S-adenosylmethionine modifies cocaine-induced DNA methylation and increases locomotor sensitization in mice
S-adenosylmethionine modifies cocaine-induced DNA methylation and increases locomotor sensitization in mice
复制标题
DOI：
10.1017/s1461145713000394
复制
发表时间：
2013-10-01
影响因子：
4.8
通讯作者：
Kalda, Anti
中科院分区：
文献类型：
--
作者：
Anier, Kaili;Zharkovsky, Alexander;Kalda, Anti
几项研究表明，个体差异是导致吸毒成瘾的关键因素，因为并非所有使用成瘾物质的人都会上瘾。有证据表明，细胞(表观基因组)的整体表观遗传状态可以受到各种环境因素的调节，如营养和化学物质。基于这些数据，我们的目的是研究环境因素如S-腺苷蛋氨酸是否通过影响表观基因组而改变可卡因诱导的基因表达和小鼠的运动敏化。结果表明，重复给予SAM(10 mM/kg)可显著增强可卡因诱导的运动敏化。利用小鼠伏隔核(NAC)组织，全基因组基因表达谱显示，重复SAM处理影响有限数量的基因，但通过钝化非特异性可卡因反应，显著改变了可卡因诱导的基因表达。在基因水平上，我们发现SAM通过抑制NAC中启动子相关的CpG岛高甲基化和低甲基化来调节可卡因诱导的DNA甲基化，但在参考组织小脑中不抑制。最后，我们的体外和体内数据表明，SAM的调节作用部分是由于下调DNMT3A mRNA而降低了甲基转移酶的活性。综上所述，我们的结果表明，影响NAC细胞表观基因组的环境因素可能会改变精神刺激剂诱导的成瘾的发展，这可能至少部分解释了为什么有些人更容易成瘾。
Several studies suggest that individual variability is a critical component underlying drug addiction as not all members of a population who use addictive substance become addicted. There is evidence that the overall epigenetic status of a cell (epigenome) can be modulated by a variety of environmental factors, such as nutrients and chemicals. Based on these data, our aim was to investigate whether environmental factors like S-adenosylmethionine (SAM) via affecting epigenome could alter cocaine-induced gene expression and locomotor sensitization in mice. Our results demonstrate that repeated SAM (10 mM/kg) pretreatment significantly potentiated cocaine-induced locomotor sensitization. Using mouse nucleus accumbens (NAc) tissue, whole-genome gene expression profiling revealed that repeated SAM treatment affected a limited number of genes, but significantly modified cocaine-induced gene expression by blunting non-specifically the cocaine response. At the gene level, we discovered that SAM modulated cocaine-induced DNA methylation by inhibiting both promoter-associated CpG-island hyper- and hypomethylation in the NAc but not in the reference tissue cerebellum. Finally, our in vitro and in vivo data show that the modulating effect of SAM is in part due to decreased methyltransferase activity via down-regulation of Dnmt3a mRNA. Taken together, our results suggest that environmental factors that affect the NAc-cell epigenome may alter the development of psychostimulant-induced addiction and this may explain, at least partly, why some individuals are more vulnerable to drug addiction.