accumulation of this chromatin-modifying enzyme. We also find that dephosphorylation of this site is critical for HDAC5 to limit cocaine reward and to reduce cocaine-primed reinstatement of drug seeking. In addition, we find that the closely-related enzyme, HDAC4, is oppositely regulated by chronic cocaine exposure, suggesting an important role for this regulation in the development of cocaine-induced behavioral plasticity. In this grant we seek to characterize the differential regulation of HDAC4 and HDAC5 and to test the importance of this regulation for cocaine reward and drug relapse behaviors in vivo. To this end, we propose the following: Specific Aim 1: In this aim, we will characterize the differential phosphorylation of HDAC4 and HDAC5 in response to cocaine exposure, in order to better understand the potential role of this regulation for cocaine reward and drug seeking behaviors. We will use established conditions and novel reagents generated in our lab to assess phosphorylation and subcellular distribution of these HDACs. Specific Aim 2: In this aim, we will utilize viral-mediated gene delivery to express phosphorylation site mutants of HDAC4 in the mouse NAc. In addition, we will use novel floxed HDAC4 conditional KO mice and viral-mediated cre expression in the adult NAc to test the necessity of HDAC4 for limiting cocaine-induced behavioral adaptations. Specific Aim 3: In this aim, we will extend our findings that cocaine triggers transient nuclear accumulation of HDAC5 to limit cocaine reward by testing the effects of the dephosphorylated HDAC5 in the most relevant model for cocaine addiction, intravenous self-administration of cocaine. Our initial findings reveal a suppression of cocaine-prime reinstatement when the dephosphorylated form of HDAC5 is expressed. We seek to expand upon these studies to determine the effect of nuclear HDAC5 on cocaine taking and seeking, motivation to work for cocaine, and propensity to reinstate drug seeking behaviors.

描述（由申请人提供）：确定调节药物体验诱导的大脑奖励可塑性的关键分子仍然是当前药物滥用研究的重要目标。我们最近发现了一种新的调节机制，可卡因刺激HDAC 5在S279的瞬时去磷酸化，诱导这种染色质修饰酶的核积累。我们还发现，该位点的去磷酸化对于HDAC 5限制可卡因奖赏和减少可卡因引发的药物寻求的恢复至关重要。此外，我们发现，密切相关的酶，HDAC 4，是相反的调节慢性可卡因暴露，这表明一个重要的作用，这种调节可卡因诱导的行为可塑性的发展。在这项研究中，我们试图描述HDAC 4和HDAC 5的差异调节，并测试这种调节对体内可卡因奖励和药物复吸行为的重要性。为此，我们提出以下建议：具体目标1：在这个目标中，我们将描述HDAC 4和HDAC 5的差异磷酸化反应可卡因暴露，为了更好地了解这种调节可卡因奖励和药物寻求行为的潜在作用。我们将使用我们实验室中建立的条件和新试剂来评估这些HDAC的磷酸化和亚细胞分布。具体目标2：在这个目标中，我们将利用病毒介导的基因递送在小鼠NAc中表达HDAC 4的磷酸化位点突变体。此外，我们将使用新的floxed HDAC 4条件性KO小鼠和病毒介导的cre在成人NAc中的表达来测试HDAC 4限制可卡因诱导的行为适应的必要性。具体目标3：在这一目标中，我们将扩展我们的发现，即可卡因触发HDAC 5的瞬时核积累，以限制可卡因奖励，通过测试去磷酸化HDAC 5在可卡因成瘾最相关的模型中的作用，静脉内自我施用可卡因。我们的初步研究结果显示，当HDAC 5的去磷酸化形式表达时，可卡因-prime恢复受到抑制。我们试图扩展这些研究，以确定核HDAC 5对可卡因服用和寻求的影响，为可卡因工作的动机，以及恢复药物寻求行为的倾向。