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

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，会干扰个人的福祉， 破坏人际关系，给社会带来负担。可卡因和其他滥用药物一样，会劫持大脑的奖赏 中枢，在大脑区域产生持久的变化，如伏隔核(NAC)，这些变化持续 上瘾的循环。临床前研究表明，可卡因和其他精神刺激剂的作用一般 基因表达的增强子和NAC中的组蛋白脱乙酰酶(HDAC)在 可卡因成瘾的发展。然而，神经生物学对特定的HDAC在 这些过程是有限的，对这些靶点的体内研究也很少。为了满足这种需求， 研究表明，这一方案集成了最先进的小动物正电子发射断层扫描(PET)技术 用可卡因自我给药模型(Coc-SA)研究NAC-HDAC IIa类(HDAC5)的作用 可卡因吸食和寻找行为过程中的酶活性。活体神经成像与神经成像的结合 纵向(重复测量)设计中的行为神经科学方法提供了一个机会 进一步了解在COC-SA的4个阶段中表观遗传活动在NAC中的作用，包括 获取、维护、灭绝和恢复。我们的总体假设是可卡因会 降低NAC中HDAC IIa类蛋白的酶活性，这将具有统计学意义 解释吸食可卡因和寻找可卡因行为的增加。三个目标将检验这一假设。(1) 用PET成像和一种新型底物PET测定NAC中HDAC IIa类酶的活性 在基础和Coc-SA阶段的配基。(2)测定HDAC IIa类酶的变化和 免疫组织化学方法检测COC-SA不同时相NAC中的蛋白质靶点。(3)确定 在寻找可卡因行为中，NAC核HDAC5对IIa类HDAC酶活性的影响。 无创PET检测与行为神经科学方法相结合研究 在吸食可卡因和寻找可卡因的行为中，NAC中HDAC IIa类酶的活性提供了一种 研究成瘾各阶段的神经生物学机制的独特策略。这个 对此应用程序的拟议研究将提供翻译知识，解决理论和 在我们对表观遗传学在可卡因成瘾中的作用的理解中存在神经生物学上的差距。这 知识将有助于开发针对表观遗传调节的新型神经疗法 治疗这种毁灭性的精神疾病。

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.