Abstract
Major depressive disorder is a global mental illness associated with severe mortality and disability. The dopaminergic system is involved in both the etiology and therapeutics of depression. Distinct functions of dopamine D1 and D2 receptor subtypes have attracted considerable research interest, and their roles in the pathogenesis of depression and interaction with antidepressants need to be comprehensively elucidated. Herein, we investigated the antidepressant effects of a candidate antidepressant from a cinnamamide derivative, M2, and examined underlying neural mechanisms. We observed that a single dose of M2 (30 mg/kg, ip) produced rapid antidepressant-like effects in mice subjected to the forced swim and tail suspension tests. Using whole-cell recordings in mouse coronal brain slices, we found that application of M2 (10–150 μM) concentration-dependently increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) of the pyramidal neurons in the medial prefrontal cortex (mPFC). Furthermore, M2-induced enhancement of sEPSC frequency was abolished by sulpiride (10 µM), a dopamine D2 receptor antagonist, but not by the dopamine receptor D1 antagonist, SCH23390 (10 μM). In addition, M2 administration significantly increased expression levels of synaptogenesis-related proteins, including p-mTOR and p-TrkB, in the mPFC at 30 min, and increased postsynaptic protein PSD-95 at 24 h. Our results demonstrated that M2 produces rapid antidepressant actions through a novel mechanism via dopamine D2 receptor-mediated enhancement of mPFC neurotransmission.
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Acknowledgements
This work was supported by funds from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12040220), the National Natural Science Foundation of China (31671049, 31371066 to YL), the National Key New Drug Creation Program of China (No. 2018ZX09711002-002-012), and the Shanghai Municipal Science and Technology Major Project and the Science and Technology Commission of Shanghai Municipality (Nos. 184319071000 and 19140903102 to YL and FG). The work in this manuscript was funded in part by a research grant from Tasly Pharma, Inc.
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YXC and XYJ performed the experiments and analyzed the data. RHX and MZ assisted with behavioral experiments. XHM, FG, and YL designed the study and supervised the project; YXC, FG, and YL wrote and edited the manuscript. All authors approved the manuscript.
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Che, Yx., Jin, Xy., Xiao, Rh. et al. Antidepressant-like effects of cinnamamide derivative M2 via D2 receptors in the mouse medial prefrontal cortex. Acta Pharmacol Sin 43, 2267–2275 (2022). https://doi.org/10.1038/s41401-021-00854-7
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DOI: https://doi.org/10.1038/s41401-021-00854-7
