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Atypical antipsychotics antagonize GABAA receptors in the ventral tegmental area GABA neurons to relieve psychotic behaviors

Molecular Psychiatry volume 28, pages 2107–2121 (2023)Cite this article

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Abstract

Psychosis is an abnormal mental condition that can cause patients to lose contact with reality. It is a common symptom of schizophrenia, bipolar disorder, sleep deprivation, and other mental disorders. Clinically, antipsychotic medications, such as olanzapine and clozapine, are very effective in treatment for psychosis. To investigate the neural circuit mechanism that is affected by antipsychotics and identify more selective therapeutic targets, we employed a strategy by using these effective antipsychotics to identify antipsychotic neural substrates. We observed that local injection of antipsychotics into the ventral tegmental area (VTA) could reverse the sensorimotor gating defects induced by MK-801 injection in mice. Using in vivo fiber photometry, electrophysiological techniques, and chemogenetics, we found that antipsychotics could activate VTA gamma-aminobutyric acid (GABA) neurons by blocking GABAA receptors. Moreover, we found that the VTAGABA nucleus accumbens (NAc) projection was crucially involved in such antipsychotic effects. In summary, our study identifies a novel therapeutic target for the treatment of psychosis and underscores the utility of a ‘bedside-to-bench’ approach for identifying neural circuits that influence psychotic disorders.

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Fig. 1: Local infusion of the olanzapine and clozapine into the VTA respectively could enhance the PPI function and reverse the sensorimotor gating injury caused by MK-801 injection in mice.
Fig. 2: Olanzapine and clozapine activate VTA DA and GABA neurons.
Fig. 3: Olanzapine and clozapine reversed the inhibition of VTA DA and GABA neurons induced by MK-801.
Fig. 4: Bidirectional regulation of the VTA GABA neurons, rather than DA neurons, could modulate sensorimotor gating.
Fig. 5: The olanzapine and clozapine antagonized GABAA receptor of the VTA GABA neurons.
Fig. 6: VTAGABA-NAc neural circuit modulated sensorimotor gating.

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Acknowledgements

We thank all members of Hu lab at ShanghaiTech University and Sun lab at the Chinese Institute for Brain Research. This work was supported by STI2030-Major Projects (grant no. 2021ZD0202800 to WS and grant no. 2021ZD0203900 to XNZ) and the National Natural Science Foundation of China (grant nos. 32192414, 61890951 and 61890950 to JH; grant no. 81701049 to XNZ).

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Author notes

  1. These authors contributed equally: Chen Lu, Xiaona Zhu, Yifan Feng.

Authors and Affiliations

  1. School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China

    Chen Lu, Xiaona Zhu, Yifan Feng, Weizhen Ao, Huoqing Luo, Fang Cai, Shulu Zhan & Ji Hu

  2. Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031, Shanghai, China

    Chen Lu

  3. University of Chinese Academy of Sciences, 100049, Beijing, China

    Chen Lu

  4. iHuman Institute, ShanghaiTech University, 201210, Shanghai, China

    Weizhen Ao

  5. Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, 200030, Shanghai, China

    Jie Li

  6. School of Life Sciences, Westlake University, 310024, Hangzhou, China

    Zilong Gao

  7. Institutes of Brain Science, Fudan University, 200032, Shanghai, China

    Ming Chen

  8. Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200025, Shanghai, China

    Hongxia Li

  9. Chinese Institute for Brain Research, 102206, Beijing, China

    Wenzhi Sun

  10. School of Basic Medical Sciences, Capital Medical University, 100069, Beijing, China

    Wenzhi Sun

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Contributions

JH, WS, XNZ, and CL conceived the study and wrote the manuscript. CL, XNZ and YFF acquired and analyzed the data. CL did the in vivo fiber photometry. XNZ did the in vitro electrophysiology. CL and YFF performed all the behavioral experiments. WZA, JL, ZLG, HQL, MC, FC, SLZ and HXL contributed to data collection, data analysis and interpretation. All authors contributed to the discussion and analysis of the results.

Corresponding authors

Correspondence to Xiaona Zhu, Wenzhi Sun or Ji Hu.

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Lu, C., Zhu, X., Feng, Y. et al. Atypical antipsychotics antagonize GABAA receptors in the ventral tegmental area GABA neurons to relieve psychotic behaviors. Mol Psychiatry 28, 2107–2121 (2023). https://doi.org/10.1038/s41380-023-01982-8

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  • DOI: https://doi.org/10.1038/s41380-023-01982-8

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