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

Background and Purpose Altered function or expression of GABA(A) 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 mu M, in vitro; 100 mg center dot kg(-1), in vivo) on the trafficking of GABA(A) receptors, as mechanisms underlying the anxiolytic effects of metformin. Key Results Metformin (100 mg center dot kg(-1), i.p. 30 min) displayed a robust and rapid anxiolytic effect, without tolerance. Metformin up-regulated the surface expression of GABA(A) 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 GABA(A) receptor-associated protein (GABARAP) and its binding to GABA(A) receptors finally resulted in the membrane insertion of GABA(A) receptors. Conclusions and Implications Metformin increased mIPSCs by up-regulating the membrane insertion of GABA(A) receptors, via a pathway involving AMPK, FoxO3a, and the GABA(A) receptor-associated protein. Thus metformin has a potential new use in the treatment of anxiety disorders.