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首页> 外文期刊>Neurobiology of disease >CREB phosphorylation regulates striatal transcriptional responses in the self-administration model of methamphetamine addiction in the rat
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CREB phosphorylation regulates striatal transcriptional responses in the self-administration model of methamphetamine addiction in the rat

机译：CREB磷酸化调节大鼠甲基苯丙胺成瘾自我给药模型中的纹状体转录反应

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Neuroplastic changes in the dorsal striatum participate in the transition from casual to habitual drug use and might play a critical role in the development of methamphetamine (METH) addiction. We examined the influence of METH self-administration on gene and protein expression that may form substrates for METH-induced neuronal plasticity in the dorsal striatum. Male Sprague-Dawley rats self-administered METH (0.1. mg/kg/injection, i.v.) or received yoked saline infusions during eight 15-h sessions and were euthanized 2. h, 24. h, or 1. month after cessation of METH exposure. Changes in gene and protein expression were assessed using microarray analysis, RT-PCR and Western blots. Chromatin immunoprecipitation (ChIP) followed by PCR was used to examine epigenetic regulation of METH-induced transcription. METH self-administration caused increases in mRNA expression of the transcription factors, c-fos and fosb, the neurotrophic factor, Bdnf, and the synaptic protein, synaptophysin (Syp) in the dorsal striatum. METH also caused changes in δFosB, BDNF and TrkB protein levels, with increases after 2 and 24. h, but decreases after 1. month of drug abstinence. Importantly, ChIP-PCR showed that METH self-administration caused enrichment of phosphorylated CREB (pCREB), but not of histone H3 trimethylated at lysine 4 (H3K4me3), on promoters of c-fos, fosb, Bdnf and Syp at 2. h after cessation of drug intake. These findings show that METH-induced changes in gene expression are mediated, in part, by pCREB-dependent epigenetic phenomena. Thus, METH self-administration might trigger epigenetic changes that mediate alterations in expression of genes and proteins serving as substrates for addiction-related synaptic plasticity.
机译：背侧纹状体的神经塑性变化参与了从偶然到惯用药物的转变，并且可能在甲基苯丙胺（METH）成瘾的发展中起关键作用。我们检查了甲基苯丙胺自我管理对基因和蛋白质表达的影响，这些基因和蛋白质表达可能构成甲基苯丙胺诱导的背侧纹状体神经元可塑性的底物。雄性Sprague-Dawley大鼠在八个15小时的疗程中自行服用METH（0.1。mg / kg /注射液，iv）或接受轭铁盐溶液输注，并在METH停止后2. h，24。h或1.个月安乐死接触。使用微阵列分析，RT-PCR和Western印迹评估基因和蛋白质表达的变化。染色质免疫沉淀（ChIP），然后进行PCR，用于检查METH诱导的转录的表观遗传调控。 METH自我管理导致背侧纹状体中转录因子c-fos和fosb，神经营养因子Bdnf和突触蛋白突触素（Syp）的mRNA表达增加。 METH还引起δFosB，BDNF和TrkB蛋白水平的变化，在停药2和24小时后增加，但在禁酒1个月后下降。重要的是，ChIP-PCR显示，METH的自我给药会导致c-fos，fosb，Bdnf和Syp的启动子在c-fos，fosb，Bdnf和Syp的启动子上富集磷酸化CREB（pCREB），但不会富集赖氨酸4（H3K4me3）上三甲基化的组蛋白H3。停止吸毒。这些发现表明，METH诱导的基因表达变化部分地由pCREB依赖的表观遗传现象介导。因此，METH自我管理可能会触发表观遗传学变化，从而介导成瘾相关突触可塑性的底物基因和蛋白质表达的变化。

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