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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology
  • Anxiety / drug therapy
  • Behavior, Animal / drug effects
  • Cognition Disorders / drug therapy
  • Cognitive Dysfunction / drug therapy
  • Disease Models, Animal
  • Dizocilpine Maleate / pharmacology
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Male
  • Maze Learning / drug effects
  • Memory, Short-Term / drug effects
  • Metformin / pharmacology*
  • Neuroprotective Agents / pharmacology
  • Prepulse Inhibition / drug effects
  • Proto-Oncogene Proteins c-akt / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reflex, Startle / drug effects
  • Schizophrenia / chemically induced
  • Schizophrenia / drug therapy*
  • Schizophrenia / metabolism


  • Antipsychotic Agents
  • Neuroprotective Agents
  • Dizocilpine Maleate
  • Metformin
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt