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Cannabidiol alleviates methamphetamine addiction via targeting ATP5A1 and modulating the ATP-ADO-A1R signaling pathway

文献类型： 外文期刊

作者： Jin, Sha;Lin, Cong;Li, Peipei;Wang, Xue;Wang, Yibo;Zhang, Cong;Wang, Xuenan;Peng, Yinghua;Li, Haohong;Lu, Yuyuan;Wang, Xiaohui

作者机构：

关键词： Cannabidiol;Methamphetamine;Addiction;Mitochondria;ATP synthetase;Adenosine triphosphate;Adenosine A1 receptor

期刊名称： ACTA PHARMACEUTICA SINICA B

ISSN： 2211-3835

年卷期： 2025 年 15 卷 10 期

页码：

收录情况： SCIE（2025版） ; ; CSCD（2025-2026年度） ; ; 科技核心（2024版）

摘要： Cannabidiol (CBD), a non-psychoactive cannabinoid, shows great promise in treating meth-amphetamine (METH) addiction. Nonetheless, the molecular target and the mechanism through which CBD treats METH addiction remain unexplored. Herein, CBD was shown to counteract METH-induced locomotor sensitization and conditioned place preference. Additionally, CBD mitigated the adverse effects of METH, such as cristae loss, a decline in ATP content, and a reduction in membrane potential. Employing an activity-based protein profiling approach, a target fishing strategy was used to uncover CBD's direct target. ATP5A1, a subunit of ATP synthase, was identified and validated as a CBD target. Moreover, CBD demonstrated the ability to ameliorate METH-induced ubiquitination of ATP5A1 via the D376 residue, thereby reversing the METH-induced reduction of ATP5A1 and promoting the assembly of ATP synthase. Pharmacological inhibition of the ATP efflux channel pannexin 1, blockade of ATP hydrolysis by a CD39 inhibitor, and blocking the adenosine A1 receptor (A1R) all attenuated the therapeutic benefits of CBD in mitigating METH-induced behavioral sensitization and CPP. Moreover, the RNA interference of ATP5A1 in the ventral tegmental area resulted in the reversal of CBD's therapeutic efficacy against METH addiction. Collectively, these data show that ATP5A1 is a target for CBD to inhibit METH-induced addiction behaviors through the ADO-A1R signaling pathway. (c) 2025 The Authors. Published by Elsevier B.V. on behalf of Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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