Metformin produces anxiolytic‐like effects in rats by facilitating GABAA receptor trafficking to membrane

• Published in: British journal of pharmacology 2019-01, Vol.176 (2), p.297-316
• Main Authors: Fan, Jun, Li, Di, Chen, Hong‐Sheng, Huang, Jian‐Geng, Xu, Jun‐Feng, Zhu, Wen‐Wen, Chen, Jian‐Guo, Wang, Fang
• Format: Article
• Language: English
• Subjects: AMP; Antidiabetics; Anxiety; Benzodiazepines; Dependence; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Drug dependence; Forkhead protein; FOXO3 protein; GABARAP protein; Inhibitory postsynaptic potentials; Insertion; Kinases; Membrane trafficking; Mental disorders; Metabolic disorders; Metformin; Open-field behavior; Protein kinase; Protein transport; Proteins; Receptor mechanisms; Research Paper; Research Papers; Transcription; γ-Aminobutyric acid A receptors
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.14519

Background and Purpose Altered function or expression of GABAA receptors contributes to anxiety disorders. Benzodiazepines are widely prescribed for the treatment of anxiety. However, the long‐term use of benzodiazepines increases the risk of developing drug dependence and tolerance. Thus, it is urgent to explore new therapeutic approaches. Metformin is widely used to treat Type 2 diabetes and other metabolic syndromes. However, the role of metformin in psychiatric disorders, especially anxiety, remains largely unknown. Experimental Approach We examined the effects of metformin on anxiety‐like behaviour of rats in open field test and elevated plus maze test. We also observed the effect of metformin (10 μM, in vitro; 100 mg·kg−1, in vivo) on the trafficking of GABAA receptors, as mechanisms underlying the anxiolytic effects of metformin. Key Results Metformin (100 mg·kg−1, i.p. 30 min) displayed a robust and rapid anxiolytic effect, without tolerance. Metformin up‐regulated the surface expression of GABAA receptors and increased miniature inhibitory postsynaptic currents (mIPSCs). AMP‐activated protein kinase (AMPK) activated by metformin‐induced stimulation of forkhead box O3a (FoxO3a) transcriptional activity, followed by increased expression of GABAA receptor‐associated protein (GABARAP) and its binding to GABAA receptors finally resulted in the membrane insertion of GABAA receptors. Conclusions and Implications Metformin increased mIPSCs by up‐regulating the membrane insertion of GABAA receptors, via a pathway involving AMPK, FoxO3a, and the GABAA receptor‐associated protein. Thus metformin has a potential new use in the treatment of anxiety disorders.