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D1R-5-HT2AR Uncoupling Reduces Depressive Behaviours via HDAC Signalling

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Neurotherapeutics

Abstract

Dopamine and serotonin signalling are associated with major depressive disorder, which is a prevalent life-threatening illness worldwide. Numerous FDA-approved dopamine/serotonin signalling-modifying drugs are available but are associated with concurrent side effects and limited efficacy. Thus, identifying and targeting their signalling pathway is crucial for improving depression treatment. Here, we determined that serotonin receptor 2A (5-HT2AR) abundantly forms a protein complex with dopamine receptor 1 (D1R) in high abundance via its carboxy-terminus in the brains of mice subjected to various chronic stress paradigms. Furthermore, the D1R/5-HT2AR interaction elicited CREB/ERK/AKT modulation during synaptic regulation. An interfering peptide (TAT-5-HT2AR-SV) agitated the D1R/5-HT2AR interaction and attenuated depressive symptoms accompanied by CREB/ERK molecule costimulation. Interestingly, HDAC antagonism but not TrkB antagonism reversed the antidepressant effect of competitive peptides. These findings revealed a novel D1R/5-HT2AR heteroreceptor complex mechanism in the pathophysiology of depression, and their uncoupling ameliorates depressive-like behaviours through HDAC-, and not BDNF-, dependent mechanisms.

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Acknowledgements

Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, 518055, China

Funding

This work was supported by Grants Science and Technology Innovation Committee of Shenzhen No: JCYJ20170810163329510; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions No: 2019SHIBS0004; Sanming Project of Medicine in Shenzhen (No. SZSM201911003) Shenzhen Key Medical Discipline Construction Fund (No.SZXK06162). National Natural Science Foundation of China (82072112). Guangdong Basic and Applied Basic Research Foundation (2022A1515110205;2023A1515011957).

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Authors and Affiliations

  1. State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China

    Weifen Li, Tahir Ali, Shengnan Mou, Qichao Gong & Shupeng Li

  2. Department of Infectious Diseases and Shenzhen Key Laboratory for Endogenous Infections, the 6th Affiliated Hospital of Shenzhen University Health Science Center, No 89, Taoyuan Road, Nanshan District, Shenzhen, 518052, China

    Weifen Li & Zhi-Jian Yu

  3. Institute of Chemical Biology, Shenzhen Bay Laboratory, Shenzhen, 518132, China

    Tahir Ali & Shupeng Li

  4. Department of Neurology, School of Medicine, Affiliated ZhongDa Hospital, Southeast University, Nanjing, China

    Ningning Li

  5. Precision Medicine Research Centre, Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China

    Ningning Li

  6. Hospital of Chengdu, University of Traditional Chinese Medicine, No.39 Shi-er-qiao Road, Chengdu, People’s Republic of China

    Liangliang Hao

  7. Campbell Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada

    Shupeng Li

  8. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Shupeng Li

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  1. Weifen Li
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Contributions

Conceptualization: WL, TA, SL; Methodology: WL, SM, and QG, Investigation and Analysis: WL, TA, and NL: Writing: TA, SL; Supervision: SL and ZY. All authors reviewed and approved the manuscript.

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Correspondence to Zhi-Jian Yu or Shupeng Li.

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Li, W., Ali, T., Mou, S. et al. D1R-5-HT2AR Uncoupling Reduces Depressive Behaviours via HDAC Signalling. Neurotherapeutics 20, 1875–1892 (2023). https://doi.org/10.1007/s13311-023-01436-7

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