CREST in the Nucleus Accumbens Core Regulates Cocaine Conditioned Place Preference, Cocaine-Seeking Behavior, and Synaptic Plasticity
CREST in the Nucleus Accumbens Core Regulates Cocaine Conditioned Place Preference, Cocaine-Seeking Behavior, and Synaptic Plasticity
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DOI：
10.1523/jneurosci.2911-17.2018
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发表时间：
2018-10-31
影响因子：
5.3
通讯作者：
Wood, Marcelo A.
中科院分区：
文献类型：
--
作者：
Alaghband, Yasaman;Kramar, Eniko;Wood, Marcelo A.
表观遗传机制导致细胞水平上的持续变化，从而导致长期的行为适应。核小体重塑是一种主要的表观遗传机制，但在药物寻求行为方面尚未得到很好的探讨。核小体重塑是由与DNA或染色质结构相互作用的多亚基复合物完成的，这些复合物具有atp依赖的酶来破坏核小体与DNA的接触并最终调节基因表达。钙反应性反激活因子（CREST）是一种转录激活因子，可与组蛋白乙酰化和核小体重塑相关的酶相互作用。本研究研究了敲除伏隔核（NAc）核心CREST对雄性小鼠和雄性大鼠的觅药行为和突触可塑性的影响。抑制NAc核心的CREST可导致可卡因诱导的条件位置偏好（CPP）和theta诱导的NAc核心的长期增强功能受损。此外，与CPP研究结果相似，通过自我给药过程，我们发现雄性大鼠NAc核心的CREST下调对可卡因本身在一级时间表上的工具反应没有影响，但在二级链时间表上的反应显著减弱，其中反应与可卡因的关联较弱。综上所述，这些结果表明，可卡因诱导的CPP、突触可塑性以及可卡因寻求行为都需要NAc核心的CREST。
Epigenetic mechanisms result in persistent changes at the cellular level that can lead to long-lasting behavioral adaptations. Nucleosome remodeling is a major epigenetic mechanism that has not been well explored with regards to drug-seeking behaviors. Nucleosome remodeling is performed by multi-subunit complexes that interact with DNA or chromatin structure and possess an ATP-dependent enzyme to disrupt nucleosome-DNA contacts and ultimately regulate gene expression. Calcium responsive transactivator (CREST) is a transcriptional activator that interacts with enzymes involved in both histone acetylation and nucleosome remodeling. Here, we examined the effects of knocking down CREST in the nucleus accumbens (NAc) core on drug-seeking behavior and synaptic plasticity in male mice as well as drug-seeking in male rats. Knocking down CREST in the NAc core results in impaired cocaine-induced conditioned place preference (CPP) as well as theta-induced long-term potentiation in the NAc core. Further, similar to the CPP findings, using a self-administration procedure, we found that CREST knockdown in the NAc core of male rats had no effect on instrumental responding for cocaine itself on a first-order schedule, but did significantly attenuate responding on a second-order chain schedule, in which responding has a weaker association with cocaine. Together, these results suggest that CREST in the NAc core is required for cocaine-induced CPP, synaptic plasticity, as well as cocaine-seeking behavior.