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Metformin attenuates antipsychotic-induced metabolic dysfunctions in MK801-induced schizophrenia-like rats

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Abstract

Rationale

Second-generation antipsychotics are the first-line medications prescribed for schizophrenic patients; however, some of them, such as olanzapine and risperidone, may induce metabolic dysfunctions during short-term treatment. Metformin is an effective adjuvant that attenuates antipsychotic-induced metabolic dysfunctions (AIMD) in clinical practice. Whether metformin can reverse AIMD and whether metformin affects the therapeutic effects of antipsychotics in animal models of schizophrenia are questions that still need to be investigated.

Methods

In this study, an animal model of schizophrenia was established by consecutive injections of MK801 during the neurodevelopmental period. In adulthood, different dosages of olanzapine or risperidone treatment were administered to the schizophrenia model animals for 14 days. Both therapeutic effects and metabolic adverse effects were measured by behavioral tests, histopathological tests, and biochemical tests. The coadministration of different doses of metformin with olanzapine or risperidone was used to evaluate the effects of metformin on both AIMD and the therapeutic effect of those antipsychotics.

Results

The MK801-treated rats showed schizophrenia-like behavior and variations in the shape and volume of the hippocampus. Both olanzapine and risperidone reversed the MK801-induced behavioral abnormalities as the dosage increased; however, they degenerated the hepatocytes in the liver and influenced the blood lipid levels and blood glucose levels. The coadministration of metformin did not affect the therapeutic effects of olanzapine or risperidone on behavioral abnormalities but attenuated the metabolic dysfunctions induced by those antipsychotics.

Conclusion

Metformin attenuated the olanzapine- and risperidone-induced metabolic dysfunctions in MK801-induced schizophrenia-like rats without reducing the therapeutic effects of the antipsychotics.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (2016YFC1306900), National Natural Science Foundation of China (81573508, 81874327), and The Strategy-Oriented Special Project of Central South University in China (ZLXD2017003).

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, China

    Chao Luo, Xu Wang, Xiaoyuan Mao, Hanxue Huang, Honghao Zhou & Zhaoqian Liu

  2. Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, 410078, China

    Chao Luo, Xu Wang, Xiaoyuan Mao, Hanxue Huang, Honghao Zhou & Zhaoqian Liu

  3. School of Life Sciences, Central South University, Changsha, 410078, Hunan, China

    Chao Luo

  4. Mental Health Institute of the Second Xiangya Hospital, National Technology Institute of Psychiatry, Key Laboratory of Psychiatry and Mental Health of Hunan Province, Central South University, No. 139, Renmin Middle Road, Changsha, 410011, China

    Yong Liu & Jingping Zhao

  5. Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, 410008, China

    Xiangping Li

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  1. Chao Luo
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  2. Xu Wang
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  3. Xiaoyuan Mao
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  4. Hanxue Huang
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  5. Yong Liu
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  7. Honghao Zhou
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  8. Zhaoqian Liu
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  9. Xiangping Li
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Correspondence to Zhaoqian Liu or Xiangping Li.

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Highlights

• One effective method to establish a schizophrenia-like animal model involves consecutive injections of MK801 during the neurodevelopmental period, which does not induce metabolic dysfunctions in adulthood.

• Short-term treatment with olanzapine and risperidone reversed the schizophrenia-like symptoms in MK801-treated male rats but induced metabolic dysfunctions as well.

• The coadministration of metformin attenuates the olanzapine- and risperidone-induced metabolic dysfunctions in an animal of schizophrenia without reducing the therapeutic effects of those antipsychotics.

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Luo, C., Wang, X., Mao, X. et al. Metformin attenuates antipsychotic-induced metabolic dysfunctions in MK801-induced schizophrenia-like rats. Psychopharmacology 237, 2257–2277 (2020). https://doi.org/10.1007/s00213-020-05524-w

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  • DOI: https://doi.org/10.1007/s00213-020-05524-w

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