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Transcranial direct current stimulation restores addictive behavior via prefrontal-striatal circuit

Molecular Psychiatry (2025)Cite this article

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Abstract

Dependence on methamphetamine (METH) is a severe brain disorder characterized by high relapse rates and cognitive decline following detoxification. Recent research suggests that transcranial direct current stimulation (tDCS) may treat addiction, but the underlying neural mechanisms remain unknown. Here, we employed METH-conditioned place preference (CPP) paradigm integrated with fMRI, electrophysiology, chemogenetics, in vivo fiber photometry recordings and a novel rodent tDCS model to examine the neural circuit underlying tDCS modulation on METH-induced addictive behavior. We demonstrated that tDCS targeted at the medial prefrontal cortex (mPFC) prevents relapse. Specifically, tDCS enhanced the activity of neurons in both the infralimbic cortex (IL) and the nucleus accumbens shell (NAcSh) simultaneously. Furthermore, chemogenetic inhibition of the IL-NAcSh circuit eliminated the modulatory effects of tDCS, while activation of the IL-NAcSh circuit was sufficient to suppress the relapse. These findings reveal that the IL-NAcSh pathway functions as a descending regulatory circuit mediating the therapeutic outcomes of tDCS in the treatment of substance use disorder, offering new insights into circuit-based neuro-modulatory treatments for addiction.

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Fig. 1: tDCS suppressed METH-primed relapse.
Fig. 2: Enhancement of IL neuronal activity by tDCS.
Fig. 3: tDCS-induced activation of the mPFC synchronizes neuronal alterations in subcortical nuclei.
Fig. 4: tDCS of the mPFC enhances neuronal activity in the NAcSh via the IL-NAcSh pathway.
Fig. 5: The IL-NAcSh circuit is both necessary and sufficient for tDCS-induced suppression of relapse.

Data availability

The datasets generated and analysed during the current study are available from the

corresponding author on reasonable request.

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Acknowledgements

We thank the SM4 (https://cstr.cn/31125.02.SHMFF.SM4.MRI) at the Steady High Magnetic Field Facility, CAS (https://cstr.cn/31125.02.SHMFF), for providing technical support and assistance in data collection and analysis.

Funding

This work was supported by grants from National Key R&D Program of China (2024YFF0507600), The Chinese National Programs for Brain Science and Brain-like Intelligence Technology (2021ZD0202101), The National Natural Science Foundation of China (32571266, 32171080, 32400919, and 32200914), the Global Select Project (DJK-LX-2022008) of the Institute of Health and Medicine, Hefei Comprehensive National Science Center, Natural Science Foundation of Anhui Province (2408085QC081), the Humanities and Social Science Fund of the Ministry of Education of China (24YJCZH014), the Fundamental Research Funds for the Central Universities (WK2110000025), the Open Fund of Key Laboratory of Philosophy and Social Science of Anhui Province on Adolescent Mental Health and Crisis Intelligence Intervention (SYS2024A06), the Open Project of the Key Laboratory of Brain-Machine Intelligence for Information Behavior - Ministry of Education, Shanghai International Studies University, Shanghai, China (2023JYBKFKT004) and Shanghai Key Laboratory of Brain-Machine Intelligence for Information Behavior.

Author information

Author notes

  1. These authors contributed equally: Huilin Zuo, Weijia Zhang.

Authors and Affiliations

  1. Department of Radiology, the First Affiliated Hospital of USTC, State Key Laboratory of Eye Health, School of Life Science, Division of Life Science and Medicine, University of Science & Technology of China, Hefei, China

    Huilin Zuo & Xiaochu Zhang

  2. Guangzhou National Laboratory, Guangzhou, China

    Weijia Zhang

  3. Key Laboratory of High Field Magnetic Resonance Imaging of Anhui Province, Strong Magnetic Field Center, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China

    Lulu Wang, Yun Wu & Yanmin Zheng

  4. Key laboratory of Brain Aging and Neurodegenerative Diseases, Fujian Medical University, Fuzhou, China

    Shun Hao

  5. Institute of Neuroscience, Kunming Medical University, Kunming, China

    Qi-Yu Chen

  6. Department of Anesthesiology, The First Affiliated Hospital of USTC, Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China

    Peng Cao & Zhi Zhang

  7. School of Life Sciences, Southern University of Science and Technology, Shenzhen, China

    Miao Ouyang

  8. Department of Neurobiology, School of Basic Medical Sciences, National Institute on Drug Dependence, Peking University, Beijing, China

    Shihao Huang & Yan-Xue Xue

  9. Songjiang Institute of medicine, Shanghai Jiao Tong University School, Shanghai, China

    Wenjie Zhou

  10. School of Business and Management, Laboratory of Applied Brain and Cognitive Sciences, Shanghai International Studies University, Shanghai, China

    Yu Pan

  11. School of Mathematics and Big Data Science, Guizhou Education University, Guiyang, China

    Wei Wei

  12. Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada

    Min Zhuo

  13. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai, China

    Tifei Yuan

  14. Department of Psychology, Anhui University of Chinese Medicine, Hefei, China

    Rujing Zha

  15. Department of Psychology, School of Humanities & Social Science, University of Science & Technology of China, Hefei, China

    Rujing Zha

  16. Application Technology Center of Physical Therapy to Brain Disorders, Institute of Advanced Technology, University of Science & Technology of China, Hefei, China

    Xiaochu Zhang

  17. Key Laboratory of Brain-Machine Intelligence for Information Behavior (Ministry of Education and Shanghai), School of Business and Management, Shanghai International Studies University, Shanghai, China

    Xiaochu Zhang

  18. Business School, Guizhou Education University, Guiyang, China

    Xiaochu Zhang

Authors
  1. Huilin Zuo
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  2. Weijia Zhang
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  3. Lulu Wang
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  17. Rujing Zha
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  18. Zhi Zhang
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  19. Xiaochu Zhang
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Contributions

ZXC, ZRJ: funding acquisition. ZHL, ZWJ, XYX: methodology. ZHL, ZWJ, PY, WW: formal analysis. ZHL: Writing original draft. ZHL, ZRJ, CP, ZZ, ZXC: Writing-review & editing. ZHL, ZWJ, WLL, WY, ZYM, HS, CQY, OYM, HSH: investigation. All authors contributed to the article and approved the submitted version.

Corresponding authors

Correspondence to Rujing Zha, Zhi Zhang or Xiaochu Zhang.

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Zuo, H., Zhang, W., Wang, L. et al. Transcranial direct current stimulation restores addictive behavior via prefrontal-striatal circuit. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03249-w

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