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Benzodiazepines are widely prescribed for the treatment of anxiety. However, the long\u2010term 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      We examined the effects of metformin on anxiety\u2010like behaviour of rats in open field test and elevated plus maze test. We also observed the effect of metformin (10\u00a0\u03bcM,\n                      <jats:italic>in vitro<\/jats:italic>\n                      ; 100\u00a0mg\u00b7kg\n                      <jats:sup>\u22121<\/jats:sup>\n                      ,\n                      <jats:italic>in vivo<\/jats:italic>\n                      ) on the trafficking of GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptors, as mechanisms underlying the anxiolytic effects of metformin.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Metformin (100\u00a0mg\u00b7kg\n                      <jats:sup>\u22121<\/jats:sup>\n                      , i.p. 30\u00a0min) displayed a robust and rapid anxiolytic effect, without tolerance. Metformin up\u2010regulated the surface expression of GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptors and increased miniature inhibitory postsynaptic currents (mIPSCs). AMP\u2010activated protein kinase (AMPK) activated by metformin\u2010induced stimulation of forkhead box O3a (FoxO3a) transcriptional activity, followed by increased expression of GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptor\u2010associated protein (GABARAP) and its binding to GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptors finally resulted in the membrane insertion of GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions and Implications<\/jats:title>\n                    <jats:p>\n                      Metformin increased mIPSCs by up\u2010regulating the membrane insertion of GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptors, via a pathway involving AMPK, FoxO3a, and the GABA\n                      <jats:sub>A<\/jats:sub>\n                      receptor\u2010associated protein. Thus metformin has a potential new use in the treatment of anxiety disorders.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.14519","type":"journal-article","created":{"date-parts":[[2018,10,15]],"date-time":"2018-10-15T01:00:01Z","timestamp":1539565201000},"page":"297-316","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["Metformin produces anxiolytic\u2010like effects in rats by facilitating\n                    <scp>\n                      GABA\n                      <sub>A<\/sub>\n                    <\/scp>\n                    receptor trafficking to membrane"],"prefix":"10.1111","volume":"176","author":[{"given":"Jun","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Basic Medicine, Tongji Medical College Huazhong University of Science and Technology  Wuhan 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