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

项目概要/摘要 可卡因成瘾是一种使人衰弱的精神健康障碍，会干扰个人的健康， 破坏人际关系，给社会带来负担。可卡因与其他滥用药物一样，会劫持大脑的奖励 中心，在大脑区域产生持久的变化，例如伏隔核（NAc），使 成瘾的循环。临床前研究表明，可卡因和其他精神兴奋剂的作用与一般药物相同。 NAc 中的组蛋白脱乙酰酶 (HDAC) 在基因表达增强子中发挥着关键作用 可卡因成瘾的发展。然而，神经生物学对特定 HDAC 的作用的理解 这些过程是有限的，并且对这些目标的体内研究很少。为了响应这样的需要 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期间的酶活性。体内神经影像学与 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 加深对 coc-SA 4 个阶段中 NAc 表观遗传活性作用的理解，包括 获取、维持、消灭和恢复。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，这将在统计上 解释可卡因吸食和寻求行为的增加。三个目标将检验这一假设。 (1) 使用 PET 成像和新型基于底物的 PET 确定 NAc 中的 HDAC IIa 酶活性 基线和 coc-SA 阶段的配体。 (2) 测定HDAC IIa类酶的变化， 使用免疫组织化学分析 coc-SA 不同阶段的 NAc 中的蛋白质靶标。 (3) 确定 NAc 中的核 HDAC5 对可卡因寻找行为期间 IIa 类 HDAC 酶活性的影响。 将非侵入性 PET 检测与行为神经科学方法相结合，研究 在可卡因吸食和寻求行为期间，NAc 中的 HDAC IIa 类酶活性提供了 研究成瘾阶段背后的神经生物学机制的独特策略。的 该应用程序的拟议研究将提供解决理论和问题的转化知识 我们对表观遗传学在可卡因成瘾中的作用的理解存在神经生物学差距。这个 知识将有助于开发针对表观遗传调节因子的新型神经疗法 并治疗这种毁灭性的心理健康障碍。

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.