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Brain Res. 2019 Sep 15;1719:30-39. doi: 10.1016/j.brainres.2019.05.023. Epub 2019 May 20.

Metformin reverses the schizophrenia-like behaviors induced by MK-801 in rats.

Author information

1
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, PR China.
2
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, PR China; School of Life Sciences, Central South University, Changsha, Hunan 410078, PR China.
3
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China.
4
Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha 410008, PR China; Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha 410078, PR China; National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, PR China. Electronic address: zqliu@csu.edu.cn.

Abstract

Schizophrenia is known to be a complex and disabling psychiatric disorder. Dopamine receptor antagonists have a significant therapeutic effect in improving the positive symptoms that are associated with the illness. Therefore, dopamine receptor antagonists are commonly used in the treatment of schizophrenia; however, they do not achieve satisfactory results in improving negative symptoms and cognitive impairment. Metformin, widely known as an antidiabetic drug, has been found to enhance spatial memory formation and improve anxiety-like behaviors in rodents. Metformin's neuroprotective effect has been well documented in several neurological disorders including Alzheimer's disease, Parkinson's disease, strokes, Huntington's disease, and seizures. In the present study, we used a rat model to explore the effect of metformin on schizophrenia-like behaviors induced by MK-801 (dizocilpine), an N-methyl-D-aspartate (NMDA) receptor antagonist. We found that the pre-pulse inhibition (PPI) deficit caused by MK-801 could be alleviated by metformin. The hyperlocomotion in the open field test induced by chronic treatment of MK-801 was reversed by administration of metformin. Metformin has no effect on the baseline level of anxiety in normal naive rats, while metformin could relieve the anxiety-like behaviors in MK-801-treatment rats, though this effect is not reaching a significant level. Additionally, metformin could significantly ameliorate working memory impairments induced by MK-801. Moreover, the increased level of phosphorylation of Akt and GSK3β in the frontal cortex induced by MK-801 was normalized by metformin. In conclusion, our results demonstrate that metformin improved schizophrenia-like symptoms in rats, and is therefore a potential agent for the treatment of schizophrenia.

KEYWORDS:

MK-801; Metformin; Rat model; Schizophrenia-like behaviors

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