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：
8676763
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/8676763
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）：确定调节药物体验引起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。我们最近确定了一种新型的调节机制，可卡因在S279上刺激HDAC5的瞬时去磷酸化，从而诱导这种染色质修饰酶的核积累。我们还发现，该站点的去磷酸化对于HDAC5限制可卡因奖励并减少可卡因培养物的恢复至关重要。此外，我们发现密切相关的酶HDAC4与慢性可卡因暴露相反，这表明这种调节在可卡因诱导的行为可塑性的发展中起着重要作用。在这笔赠款中，我们试图表征HDAC4和HDAC5的差异调节，并测试该调节对可卡因奖励和体内药物复发行为的重要性。为此，我们提出以下内容：具体目标1：在此目标中，我们将表征HDAC4和HDAC5对可卡因暴露的差异磷酸化，以便更好地了解这种调节对可卡因奖励和寻求药物寻求药物的潜在作用。我们将使用实验室中生成的既定条件和新的试剂来评估这些HDAC的磷酸化和亚细胞分布。具体目标2：在此目标中，我们将利用病毒介导的基因递送来表达小鼠NAC中HDAC4的磷酸化位点突变体。此外，我们将使用新型的Floxed HDAC4条件KO小鼠和成年NAC中病毒介导的CRE表达来测试HDAC4的必要性，以限制可卡因诱导的行为适应。具体目的3：在此目标中，我们将扩展发现可卡因会触发HDAC5的短暂核积累，以限制可卡因奖励，以测试可卡因成瘾模型中去磷酸化的HDAC5在最相关的模型中的效果，静脉内自我服用可卡因。我们的最初发现表明，当表达了hDAC5的去磷酸化形式时，可卡因促销的抑制作用。我们试图扩展这些研究，以确定核HDAC5对可卡因服用和寻求可卡因的影响，为可卡因工作的动机以及恢复寻求药物行为的倾向。