Epigenetic mechanimsms in cocaine reward

描述(申请人提供)：毒瘾和滥用是一个全球性的问题，对医疗保健系统和个人及其家人的生活产生巨大的压力。反复接触滥用药物会改变神经系统的功能，并产生鼓励继续使用药物的状态。这些变化发生在神经系统的多个层面，包括大脑奖励回路内的功能变化。在这个系统中，已知的一个区域在调节药物滥用的回报方面和反复药物暴露的许多动物行为后果方面具有重要作用，这就是伏隔核(NAC)。表观遗传变化在一定程度上是由IIa类组蛋白脱乙酰酶(HDAC)等酶介导的，这些酶可以在基因转录水平产生长期的经验依赖性变化，从而导致蛋白质表达的变化。IIa类HDAC此前被认为与NAC介导的药物奖励和相关行为有关。了解HDAC的调节在控制药物相关行为中的作用可以确定导致成瘾的途径。这些机制将成为未来药物治疗的目标，以治疗成瘾和改善戒毒。HDAC4是IIa类家族中的一员，此前通过其在NAC中的转录调控活动参与了与药物相关的行为。先前的研究表明，在NAC中过度表达HDAC4可以对抗可卡因的奖赏效应。当定位于细胞核时，IIa类HDAC抑制了一些基因的转录，包括那些已知对精神刺激剂反应重要的基因。当IIa类HDAC被转移到细胞质时，这种活性被扰乱。IIa类HDACs的磷酸化状态支配其核质定位，可卡因已被证明改变了密切相关的HDAC5的磷酸化和定位。目前尚不清楚可卡因如何影响HDAC4的磷酸化和定位，以及HDAC4的定位对可卡因的奖赏效应有什么影响。这项建议将确定慢性或急性可卡因给药对HDAC4亚细胞定位和磷酸化状态的影响。受这些发现的启发，将产生并表征增强特定本地化模式的HDAC4突变形式。然后，这些突变形式将与HDAC4的条件敲除一起用于探索HDAC4的表达和定位在可卡因奖励中的作用。这些实验将解决我们对HDAC4的调节、本地化和在奖励中的作用的知识差距。了解可卡因如何影响HDAC4的S定位，以及它的活性如何影响可卡因奖励，这只是一系列关于该分子在可卡因成瘾中作用的有希望的研究的开始

DESCRIPTION (provided by applicant): Drug addiction and abuse is a global problem that produces a significant strain on healthcare systems and the lives of individuals and their families. Repeated exposure to drugs of abuse alters the function of the nervous system and produce states that encourage continued drug use. These alterations occur at multiple levels of the nervous system, including functional changes within the brain's reward circuit. One region of this system known to be important in mediating the rewarding aspects of drugs of abuse and many of the animal behavioral consequences of repeated drug exposure is the Nucleus Accumbens (NAc). Epigenetic changes are mediated in part by enzymes such as class IIa histone deacetylases (HDACs) that can produce long lasting experience-dependent changes in the level of gene transcription and thusly protein expression. Class IIa HDACs have been previously implicated in drug reward and associated behaviors mediated by the NAc. Understanding the role of HDACs' regulation in the control of drug related behavior could identify pathways that contribute to addiction. These mechanisms will be future targets for pharmacotherapies to treat addiction and improve abstinence. HDAC4 is a member of the Class IIa family previously implicated in drug-related behaviors via its transcriptional regulation activty in the NAc. Previous research has shown that over-expression of HDAC4 in the NAc can oppose cocaine's rewarding effects. When localized to the nucleus, Class IIa HDACs repress the transcription of a number of genes, including those known to be important for responses to psychostimulants. This activity is disrupted when Class IIa HDACs are translocated to the cytoplasm. The phosphorylation state of Class IIa HDACs governs their nucleo-cytoplasmic localization and cocaine has been shown to alter the phosphorylation and localization of the closely related HDAC5. It is still unknown how cocaine impacts HDAC4 phosphorylation and localization and what effect HDAC4 localization has on the rewarding effects of cocaine. This proposal will identify the effect of chronic or acute cocaine administration on the subcellular localization and phosphorylation state of HDAC4. Informed by these findings, mutant forms of HDAC4 that enhance specific localization patterns will be generated and characterized. These mutant forms will then be used, along with conditional knockout of HDAC4, to probe the role of HDAC4 expression and localization on cocaine reward. These experiments will address the gap in our knowledge of the regulation, localization, and role in reward of HDAC4. Understanding how HDAC4's localization is affected by cocaine and how it's activity affects cocaine reward is only the start in a series of promising studies into the role of this molecule in cocaine addiction