Laboratory of Molecular Basis of Behavior, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland.
Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
Mol Psychiatry. 2023 Feb;28(2):733-745. doi: 10.1038/s41380-022-01849-4. Epub 2022 Nov 10.
Alcohol use disorder (AUD) is a chronic and fatal disease. The main impediment of the AUD therapy is a high probability of relapse to alcohol abuse even after prolonged abstinence. The molecular mechanisms of cue-induced relapse are not well established, despite the fact that they may offer new targets for the treatment of AUD. Using a comprehensive animal model of AUD, virally-mediated and amygdala-targeted genetic manipulations by CRISPR/Cas9 technology and ex vivo electrophysiology, we identify a mechanism that selectively controls cue-induced alcohol relapse and AUD symptom severity. This mechanism is based on activity-regulated cytoskeleton-associated protein (Arc)/ARG3.1-dependent plasticity of the amygdala synapses. In humans, we identified single nucleotide polymorphisms in the ARC gene and their methylation predicting not only amygdala size, but also frequency of alcohol use, even at the onset of regular consumption. Targeting Arc during alcohol cue exposure may thus be a selective new mechanism for relapse prevention.
酒精使用障碍（AUD）是一种慢性且致命的疾病。AUD 治疗的主要障碍是即使在长时间禁欲后，也极有可能重新开始酗酒。尽管线索诱导的复发的分子机制尚未得到充分确立，但它们可能为 AUD 的治疗提供新的靶点。我们使用 AUD 的综合动物模型，通过病毒介导和 CRISPR/Cas9 技术靶向杏仁核的基因操作以及离体电生理学，确定了一种选择性控制线索诱导的酒精复发和 AUD 症状严重程度的机制。这种机制基于活性调节细胞骨架相关蛋白（Arc）/ARG3.1 依赖性杏仁核突触可塑性。在人类中，我们鉴定了 ARC 基因中的单核苷酸多态性及其甲基化，这些多态性和甲基化不仅可以预测杏仁核的大小，还可以预测饮酒的频率，甚至在开始规律饮酒时也是如此。因此，在酒精线索暴露期间靶向 Arc 可能是预防复发的一种新的选择性机制。
