Tian Weiping, Wang Jiesi, Zhang Ke, Teng Huajing, Li Chong, Szyf Moshe, Sun Zhong Sheng, Zhao Mei
Key Lab of Mental Health, Institute of Psychology, Chinese Academy of Sciences, 16 Lincui Rd., Beijing 100101, China.
Tianjin Research Center of Basic Medical Science, Tianjin Medical University, Tianjin, 300070, China.
Sci Rep. 2016 Feb 25;6:22087. doi: 10.1038/srep22087.
Abnormal BDNF signaling contributes to the structural and behavioral plasticity induced by drugs of abuse. However, the mechanisms regulating expression of Bdnf in drug addiction remain elusive. In the present study, using the conditioned place preference (CPP) model, we showed that expression of Bdnf IV is upregulated in the nucleus accumbens (NAc) of conditioned animals while Bdnf I is upregulated in cocaine-treated mice irrespective of conditioning. The methylation level of a putative c-MYB binding site in the promoter region of Bdnf IV was significantly decreased in the NAc under cocaine CPP conditioning but remained unchanged without conditioning, concurrently with increased binding of c-MYB to this site. Exon IV promoter/luciferase reporter assays revealed that transactivation of Bdnf by c-MYB was blocked by methylation of this c-MYB binding site. Administration of methionine, a precursor of SAM, inhibited cocaine CPP, reversed demethylation of c-MYB binding site and induction of Bdnf IV expression by cocaine CPP. Our results imply that Bdnf IV demethylation at c-MYB binding site is involved in cocaine-triggered seeking behavior, whereas Bdnf I responds to the immediate pharmacological effects of cocaine.
异常的脑源性神经营养因子（BDNF）信号传导促成了由滥用药物诱导的结构和行为可塑性。然而，在药物成瘾中调节Bdnf表达的机制仍不清楚。在本研究中，我们使用条件性位置偏爱（CPP）模型表明，在条件化动物的伏隔核（NAc）中，Bdnf IV的表达上调，而在可卡因处理的小鼠中，无论是否进行条件化，Bdnf I均上调。在可卡因CPP条件下，Bdnf IV启动子区域中一个假定的c-MYB结合位点的甲基化水平在NAc中显著降低，但在未进行条件化时保持不变，同时c-MYB与该位点的结合增加。外显子IV启动子/荧光素酶报告基因分析显示，c-MYB对Bdnf的反式激活被该c-MYB结合位点的甲基化所阻断。给予蛋氨酸（SAM的前体）可抑制可卡因CPP，逆转c-MYB结合位点的去甲基化以及可卡因CPP诱导的Bdnf IV表达。我们的结果表明，c-MYB结合位点处的Bdnf IV去甲基化参与了可卡因引发的觅药行为，而Bdnf I则对可卡因的直接药理作用作出反应。
