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Sigma-1 receptor ligands improves ventricular repolarization-related ion remodeling in rats with major depression disorder

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Abstract

Rationale

It has been reported that patients with major depressive disorder (MDD) are prone to developing ventricular arrhythmias. Moreover, the Sigma-1 receptor not only plays a crucial role in MDD but has also been shown to have antiarrhythmic properties. The Sigma-1 receptor is a common receptor related to depression and ventricular arrhythmias.

Objective

We analyzed the effects of the Sigma-1 receptor on depression and ventricular repolarization-related ion remodeling in MDD rats.

Methods

MDD was induced in rats by chronic unpredictable mild stress (CUMS), and 28 days later, the rats were subjected to behavior tests. Protein expression was measured by western blotting, and cardiac morphological changes were observed by Masson staining. Electrophysiological measurement of the myocardium was performed with the whole-cell patch-clamp technique.

Results

Compared with the control rats, the MDD rats exhibited lower transient outward potassium current (Ito) and L-type calcium current (ICa-L) amplitudes. On the other hand, a trend of depolarization of Ito and hyperpolarization of ICa-L was observed in the MDD rats. Thus, we investigated the effect of fluvoxamine, a Sigma-1 receptor agonist, on Ito and ICa-L. Fluvoxamine enhanced Ito and altered its current kinetics, as shown by acceleration of activation and recovery from inactivation. In contrast, fluvoxamine inhibited the Ca2+ by hyperpolarizing the steady-state activation of ICa-L. All these effects were blocked by BD1047.

Conclusion

Taken together, our results indicate that Sigma-1 receptor modulates the functions of Ito and ICa-L to possibly exert antiarrhythmic effects.

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Abbreviations

MDD:

Major depressive disorder

CUMS:

Chronic unpredictable mild stress

CTL:

Control

Flu:

Fluvoxamine

BD:

BD1047

HP:

Holding potential

SSRI:

Selective serotonin reuptake inhibitor

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Funding

This research was supported by Grants from the Nature Science Foundation of China (No: 81800447) and the Nature Science Foundation of Hebei Province (No: 2017CFB204).

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Author notes

  1. Yan Guo, Cui Zhang, Bo Shen and Bo Yang contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China

    Yan Guo, Cui Zhang, Xiuhuan Chen, Xin Liu, Tianxin Ye, Yuhong Fo, Shaobo Shi, Chuan Qu, Jinjun Liang, Bo Shen & Bo Yang

  2. Cardiovascular Research Institute, Wuhan University, Wuhan, People’s Republic of China

    Yan Guo, Cui Zhang, Xiuhuan Chen, Xin Liu, Tianxin Ye, Yuhong Fo, Shaobo Shi, Chuan Qu, Jinjun Liang, Bo Shen & Bo Yang

  3. Hubei Key Laboratory of Cardiology, Wuhan, People’s Republic of China

    Yan Guo, Cui Zhang, Xiuhuan Chen, Xin Liu, Tianxin Ye, Yuhong Fo, Shaobo Shi, Chuan Qu, Jinjun Liang, Bo Shen & Bo Yang

Authors
  1. Yan Guo
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Contributions

Yan Guo and Cui Zhang conceived and designed the research; Yan Guo and Xiuhuan Chen performed the experiments; Yan Guo, Xin Liu, and Xiuhuan Chen analyzed the data; Tianxin Ye and Yuhong Fo interpreted the results of the experiments; Yan Guo and Tianxin Ye prepared the figures; Yan Guo drafted the manuscript; Shaobo Shi, Chuan Qu, and Jinjun Liang edited and revised the manuscript; and Bo Shen and Bo Yang approved the final version of manuscript

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Correspondence to Bo Shen or Bo Yang.

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All animal care and experiments were carried out in accordance with the Guide for Care and Use of Laboratory Animals and were approved by the animal experiment management center of Wuhan University.

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Guo, Y., Zhang, C., Chen, X. et al. Sigma-1 receptor ligands improves ventricular repolarization-related ion remodeling in rats with major depression disorder. Psychopharmacology 238, 487–499 (2021). https://doi.org/10.1007/s00213-020-05697-4

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