Effects of cocaine taking and seeking on histone deacetylase class IIa enzyme activity in the nucleus accumbens of rats

可卡因吸食和寻找对大鼠伏隔核组蛋白脱乙酰酶 IIa 类酶活性的影响

• 批准号: 9308482
• 负责人: Shane Alan Perrine
• 金额: $ 59.04万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9308482
• 关键词: Address; Adult; American; Animal Model; Animals; Autopsy; Autoradiography; Behavior; Behavior Control; Behavioral; Biological Assay; Brain; Brain imaging; Brain region; Cell Nucleus; Cells; Characteristics; Chromatin; Chronic; Cleaved cell; Cocaine; Cocaine Abuse; Cocaine Dependence; Complement; Country; Cues; Data; Development; Disease; Enhancers; Enzymes; Epigenetic Process; Extinction (Psychology); Family; Family Relationship; Female; Friends; Gene Expression; Gene Expression Regulation; Gene Targeting; Genetic; HDAC3 gene; HDAC4 gene; Healthcare Systems; Histone Deacetylase; Histones; Image; Imaging Techniques; Immunohistochemistry; Individual; K-18 conjugate; Knowledge; Ligands; Maintenance; Measures; Mediating; Mental Health; Mental disorders; Methods; Modeling; Molecular; Neurobiology; Neurons; Neurosciences; Nuclear; Nucleus Accumbens; Pharmaceutical Preparations; Phase; Plague; Play; Positron-Emission Tomography; Process; Proteins; Rattus; Regulation; Rewards; Role; SECTM1 gene; Sampling; Self Administration; Signal Transduction; Slice; Societies; Stimulus; System; Techniques; Testing; Time; Transcription Repressor/Corepressor; Transferase; United States; Viral; X-Ray Computed Tomography; addiction; base; cocaine use; cohort; design; drug of abuse; enzyme activity; in vivo; insight; longitudinal design; longitudinal positron emission tomography; male; motivated behavior; multimodality; mutant; neurobiological mechanism; neuroimaging; novel; novel therapeutics; overexpression; preclinical study; psychostimulant; public health relevance; radiotracer; response; vector control

Project Summary / Abstract Cocaine addiction is a debilitating mental health disorder that interferes with an individual’s well-being, disrupts relationships, and burdens society. Cocaine, like other drugs of abuse, hijacks the brain’s reward center, producing enduring changes in brain regions, such as the nucleus accumbens (NAc), that perpetuate the cycle of addiction. Preclinical studies show that cocaine and other psychostimulants act as general enhancers of gene expression and that histone deacetylases (HDACs) in the NAc play a key role in the development of cocaine addiction. However, neurobiological understanding of the role of specific HDACs in these processes is limited and there are few in vivo studies on these targets. In response to the need for such studies, this proposal integrates state-of-the-art small animal positron emission tomography (PET) techniques with a model of cocaine self-administration (coc-SA) to study the role of NAc HDAC Class IIa (HDAC5) enzymatic activity during cocaine taking and seeking behaviors. The combination of in vivo neuroimaging and behavioral neuroscience methods in a longitudinal (repeated-measures) design presents an opportunity to advance understanding of the role of epigenetic activity in the NAc during the 4 phases of coc-SA, including acquisition, maintenance, extinction, and reinstatement. Our overall hypothesis is that cocaine will decrease the enzymatic activity of HDAC Class IIa proteins in the NAc, which will statistically explain increases in cocaine taking and seeking behaviors. Three aims will test this hypothesis. (1) Determine HDAC Class IIa enzymatic activity in the NAc using PET imaging and a novel substrate-based PET ligand at baseline and during the phases of coc-SA. (2) Determine the changes in HDAC Class IIa enzymes and protein targets in the NAc at the different phases of coc-SA using immunohistochemistry. (3) Determine the effect of nuclear HDAC5 in the NAc on class IIa HDAC enzymatic activity during cocaine seeking behavior. The combination of non-invasive PET assays with behavioral neuroscience methods to study the role of HDAC Class IIa enzyme activity in the NAc during cocaine taking and seeking behaviors provides a unique strategy to study the neurobiological mechanisms that underlie the stages of addiction. The proposed studies of this application will deliver translational knowledge that addresses theoretical and neurobiological gaps in our understanding of the role of epigenetics in cocaine addiction. This knowledge will aid in the development of novel neurotherapeutics that target epigenetic regulators and treat this devastating mental health disorder.

项目摘要 /摘要 可卡因成瘾是一种使人衰弱的心理健康障碍，会干扰个人的幸福感， 破坏人际关系，伯恩斯社会。与其他滥用药物一样，可卡因劫持了大脑的奖励 中心，产生脑区域的持久变化，例如伏隔核（NAC），使人永存 成瘾的循环。临床前研究表明，可卡因和其他心理刺激物作为一般起作用 NAC中基因表达的增强子和组蛋白脱乙酰基酶（HDAC）在 可卡因成瘾的发展。但是，神经生物学对特定HDAC在 这些过程受到限制，对这些靶标的体内研究很少。应对这种需求 研究，该提案整合了最先进的小动物正电子发射断层扫描（PET）技术 使用可卡因自我管理模型（COC-SA）研究NAC HDAC IIA（HDAC5）的作用 可卡因服用和寻求行为期间的酶促活性。体内神经影像和 纵向（重复测量）设计中的行为神经科学方法提供了机会 在COC-SA的4个阶段，包括 获取，维护，扩展和恢复原状。我们的总体假设是可卡因将 减少NAC中HDAC IIA类蛋白的酶活性，这将在统计上 解释可卡因采取和寻求行为的增加。三个目标将检验这一假设。 （1） 使用PET成像和新型的底物PET确定NAC中HDAC类IIA酶活性 基线和COC-SA期间的配体。 （2）确定HDAC类IIA酶的变化和 使用免疫组织化学，NAC中NAC的蛋白质靶标在COC-SA的不同阶段。 （3）确定 NAC中核HDAC5对可卡因寻求行为期间IIA HDAC酶活性的影响。 非侵入性宠物分析与行为神经科学方法的结合，以研究的作用 可卡因服用和寻求行为期间NAC中NAC中的HDAC类IIA酶活性提供了 研究成瘾阶段的神经生物学机制的独特策略。 对该应用的拟议研究将提供转化知识，以解决理论和 神经生物学差距在我们对表观遗传学在可卡因成瘾中的作用的理解中。这 知识将有助于开发针对表观遗传调节剂的新型神经疗法 并治疗这种毁灭性的心理健康障碍。