The effects of single-dose injections of modafinil and methamphetamine on epigenetic and functional markers in the mouse medial prefrontal cortex: potential role of dopamine receptors.
The effects of single-dose injections of modafinil and methamphetamine on epigenetic and functional markers in the mouse medial prefrontal cortex: potential role of dopamine receptors.
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DOI：
10.1016/j.pnpbp.2018.07.019
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发表时间：
2019-01-10
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;Torres OV;Jayanthi S;Gomez N;Sosa MH;Bernardi A;Urbano FJ;García-Rill E;Cadet JL;Bisagno V
使用冰毒会导致神经适应，对前额皮质 (PFC) 产生负面影响，导致动物和人类成瘾和相关的认知能力下降。相比之下，莫达非尼通过增强 PFC 功能来增强认知能力。积累的证据表明，包括莫达非尼和冰毒在内的精神兴奋药物通过表观遗传修饰来调节基因表达。在本研究中，我们测量了单剂量注射莫达非尼和 METH 对给药 1 小时后安乐死小鼠内侧 PFC (mPFC) 中乙酰化组蛋白 H3 (H3ac) 和 H4ac、脱乙酰酶 HDAC1 和 HDAC2 以及 NMDA 亚基 GluN1 蛋白水平的影响。为了测试多巴胺 (DA) 受体 (DR) 是否参与两种药物的生化作用，我们在给予 METH 和莫达非尼前 30 分钟注射 D1Rs 拮抗剂 SCH23390 或 D2Rs 拮抗剂雷氯必利。我们评估了每种药物对表达 D1R 的 V 层锥体神经元谷氨酸突触传递的影响。我们还测量了 DA、NE、食欲素、组胺和谷氨酸受体等多个基因启动子处 H3ac 和 H4ac 的富集及其 mRNA 表达，因为它们对慢性莫达非尼和 METH 治疗有反应。急性莫达非尼和冰毒注射对总组蛋白乙酰化产生类似的影响，增加 H3ac 并减少 H4ac，并且还增加小鼠 mPFC 中的 HDAC1、HDAC2 和 GluN1 蛋白水平。此外，通过使用 D1R 和 D2R 拮抗剂进行预处理可以防止药物的作用。具体而言，H4ac、HDAC2 和 GluN1 的变化对 SCH23390 有反应，而 H3ac 和 GluN1 的变化对雷氯必利有反应。转基因 BAC-Drd1a-tdTomato 小鼠的全细胞膜片钳显示，METH（而非莫达非尼）诱导 EPSC 的配对脉冲促进，表明谷氨酸释放到 V 层锥体神经元的突触前概率降低。对特定启动子处组蛋白 3/4 富集的分析表明：i) 药物对组蛋白 3 乙酰化有明显影响，莫达非尼增加了 Drd1 和 Adra1b 启动子处的 H3ac，但 METH 增加了 Adra1a 处的 H3ac； ii) 对组蛋白 4 乙酰化富集有明显影响，莫达非尼增加 Drd2 启动子处的 H4ac 并减少 Hrh1 处的 H4ac，但 METH 增加 Drd1 处的 H4ac； iii) 两种精神兴奋剂的类似效果，增加 Drd2、Hcrtr1 和 Hrh1 启动子处的 H3ac，减少 Hrh3 处的 H3ac，增加 Hcrtr1 处的 H4ac，以及减少 Hcrtr2、Hrh3 和 Grin1 启动子处的 H4ac。有趣的是，只有 METH 才能改变组蛋白乙酰化状态基因的 mRNA 水平，从而诱导 Drd1a、Adra1a、Hcrtr1 和 Hrh1 表达增加，并减少 Grin1。我们的研究表明，尽管急性冰毒和莫达非尼都可以增加 mPFC 中的 DA 神经传递，但存在相似和对比的表观遗传和转录后果，这可能解释了它们不同的临床效果。
METH use causes neuroadaptations that negatively impact the prefrontal cortex (PFC) leading to addiction and associated cognitive decline in animals and humans. In contrast, modafinil enhances cognition by increasing PFC function. Accumulated evidence indicates that psychostimulant drugs, including modafinil and METH, regulate gene expression via epigenetic modifications. In this study, we measured the effects of single-dose injections of modafinil and METH on the protein levels of acetylated histone H3 (H3ac) and H4ac, deacetylases HDAC1 and HDAC2, and of the NMDA subunit GluN1 in the medial PFC (mPFC) of mice euthanized 1 hr after drug administration. To test if dopamine (DA) receptors (DRs) participate in the biochemical effects of the two drugs, we injected the D1Rs antagonist, SCH23390, or the D2Rs antagonist, raclopride, 30 min before administration of METH and modafinil. We evaluated each drug effect on glutamate synaptic transmission in D1R-expressing layer V pyramidal neurons. We also measured the enrichment of H3ac and H4ac at the promoters of several genes including DA, NE, orexin, histamine, and glutamate receptors, and their mRNA expression, since they are responsive to chronic modafinil and METH treatment. Acute modafinil and METH injections caused similar effects on total histone acetylation, increasing H3ac and decreasing H4ac, and they also increased HDAC1, HDAC2 and GluN1 protein levels in the mouse mPFC. In addition, the effects of the drugs were prevented by pre-treatment with D1Rs and D2Rs antagonists. Specifically, the changes in H4ac, HDAC2, and GluN1 were responsive to SCH23390, whereas those of H3ac and GluN1 were responsive to raclopride. Whole-cell patch clamp in transgenic BAC-Drd1a-tdTomato mice showed that METH, but not modafinil, induced paired-pulse facilitation of EPSCs, suggesting reduced presynaptic probability of glutamate release onto layer V pyramidal neurons. Analysis of histone 3/4 enrichment at specific promoters revealed: i) distinct effects of the drugs on histone 3 acetylation, with modafinil increasing H3ac at Drd1 and Adra1b promoters, but METH increasing H3ac at Adra1a; ii) distinct effects on histone 4 acetylation enrichment, with modafinil increasing H4ac at the Drd2 promoter and decreasing it at Hrh1, but METH increasing H4ac at Drd1; iii) comparable effects of both psychostimulants, increasing H3ac at Drd2, Hcrtr1, and Hrh1 promoters, decreasing H3ac at Hrh3, increasing H4ac at Hcrtr1, and decreasing H4ac at Hcrtr2, Hrh3, and Grin1 promoters. Interestingly, only METH altered mRNA levels of genes with altered histone acetylation status, inducing increased expression of Drd1a, Adra1a, Hcrtr1, and Hrh1, and decreasing Grin1. Our study suggests that although acute METH and modafinil can both increase DA neurotransmission in the mPFC, there are similar and contrasting epigenetic and transcriptional consequences that may account for their divergent clinical effects.
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影响因子：
3.4
作者：
Cadet JL;Bisagno V
通讯作者：
Bisagno V
影响因子：
2.5
作者：
Ishizuka, Tomoko;Murotani, Tomotaka;Yamatodani, Atsushi
通讯作者：
Yamatodani, Atsushi
DOI：
10.1016/j.pnpbp.2017.12.009
发表时间：
2018-03-02
影响因子：
5.6
作者：
González B;Jayanthi S;Gomez N;Torres OV;Sosa MH;Bernardi A;Urbano FJ;García-Rill E;Cadet JL;Bisagno V
通讯作者：
Bisagno V
影响因子：
5
作者：
ANDERSEN, PH
通讯作者：
ANDERSEN, PH
影响因子：
16.2
作者：
Alarcón, JM;Malleret, G;Barco, A
通讯作者：
Barco, A