Antidepressant-like effects of cinnamamide derivative M2 via D2 receptors in the mouse medial prefrontal cortex

Yan-xin Che1, Xiao-yan Jin1, Rong-hua Xiao1, Ming Zhang2,3, Xiao-hui Ma4, Fei Guo2,3, Yang Li1,2,3
1 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China
2 CAS Key Laboratory of Receptor Research, Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
3 University of Chinese Academy of Sciences, Beijing 100049, China
4 State Key Laboratory of Core Technology in Innovative Chinese Medicine, Tasly Pharmaceutical Group Co., Ltd., Tianjin 300410, China
Correspondence to: Fei Guo:, Yang Li:,
DOI: 10.1038/s41401-021-00854-7
Received: 21 October 2021
Accepted: 27 December 2021
Advance online: 25 January 2022


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.
Keywords: depression; D2 receptor; medial prefrontal cortex; pyramidal neurons; mTOR; TrkB

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