Cannabidiol alleviates methamphetamine addiction via targeting ATP5A1 and modulating the ATP-ADO-A1R signaling pathway.
10.1016/j.apsb.2025.08.011
- Author:
Sha JIN
1
;
Cong LIN
1
;
Peipei LI
2
;
Xue WANG
3
;
Yibo WANG
1
;
Cong ZHANG
1
;
Xuenan WANG
2
;
Yinghua PENG
4
;
Haohong LI
5
;
Yuyuan LU
6
;
Xiaohui WANG
1
Author Information
1. Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
2. Shandong Institute of Brain Science and Brain-inspired Research, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, China.
3. Department of Anesthesiology, Lequn Branch, the First Hospital of Jilin University, Changchun 130021, China.
4. State Key Laboratory for Molecular Biology of Special Economic Animal, Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun 130112, China.
5. The MOE Frontier Research Center of Brain and Brain-Machine Integration, Zhejiang University School of Brain Science and Brain Medicine, Hangzhou 310058, China.
6. School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China.
- Publication Type:Journal Article
- Keywords:
ATP synthetase;
ATP5A1;
Addiction;
Adenosine A1 receptor;
Adenosine triphosphate;
Cannabidiol;
Methamphetamine;
Mitochondria
- From:
Acta Pharmaceutica Sinica B
2025;15(10):5261-5276
- CountryChina
- Language:English
-
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.
