Binge drinking is a frequent pattern of ethanol consumption within Alcohol Use Disorders (AUDs). 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.

酗酒是酒精使用障碍 (AUD) 中常见的酒精消耗模式。类似暴饮暴食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，包括基因表达调节。在这项研究中，我们通过以下方法检查了类似酗酒对成年 C57BL/6J 雄性小鼠前额叶皮层 (PFC) 的影响为期 4 天的黑暗中饮酒 (DID) 范例。PARP 在相关基因表达和行为变化中的作用通过在最后一天 DID 施用 PARP 抑制剂 ABT-888 进行评估。然后，我们对与 DID 消耗的乙醇或 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 PFC 中接种 HSV-PARP1 载体，并进行 DID 实验以验证过表达的 PARP1 是否会增加饮酒量。我们证实酒精会增加Parp1PFC中的基因表达和PARP活性。RNA-seq 显示 DID 消耗的乙醇显着改变了 41 个基因的表达，ABT-888 显示了 48 个基因的表达。这些结果在 10 个已验证基因中的 7 个中通过 qPCR 得到证实，其中 4 个以前与成瘾有关。ABT-888 减少，PFC PARP1 的过表达增加了 DID 乙醇消耗。在我们的模型中，酗酒导致可能与成瘾有关的基因的 PFC 表达发生特定变化。药理学 PARP 抑制被证明可有效逆转这些变化并防止进一步饮酒。我们的研究结果表明乙醇诱导的 PARP1 参与了增强类似暴饮暴食的成瘾行为。