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Decreased efficacy of the ketamine and scopolamine-induced sustained antidepressant-like effects in rats receiving metformin

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Abstract

Background

Metformin is the most widely used drug for treating type 2 diabetes mellitus (DM), which frequently co-occurs with depressive disorders. Thus, patients with depression are likely to receive metformin. Metformin activates AMP-activated kinase (AMPK), which inhibits mechanistic target of rapamycin complex 1 (mTORC1) signaling. mTORC1 activation is essential for the antidepressant effects of ketamine and scopolamine. Thus, we hypothesized that metformin may attenuate ketamine- or scopolamine-induced antidepressant efficacies by blocking their mTORC1 activation.

Methods

We assessed the acute and sustained antidepressant-like actions of ketamine and scopolamine in male Sprague–Dawley rats subjected to the forced swim test with or without metformin pretreatment. The expressions of AMPK, mTORC1, and brain-derived neurotrophic factor (BDNF) in their prefrontal cortex were assessed.

Results

Metformin (50 mg/kg) attenuated the sustained, but not acute, antidepressant-like effects of ketamine (10 mg/kg) and scopolamine (25 μg/kg). Although metformin reduced mTORC1 downstream activated P70S6K, it did not significantly alter mTORser2448 activation and even increased BDNF expression. Notably, ketamine, scopolamine, and metformin all exerted significant antidepressant-like actions, as evidenced by increased AMPK phosphorylation and BDNF expression.

Conclusions

Metformin-induced attenuation of sustained antidepressant-like effects are not directly dependent on AMPK-deactivated mTORC1. Our results indicate the complexity of interactions between AMPK, BDNF, and mTORC1. Further research, including mechanistic studies, is warranted to comprehensively evaluate the application of metformin in patients receiving mTORC1-based antidepressants.

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Abbreviations

AMPK:

AMP-activated kinase

ANOVA:

Analysis of variance

BDNF:

Brain-derived neurotrophic factor

DM:

Diabetes mellitus

FST:

Forced swim test

Ip :

Intraperitoneal

mTOR:

Mechanistic target of rapamycin

mTORC1:

MTOR complex 1

mTORC2:

MTOR complex 2

NMDAR:

N-Methyl-d-aspartate receptor

OFT:

Open-field test

P70S6K:

P70S6 kinase

PFC:

Prefrontal cortex

SE:

Standard error

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Funding

This work was supported by the Ministry of Science and Technology, Taiwan (MOST 106-2314-B-039-029-MY3, MOST 109-2314-B-039-040, MOST 109-2320-B-039-046, and MOST 110-2320-B-039-037), China Medical University Hospital, Taiwan (DMR-107-094, DMR-108-092), China Medical University, Taiwan (CMU110-MF-87), and Tsaotun Psychiatric Center, Ministry of Health and Welfare, Nantou, Taiwan (TTPC-110018).

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Authors and Affiliations

  1. Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan

    Han-Wen Chuang

  2. Department of Anatomy, China Medical University, No.91, Hsueh-Shih Road, Taichung, 404333, Taiwan

    I.-Hua Wei

  3. Department of Medicine, China Medical University, Taichung, Taiwan

    Chun-Te Li

  4. Tsaotun Psychiatric Center, Ministry of Health and Welfare, No. 161, Yu-Pin Road Tsaotun Township, Nantou, 54249, Taiwan

    Chih-Chia Huang

  5. Department of Psychiatry, China Medical University, Taichung, Taiwan

    Chih-Chia Huang

  6. Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan

    Chih-Chia Huang

  7. Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan

    Chih-Chia Huang

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  1. Han-Wen Chuang
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Contributions

H-WC, I-HW, and C-CH contributed to the study design. H-WC, I-HW, C-TL, and C-CH all contributed to the study implementation. C-CH contributed to the statistical analysis of the data. H-WC, I-HW, and C-CH all contributed to the writing of the manuscript. All authors have approved this final manuscript.

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Correspondence to I.-Hua Wei or Chih-Chia Huang.

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Chuang, HW., Wei, IH., Li, CT. et al. Decreased efficacy of the ketamine and scopolamine-induced sustained antidepressant-like effects in rats receiving metformin. Pharmacol. Rep 74, 340–352 (2022). https://doi.org/10.1007/s43440-021-00342-z

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  • DOI: https://doi.org/10.1007/s43440-021-00342-z

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