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Dopamine D1 receptor in medial prefrontal cortex mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits

Neuropsychopharmacology (2024)Cite this article

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Abstract

Trace amine-associated receptor 1 (TAAR1) is an intracellular expressed G-protein-coupled receptor that is widely expressed in major dopaminergic areas and plays a crucial role in modulation of central dopaminergic neurotransmission and function. Pharmacological studies have clarified the roles of dopamine D1 receptor (D1R) in the medial prefrontal cortex (mPFC) in cognitive function and social behaviors, and chronic stress can inhibit D1R expression due to its susceptibility. Recently, we identified TAAR1 in the mPFC as a potential target for treating chronic stress-induced cognitive and social dysfunction, but whether D1R is involved in mediating the effects of TAAR1 agonist remains unclear. Combined genomics and transcriptomic studies revealed downregulation of D1R in the mPFC of TAAR1−/− mice. Molecular dynamics simulation showed that hydrogen bond, salt bridge, and Pi–Pi stacking interactions were formed between TAAR1 and D1R indicating a stable TAAR1–D1R complex structure. Using pharmacological interventions, we found that D1R antagonist disrupted therapeutic effect of TAAR1 partial agonist RO5263397 on stress-related cognitive and social dysfunction. Knockout TAAR1 in D1-type dopamine receptor-expressing neurons reproduced adverse effects of chronic stress, and TAAR1 conditional knockout in the mPFC led to similar deficits, along with downregulation of D1R expression, all of these effects were ameliorated by viral overexpression of D1R in the mPFC, suggesting the functional interaction between TAAR1 and D1R. Collectively, our data elucidate the possible molecular mechanism that D1R in the mPFC mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits.

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Fig. 1: Effects of TAAR1 on the expression of monoamine neurotransmitter receptors in the mPFC.
Fig. 2: A structural model of the trace amine-associated receptor 1 and dopamine D1 receptor complex.
Fig. 3: Inhibition of D1R affected the therapeutic effect of TAAR1 partial agonist on chronic stress-related cognitive and social impairment.
Fig. 4: Overexpression of D1R in the mPFC reversed cognitive deficits related to knocking out TAAR1 on D1 receptor-expressing neurons.
Fig. 5: Overexpression of D1R recovered cognitive and social deficits caused by TAAR1 specific knockout in the mPFC.

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Funding

This work was supported by the National Natural Science Foundation of China (82071528, 81771468, 82171529, 82271569).

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  1. These authors contributed equally: Meng Sun, Yue Zhang.

Authors and Affiliations

  1. Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, China

    Meng Sun, Yue Zhang, Xian-Qiang Zhang, Ji-Tao Li, Tian-Mei Si & Yun-Ai Su

  2. Research Triangle Institute, Research Triangle Park, NC, 27709, USA

    Yanan Zhang

  3. Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, 310058, Hangzhou, China

    Xiao-Dong Wang

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Contributions

Meng Sun: investigation, formal analysis, methodology, writing – original draft. Yue Zhang: investigation, formal analysis, methodology, writing – original draft. Xian-Qiang Zhang: investigation, formal analysis, methodology. Yanan Zhang: resources, investigation. Xiao-Dong Wang: conceptualization, investigation. Ji-Tao Li: conceptualization, investigation, supervision, writing – review & editing. Tian-Mei Si: conceptualization, funding acquisition, supervision, writing – review & editing. Yun-Ai Su: conceptualization, funding acquisition, investigation, supervision, writing – review & editing.

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Sun, M., Zhang, Y., Zhang, XQ. et al. Dopamine D1 receptor in medial prefrontal cortex mediates the effects of TAAR1 activation on chronic stress-induced cognitive and social deficits. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01866-7

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