Epigenetic mechanimsms in cocaine reward

药物成瘾和滥用是一个全球性问题，对医疗保健系统和个人及其家庭的生活产生重大压力。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。已知该系统的一个区域在介导药物滥用的奖励方面和重复药物暴露的许多动物行为后果中是重要的，该区域是伏隔核（NAc）。表观遗传变化部分由酶如IIa类组蛋白脱乙酰酶（HDAC）介导，其可以在基因转录水平中产生长期持续的经验依赖性变化，从而产生蛋白质表达。IIa类HDAC先前已涉及NAc介导的药物奖励和相关行为。了解HDAC在控制药物相关行为中的作用可以确定导致成瘾的途径。这些机制将是未来药物治疗成瘾和改善戒断的目标。HDAC4是IIa类家族的成员，以前通过其在NAc中的转录调节活性参与药物相关行为。先前的研究表明，NAc中HDAC4的过度表达可以对抗可卡因的奖励作用。当定位于细胞核时，IIa类HDAC抑制许多基因的转录，包括已知对精神兴奋剂反应重要的基因。当IIa类HDAC易位到细胞质时，这种活性被破坏。IIa类HDAC的磷酸化状态控制其核质定位，并且可卡因已显示改变密切相关的HDAC 5的磷酸化和定位。可卡因如何影响HDAC4磷酸化和定位以及HDAC4定位对可卡因的奖励作用有什么影响仍然是未知的。该提案将确定慢性或急性可卡因给药对HDAC4的亚细胞定位和磷酸化状态的影响。根据这些发现，将产生和表征增强特定定位模式的HDAC4突变形式。这些突变体形式然后将与HDAC 4的条件性敲除一起沿着用于探测HDAC 4表达和定位对可卡因奖赏的作用。这些实验将解决我们对HDAC 4的调节、定位和奖励作用的知识中的差距。了解HDAC4的定位如何受到可卡因的影响，以及它的活性如何影响可卡因的奖励，只是一系列关于这种分子在可卡因成瘾中的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