Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, USA.
Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
Addict Biol. 2018 Mar;23(2):653-664. doi: 10.1111/adb.12522. Epub 2017 Jun 21.
Epigenetic mechanisms have been proposed to contribute to persistent aspects of addiction-related behaviors. One family of epigenetic molecules that may regulate maladaptive behavioral changes produced by cocaine use are the histone deacetylases (HDACs)-key regulators of chromatin and gene expression. In particular, the class IIa HDACs (HDAC4, HDAC5, HDAC7 and HDAC9) respond to changes in neuronal activity by modulating their distribution between the nucleus and cytoplasm-a process controlled in large part by changes in phosphorylation of conserved residues. Cocaine triggers a transient nuclear accumulation of HDAC5 that functions to limit the development of cocaine reward behavior. However, the role and regulation of the close family member, HDAC4, in cocaine behaviors remain largely unknown. In this study, we report that cocaine and cAMP signaling in striatum produced differential phosphorylation and subcellular localization of HDAC4 and HDAC5. Unlike HDAC5, cocaine exposure induced a modest hyperphosphorylation and nuclear export of HDAC4. Genetic deletion of HDAC4 in the nucleus accumbens reduced acute cocaine-produced locomotion, maximum locomotor sensitization and cocaine reward-related behavior. Interestingly, overexpression of an HDAC4 cytoplasm-concentrated mutant (S266E) increased cocaine reward behavior in the cocaine conditioned place preference assay, suggesting that cocaine-induced nuclear export of HDAC4 might function to facilitate the development of cocaine reward behaviors through a role in the cell cytoplasm. Together, our findings suggest that, despite high sequence homology, HDAC4 and HDAC5 are oppositely regulated by cocaine-induced signaling in vivo and have distinct roles in regulating cocaine behaviors.
表观遗传机制被认为有助于成瘾相关行为的持久方面。一组可能调节可卡因使用引起的适应性行为改变的表观遗传分子是组蛋白去乙酰化酶（HDACs）-染色质和基因表达的关键调节剂。特别是，IIa 类 HDACs（HDAC4、HDAC5、HDAC7 和 HDAC9）通过调节其在核和细胞质之间的分布来响应神经元活动的变化-这一过程主要受保守残基磷酸化变化的控制。可卡因触发 HDAC5 的短暂核积累，其功能是限制可卡因奖励行为的发展。然而，近亲 HDAC4 在可卡因行为中的作用和调节仍知之甚少。在这项研究中，我们报告说，纹状体中的可卡因和 cAMP 信号转导导致 HDAC4 和 HDAC5 的磷酸化和亚细胞定位不同。与 HDAC5 不同，可卡因暴露诱导 HDAC4 适度过度磷酸化和核输出。在伏隔核中敲除 HDAC4 减少了急性可卡因引起的运动、最大运动敏化和可卡因奖赏相关行为。有趣的是，过表达 HDAC4 细胞质浓缩突变体（S266E）增加了可卡因条件性位置偏好试验中的可卡因奖赏行为，这表明可卡因诱导的 HDAC4 核输出可能通过在细胞质中的作用促进可卡因奖赏行为的发展。总之，我们的研究结果表明，尽管 HDAC4 和 HDAC5 具有高度的序列同源性，但它们在体内被可卡因诱导的信号相反调节，并且在调节可卡因行为方面具有不同的作用。
