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Treadmill exercise training inhibits morphine CPP by reversing morphine effects on GABA neurotransmission in D2-MSNs of the accumbens-pallidal pathway in male mice

Neuropsychopharmacology (2024)Cite this article

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Abstract

Relapse is a major challenge in the treatment of drug addiction, and exercise has been shown to decrease relapse to drug seeking in animal models. However, the neural circuitry mechanisms by which exercise inhibits morphine relapse remain unclear. In this study, we report that 4-week treadmill training prevented morphine conditioned place preference (CPP) expression during abstinence by acting through the nucleus accumbens (NAc)-ventral pallidum (VP) pathway. We found that neuronal excitability was reduced in D2-dopamine receptor-expressing medium spiny neurons (D2-MSNs) following repeated exposure to morphine and forced abstinence. Enhancing the excitability of NAc D2-MSNs via treadmill training decreased the expression of morphine CPP. We also found that the effects of treadmill training were mediated by decreasing enkephalin levels and that restoring opioid modulation of GABA neurotransmission in the VP, which increased neurotransmitter release from NAc D2-MSNs to VP, decreased morphine CPP. Our findings suggest the inhibitory effect of exercise on morphine CPP is mediated by reversing morphine-induced neuroadaptations in the NAc-to-VP pathway.

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Fig. 1: Effect of treadmill exercise on morphine CPP-induced can alter c-Fos expression in NAc and VP.
Fig. 2: Effect of treadmill exercise on the excitability of NAc D2-MSNs in morphine-abstinent mice.
Fig. 3: Effect of treadmill exercise on GABA neurotransmission from NAc D2-MSNs to VP.
Fig. 4: Effect of exercise on endogenous MOR tone on D2-MSNs terminals in VP.
Fig. 5

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Data availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

We would like to thank all members of Yuan lab at the Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine. We especially thank Dr. J.-J.D. and T.Z. for their generous help and comments on the manuscript with this project. We also appreciate Dr. Y.-D.Z. for valuable advice for data analyses.

Funding

This work was supported by the Basic research project of Shanghai 2023 Science and Technology Innovation Action Plan (23JC1401800/23JC1401801/23JC1401802), the Natural Science Foundation of Shanghai (20ZR1448400), the Science and Technology Innovation 2030- Major Project (2021ZD0203501) and the Postdoctoral Science Foundation of China (2023M742355 and GZC20231656).

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  1. These authors contributed equally: Yi-Gang Dong, Yixia Gan.

Authors and Affiliations

  1. Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai, 200241, China

    Yi-Gang Dong, Yixia Gan, Haifeng Shi, Shanghua Dai, Ruibo Yu, Xinyi Li, Fanglin Wang & Yi Dong

  2. College of Physical Education and Health, East China Normal University, Shanghai, 200241, China

    Yi-Gang Dong, Yixia Gan, Haifeng Shi, Shanghua Dai, Ruibo Yu, Xinyi Li, Fanglin Wang & Yi Dong

  3. Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China

    Yingmei Fu, Ke Zhang & Ti-Fei Yuan

  4. Department of Anesthesiology, Affiliated Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China

    Ke Zhang

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Contributions

YD, T-FY and Y-GD conceived the study. Y-GD established animal models and conducted the behavioral experiments. Y-GD, HS and SD performed the immunohistochemical and molecular experiments. YG performed electrophysiological recording. YF, RY, XL and KZ helped with some of the experiments. Y-GD, YG, YF and FW collected and analyzed data. Y-GD, YD, T-FY and YF wrote the manuscript. YD and T-FY supervised the project.

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Correspondence to Ti-Fei Yuan or Yi Dong.

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Dong, YG., Gan, Y., Fu, Y. et al. Treadmill exercise training inhibits morphine CPP by reversing morphine effects on GABA neurotransmission in D2-MSNs of the accumbens-pallidal pathway in male mice. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01869-4

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