College of Medicine, Ajman University, Ajman, UAE; Department of Anatomy, College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, UAE.
Division of Biochemistry, Department of Medicine, University of Fribourg, CH-1700 Fribourg, Switzerland.
Eur Neuropsychopharmacol. 2020 Aug;37:70-81. doi: 10.1016/j.euroneuro.2020.06.011. Epub 2020 Jul 6.
Recent studies have shown that Lethal-7 (let-7) microRNA (miRNA) is involved in a wide range of psychiatric disorders such as anxiety, depression, schizophrenia, and cocaine addiction. However, the exact role of let-7d miRNA in regulating ethanol intake and preference remains to be elucidated. The aim of the present study was to clarify the role of accumbal let-7d in controlling ethanol-related behaviors in adult rats. For this purpose, stereotaxic injections of let-7d-overexpressing lentiviral vectors (LV) were administered bilaterally into the nucleus accumbens (Nacc) of Wistar rats. The ethanol-related behaviors were investigated using the two-bottle choice (TBC) access paradigm, in which the rats had access to 2.5, 5, and 10% ethanol solutions, the grid hanging test (GHT) and ethanol-induced loss-of-righting-reflex (LORR) test. The results showed that intra-accumbally administered let-7d-overexpressing LV significantly decreased ethanol intake and preference without having significant effects on body weight, consumption or preference for tastants (saccharin and quinine) or ethanol metabolism. Furthermore, accumbal let-7d increased resistance to ethanol-induced sedation in the GHT and LORR test. Most importantly, the data showed that the dopamine D3 receptor (D3R) was a candidate target of let-7d In fact, and using real time PCR, let-7d was found to directly target D3R mRNA to decrease its expression. Further analyses proved that D3R expression was negatively correlated with the levels of let-7d and ethanol-related behaviors parameters. Taken together, the data indicating that let-7d impaired ethanol-related behaviors by targeting D3R will open up new exciting possibilities and might provide potential therapeutic evidence for alcoholism.
最近的研究表明，致死-7（let-7）微小 RNA（miRNA）参与了广泛的精神疾病，如焦虑、抑郁、精神分裂症和可卡因成瘾。然而，let-7d miRNA 在调节乙醇摄入和偏好中的确切作用仍有待阐明。本研究旨在阐明伏隔核中 let-7d 在控制成年大鼠乙醇相关行为中的作用。为此，将过表达 let-7d 的慢病毒载体（LV）立体定向注射到 Wistar 大鼠的伏隔核（Nacc）中。使用双瓶选择（TBC）访问范式研究乙醇相关行为，其中大鼠可以访问 2.5%、5%和 10%乙醇溶液、网格悬挂测试（GHT）和乙醇诱导的翻正反射丧失（LORR）测试。结果表明，内侧注射 let-7d 过表达 LV 可显著减少乙醇摄入和偏好，而对体重、对味觉（糖精和奎宁）或乙醇代谢的消耗或偏好无显著影响。此外，伏隔核中的 let-7d 增加了 GHT 和 LORR 测试中对乙醇诱导镇静的抵抗力。最重要的是，数据表明多巴胺 D3 受体（D3R）是 let-7d 的候选靶标。事实上，通过实时 PCR 发现 let-7d 直接靶向 D3R mRNA 以降低其表达。进一步的分析证明 D3R 表达与 let-7d 的水平和乙醇相关行为参数呈负相关。总之，表明 let-7d 通过靶向 D3R 损害乙醇相关行为的数据将开辟新的令人兴奋的可能性，并可能为酒精中毒提供潜在的治疗证据。
