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Reduced motor cortex GABABR function following chronic alcohol exposure

Molecular Psychiatry volume 26, pages 383–395 (2021)Cite this article

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Abstract

The GABAB receptor (GABABR) agonist baclofen has been used to treat alcohol and several other substance use disorders (AUD/SUD), yet its underlying neural mechanism remains unclear. The present study aimed to investigate cortical GABABR dynamics following chronic alcohol exposure. Ex vivo brain slice recordings from mice chronically exposed to alcohol revealed a reduction in GABABR-mediated currents, as well as a decrease of GABAB1/2R and G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) activities in the motor cortex. Moreover, our data indicated that these alterations could be attributed to dephosphorylation at the site of serine 783 (ser-783) in GABAB2 subunit, which regulates the surface expression of GABABR. Furthermore, a human study using paired-pulse-transcranial magnetic stimulation (TMS) analysis further demonstrated a reduced cortical inhibition mediated by GABABR in patients with AUD. Our findings provide the first evidence that chronic alcohol exposure is associated with significantly impaired cortical GABABR function. The ability to promote GABABR signaling may account for the therapeutic efficacy of baclofen in AUD.

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Fig. 1: Alcohol exposure decreased GABABR functioning in M1 layer V PNs.
Fig. 2: Alcohol exposure reduced baclofen suppression of neuronal firing.
Fig. 3: Alcohol exposure reduced GABABR and GIRK expression in the motor cortex.
Fig. 4: Reversal of alcohol-induced suppression in the motor cortex.
Fig. 5: Human AUD subjects exhibited reduced cortical GABABR-mediated inhibition.

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Data availability

The original data are available from the corresponding author upon request.

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Acknowledgements

We thank Ke Zhang and Zhuang Peng for help during data collection and management.

Funding

The study was supported by NSFC grants (81822017, 81901349, 31771215), the Science and Technology Commission of Shanghai Municipality (18QA1403700, 18JC1420304, 18140901700), Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (20181715), Hundred-talent Fund from Shanghai Municipal Commission of Health (2018BR21), Medicine and Engineering Interdisciplinary Research Fund of Shanghai Jiao Tong University (ZH2018ZDA30, ZH2018QNA39), and innovative research team of high-level local universities in Shanghai. VV is supported by the Medical Research Council MR/P008747/1.

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Author notes

  1. These authors contributed equally: Shi-Yu Peng, Zhe Shi, Dong-Sheng Zhou

Authors and Affiliations

  1. Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Shi-Yu Peng, Xin-Yue Wang, Wei-Di Wang, Guan-Ning Lin & Ti-Fei Yuan

  2. Division of Stem Cell Regulation and Application, Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha, Hunan, China

    Zhe Shi

  3. Ningbo Kangning Hospital, Ningbo, Zhejiang, China

    Dong-Sheng Zhou, Xing-Xing Li & Xiao-Li Liu

  4. School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China

    Guan-Ning Lin

  5. Institute of Life Sciences, Nanchang University, Nanchang, Jiangxi, China

    Bing-Xing Pan

  6. Department of Psychiatry, University of Cambridge, Cambridge, UK

    Valerie Voon

  7. Center for Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, PA, USA

    Anthony A. Grace

  8. Center for Social and Affective Neuroscience, Department of Biomedical and Clinical Sciences,, Linköping University, Linköping, Sweden

    Markus Heilig

  9. Department of Psychiatry and Behavioral Sciences, State University of New York Upstate Medical University, Syracuse, NY, USA

    Ma-Li Wong

  10. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China

    Ti-Fei Yuan

  11. TianQiao and Chrissy Chen Institute for Translational Research, Shanghai, China

    Ti-Fei Yuan

  12. The State Key Laboratory of Brain and Cognitive Sciences, The University of Hong Kong, Hong Kong, China

    Ti-Fei Yuan

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Contributions

S-YP, ZS, D-SZ, and T-FY designed the study; S-YP, ZS, D-SZ, X-YW, X-XL, X-LL, W-DW, and G-NL performed the study; S-YP, ZS, D-SZ, X-YW, B-XP, VV, AAG, MH, M-LW, and T-FY analyzed the results and wrote the paper together; and all authors have read and approved the final version of the manuscript.

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Correspondence to Ti-Fei Yuan.

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Peng, SY., Shi, Z., Zhou, DS. et al. Reduced motor cortex GABABR function following chronic alcohol exposure. Mol Psychiatry 26, 383–395 (2021). https://doi.org/10.1038/s41380-020-01009-6

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