A Selective M1 and M3 Receptor Antagonist, Penehyclidine Hydrochloride, Exerts Antidepressant-Like Effect in Mice

  • Xiaojing Sun
  • Congcong Sun
  • Lingyan Zhai
  • Wei DongEmail author
Original Paper


Recent studies indicate that anti-muscarinic receptor is a prospective strategy to treat depression. Although non-selective antagonist of muscarinic receptor scopolamine exhibits rapid and robust antidepressant-like effect, it still has various side effects including abuse risk. Penehyclidine hydrochloride (PHC) is a novel clinical anti-cholinergic drug derived from scopolamine in China, which selectively blocks M1 and M3 muscarinic receptor. Therefore, the objective of this study was to evaluate whether PHC would manifest antidepressant-like effects. Forced swim test (FST), tail suspension test (TST) and chronic unpredictable mild stress (CUMS) model of depression were explored to assess the antidepressant-like effect. Western blotting was further performed to detect the effects of PHC on the brain-derived neurotrophic factor (BDNF) signal cascade. Immunofluorescence was used to observe the activation of astrocyte. Moreover, different pharmacological inhibitors were applied to clarify the antidepressant-like mechanism. The results of the present experiments revealed that PHC decreased the immobility time of FST and TST in mice. In the CUMS model, PHC rapidly ameliorated anhedonia-like behavior (within 4 days), accompanying with the enhanced expression of BDNF and phosphorylation of extracellular signal-related kinase 1/2 (ERK1/2) in the hippocampus. In addition, blockade of the BDNF release by verapamil and activation of its Trk B receptor by K252a, rather than inhibition of opioid system by naloxone or sigma receptor by BD1047, abolished the antidepressant-like effects of PHC in mice. The findings suggest that PHC, an anti-muscarinic drug in clinical use, elicits rapid onset antidepressant-like effect, shedding light on the development of new antidepressants.


Penehyclidine hydrochloride Muscarinic receptor Depression Antidepressant-like effect 



This work was supported by fund from Xuzhou Medical University (2018kj05), and Priority Academic Program Development of Jiangsu Higher Education Institutes (PAPD).

Compliance with Ethical Standards

Conflict of Interest

The authors declare no conflict of interest.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Xiaojing Sun
    • 1
  • Congcong Sun
    • 2
  • Lingyan Zhai
    • 3
  • Wei Dong
    • 1
    Email author
  1. 1.Basic Medical CollegeXuzhou Medical UniversityXuzhouChina
  2. 2.Department of NeurologyQilu Hospital of Shandong UniversityJinanChina
  3. 3.Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityXuzhouChina

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