Metformin Ameliorates Lipopolysaccharide-Induced Depressive-Like Behaviors and Abnormal Glutamatergic Transmission

SIMPLE SUMMARY: Metformin is a promising drug for diabetes and has been reported to have antidepressant effects in depression patients or patients with comorbid depression and other diseases. However, it is largely unclear how metformin ameliorates depressive-like behaviors. To this end, we injected mice with a bacterial endotoxin (lipopolysaccharide) to induce depressive-like behaviors such as increased immobility in the forced swimming test and tail suspension test. In this depression mouse model, metformin administration ameliorated depressive-like behaviors. Glutamate is a major excitatory signal for the communications between neurons in the brain. Dysfunction of glutamatergic neurotransmission is implicated in the pathogenesis of depression. Glutamatergic transmission was elevated in our depression mouse model. Metformin administration also recovered the glutamatergic transmission deficit in the model. Taken together, our results suggest metformin had antidepressant effects and can correct abnormal glutamatergic transmission in the lipopolysaccharide-induced depression mouse model. These findings provide new insights into the underlying mechanism by which metformin acts against depression. ABSTRACT: Metformin, a first-line drug for type 2 diabetes mellitus (T2DM), has been found to reduce depressive symptoms in patients with comorbid depression and other diseases. However, it is largely unclear how metformin ameliorates depressive-like behaviors. Here, we used lipopolysaccharide (LPS) to induce depressive-like behaviors in mice and found that LPS-treated mice exhibited increased immobility in the forced swimming test (FST) and tail suspension test (TST), as well as increased glutamatergic transmission. Furthermore, metformin administration in the LPS-treated mice ameliorated depressive-like behaviors and elevated glutamatergic transmission. Our results suggest that metformin has antidepressant effects and can correct abnormal glutamatergic transmission, providing an insight into the underlying mechanism by which metformin acts against depression.