Jun Fan1, Di Li1, Hong-Sheng Chen1, Jian-Geng Huang2, Jun-Feng Xu1, Wen-Wen Zhu2, Jian-Guo Chen1,3,4,5,6, Fang Wang1,3,4,5,6. 1. Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 2. Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 3. The Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, China. 4. Hubei Key Laboratory of Drug Target Research and Pharmacodynamic Evaluation (HUST), Wuhan, China. 5. Laboratory of Neuropsychiatric Diseases, The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China. 6. The Collaborative-Innovation Center for Brain Science, Wuhan, China.
Abstract
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.
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.
Authors: R O Tasan; A Bukovac; Y N Peterschmitt; S B Sartori; R Landgraf; N Singewald; G Sperk Journal: Neuroscience Date: 2011-03-31 Impact factor: 3.590
Authors: Julia K Brynildsen; Bridgin G Lee; Isaac J Perron; Sunghee Jin; Sangwon F Kim; Julie A Blendy Journal: Proc Natl Acad Sci U S A Date: 2018-04-02 Impact factor: 11.205