Modulation of Poly ADP Ribose Polymerase (PARP) Levels and Activity by Alcohol Binge-Like Drinking in Male Mice.
Modulation of Poly ADP Ribose Polymerase (PARP) Levels and Activity by Alcohol Binge-Like Drinking in Male Mice.
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DOI：
10.1016/j.neuroscience.2020.09.010
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发表时间：
2020-11-10
期刊：
影响因子：
3.3
通讯作者：
Gavin DP
中科院分区：
文献类型：
--
作者：
Vallerini GP;Cheng YH;Chase KA;Sharma RP;Kusumo H;Khakhkhar S;Feinstein DL;Guizzetti M;Gavin DP
酗酒是酒精使用障碍中一种常见的乙醇摄入模式。类似酗酒的乙醇暴露会增加聚（ADP - 核糖）聚合酶（PARP）的表达和活性。PARP酶与成瘾有关，并在细胞中发挥多种作用，包括基因表达调控。在这项研究中，我们通过为期4天的黑暗饮酒（DID）模式，研究了类似酗酒行为对成年C57BL/6J雄性小鼠前额叶皮质（PFC）的影响。通过在最后一天的DID中给予PARP抑制剂ABT - 888，评估了PARP在相关基因表达和行为变化中的作用。然后，我们对与DID摄入乙醇或ABT - 888治疗相关的PFC基因表达变化进行了RNA - seq分析。另一组小鼠在前额叶皮质接种HSV - PARP1载体，并进行DID实验，以验证过表达的PARP1是否会增加乙醇摄入量。我们证实，酒精会增加前额叶皮质中Parp1基因的表达和PARP的活性。RNA - seq显示，DID摄入乙醇使41个基因的表达发生显著改变，ABT - 888使48个基因的表达发生显著改变。通过对10个验证基因中的7个进行qPCR验证，这些结果得到了证实，其中4个基因先前已与成瘾相关。ABT - 888减少了乙醇摄入量，而前额叶皮质PARP1的过表达增加了DID中的乙醇摄入量。在我们的模型中，酗酒导致前额叶皮质中可能与成瘾有关的基因表达发生特定改变。PARP的药理抑制被证明可有效逆转这些变化并防止进一步的酒精摄入。我们的结果表明，乙醇诱导的PARP1参与了类似酗酒的成瘾行为的强化。
Binge drinking is a frequent pattern of ethanol consumption within Alcohol Use Disorders. Binge-like ethanol exposure increases Poly(ADP-ribose) polymerase (PARP) expression and activity. PARP enzymes have been implicated in addiction and serve multiple roles in the cell, including gene expression regulation. In this study, we examined the effects of binge-like alcohol consumption in the prefrontal cortex (PFC) of adult C57BL/6J male mice via a 4-day drinking-in-the-dark (DID) paradigm. The role of PARP in associated gene expression and behavioral changes was assessed by administering the PARP inhibitor ABT-888 on the last DID day. We then conducted an RNA-seq analysis of the PFC gene expression changes associated with DID-consumed ethanol or ABT-888 treatment. A separate cohort of mice was inoculated with an HSV-PARP1 vector in the PFC and subject to a DID experiment to verify whether overexpressed PARP1 increased ethanol drinking. We confirmed that alcohol increases Parp1 gene expression and PARP activity in the PFC. RNA-seq showed significantly altered expression of 41 genes by DID-consumed ethanol, and of 48 genes by ABT-888. These results were confirmed by qPCR in 7 of the 10 genes validated, 4 of which have been previously associated with addiction. ABT-888 reduced, and overexpression of PFC PARP1 increased DID ethanol consumption. In our model, alcohol binge drinking induced specific alterations in the PFC expression of genes potentially involved in addiction. Pharmacological PARP inhibition proved effective in reversing these changes and preventing further alcohol consumption. Our results suggest an involvement of ethanol-induced PARP1 in reinforcing binge-like addictive behavior.
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