Repeated methamphetamine and modafinil induce differential cognitive effects and specific histone acetylation and DNA methylation profiles in the mouse medial prefrontal cortex.
Repeated methamphetamine and modafinil induce differential cognitive effects and specific histone acetylation and DNA methylation profiles in the mouse medial prefrontal cortex.
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DOI：
10.1016/j.pnpbp.2017.12.009
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发表时间：
2018-03-02
影响因子：
5.6
通讯作者：
Bisagno V
中科院分区：
文献类型：
--
作者：
González B;Jayanthi S;Gomez N;Torres OV;Sosa MH;Bernardi A;Urbano FJ;García-Rill E;Cadet JL;Bisagno V
甲基苯丙胺和莫达非尼是具有不同长期认知特征的精神刺激剂：甲基苯丙胺会使人上瘾并导致认知能力下降，而莫达非尼几乎没有滥用倾向，是认知增强剂。越来越多的证据表明，滥用药物和其他精神药物在大脑中诱导的持久变化背后有基因调控的表观遗传学机制，例如通过组蛋白3和4尾乙酰化(H3ac和H4ac)和DNA胞嘧啶甲基化(5-MC)控制基因表达。小鼠接受为期7天的重复冰毒、莫达非尼或赋形剂治疗，并在新的对象识别(NOR)测试中进行评估，或在最后一次注射后4天处死进行分子分析。我们评估了内侧前额叶皮质H3ac、H4ac和5-MC的总水平、H3ac和H4ac启动子浓缩(CHIP)以及与觉醒、觉醒和认知控制有关的神经递质系统的基因表达，如多巴胺能(DRD1和DRD2)、α肾上腺素能(Adra1a和Adra1b)、食欲素能(Hcrtr1和Hcrtr2)、组胺能(HRH1和HRH3)和谷氨酸能(AMPA Gria1和NMDA Grin1)受体。在NOR测试中，重复冰毒和莫达非尼治疗引起了不同的认知结果，其中莫达非尼治疗的小鼠作为对照组，冰毒治疗的小鼠表现出识别记忆受损。甲硫氨酸处理组小鼠体内总H3ac和H4ac水平降低，5-MC水平升高，H3ac在Drd2、Hcrtr1/2、HRH1和Grin1启动子上的丰度降低，而在DRd1、HRH1和Grin1启动子上的H4ac丰度增加；莫达非尼治疗的小鼠没有这些影响，并显示出H3ac浓缩和Adra1b的mRNA表达增加。莫达非尼和METH表现出类似的作用，与降低HHH3的H3ac，增加Hcrtr1的H4ac，降低Hcrtr2的mRNA表达有关。本文描述的冰毒引起的特殊表观遗传学和转录变化可能与药物的长期认知衰退效应及其对mPFC功能的不利影响有关。长期服用莫达非尼缺乏类似的表观遗传效应支持这一观点。
Methamphetamine (METH) and modafinil are psychostimulants with different long-term cognitive profiles: METH is addictive and leads to cognitive decline, whereas modafinil has little abuse liability and is a cognitive enhancer. Increasing evidence implicates epigenetic mechanisms of gene regulation behind the lasting changes that drugs of abuse and other psychotropic compounds induce in the brain, like the control of gene expression by histones 3 and 4 tails acetylation (H3ac and H4ac) and DNA cytosine methylation (5-mC). Mice were treated with a seven-day repeated METH, modafinil or vehicle protocol and evaluated in the novel object recognition (NOR) test or sacrificed 4 days after last injection for molecular assays. We evaluated total H3ac, H4ac and 5-mC levels in the medial prefrontal cortex (mPFC), H3ac and H4ac promotor enrichment (ChIP) and mRNA expression (RT-PCR) of neurotransmitter systems involved in arousal, wakefulness and cognitive control, like dopaminergic (Drd1 and Drd2), α-adrenergic (Adra1a and Adra1b), orexinergic (Hcrtr1 and Hcrtr2), histaminergic (Hrh1 and Hrh3) and glutamatergic (AMPA Gria1 and NMDA Grin1) receptors. Repeated METH and modafinil treatment elicited different cognitive outcomes in the NOR test, where modafinil-treated mice performed as controls and METH-treated mice showed impaired recognition memory. METH-treated mice also showed i) decreased levels of total H3ac and H4ac, and increased levels of 5-mC, ii) decreased H3ac enrichment at promoters of Drd2, Hcrtr1/2, Hrh1 and Grin1, and increased H4ac enrichment at Drd1, Hrh1 and Grin1, iii) increased mRNA of Drd1a, Grin1 and Gria1. Modafinil-treated mice shared none of these effects and showed increased H3ac enrichment and mRNA expression at Adra1b. Modafinil and METH showed similar effects linked to decreased H3ac in Hrh3, increased H4ac in Hcrtr1, and decreased mRNA expression of Hcrtr2. The specific METH-induced epigenetic and transcriptional changes described here may be related to the long-term cognitive decline effects of the drug and its detrimental effects on mPFC function. The lack of similar epigenetic effects of chronic modafinil administration supports this notion.
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大鼠暴食甲基苯丙胺后逆转特异性学习障碍：可能涉及纹状体多巴胺。
影响因子：
7.6
作者：
Izquierdo, Alicia;Belcher, Annabelle M.;Scott, Lori;Cazares, Victor A.;Chen, Jack;O'Dell, Steven J.;Malvaez, Melissa;Wu, Tiffany;Marshall, John F.
通讯作者：
Marshall, John F.
影响因子：
3.4
作者：
Cadet JL;Bisagno V
通讯作者：
Bisagno V
影响因子：
3
作者：
Braren SH;Drapala D;Tulloch IK;Serrano PA
通讯作者：
Serrano PA
影响因子：
2.5
作者：
Ishizuka, Tomoko;Murotani, Tomotaka;Yamatodani, Atsushi
通讯作者：
Yamatodani, Atsushi
影响因子：
2.3
作者：
Gozen, Oguz;Balkan, Burcu;Pogun, Sakire
通讯作者：
Pogun, Sakire