Cannabidiol alleviates methamphetamine addiction via targeting ATP5A1 and modulating the ATP–ADO–A1R signaling pathway
Year: 2025
Type: article
Abstract: Cannabidiol (CBD), a non-psychoactive cannabinoid, shows great promise in treating methamphetamine (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.
Source: Acta Pharmaceutica Sinica B
Authors: Sha Jin, Cong Lin, Peipei Li, Xue Wang, Yibo Wang, Cong Zhang, Xuenan Wang, Yinghua Peng, Haohong Li, Yuyuan Lu, Xiaohui Wang
Institutions: Hunan Institute of Science and Technology, University of Science and Technology of China, Chinese Academy of Sciences, Changchun Institute of Applied Chemistry, Shandong First Medical University, First Hospital of Jilin University, Zhejiang University, Chinese Academy of Agricultural Sciences, Institute of Special Animal and Plant Sciences, State Key Laboratory of Polymer Physics and Chemistry
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,600
Funders: Northeast Normal University, National Natural Science Foundation of China, Chinese Academy of Sciences, Ministry of Education, Natural Science Foundation of Hunan Province, Zhejiang University, Chinese Academy of Agricultural Sciences, Department of Science and Technology of Jilin Province, Shandong First Medical University, Institute of Biophysics, Chinese Academy of Sciences, CAS Key Laboratory of Human-Machine Intelligence-Synergy Systems, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences
OpenAlex ID: W4413371258