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Qingchuan Hu,1–3,* Peng Shen,1,2,4,* Shunjie Bai,1–3,* Meixue Dong,1,2,4,* Zihong Liang,1,2,4,5 Zhi Chen,1,2,6 Wei Wang,1,2,6 Haiyang Wang,1,2 Siwen Gui,1,2 Pengfei Li,1,2 Peng Xie1–4,6 1Chongqing Key Laboratory of Neurobiology, 2Institute of Neuroscience and the Collaborative Innovation Center for Brain Science, 3Key Laboratory of Laboratory Medical Diagnostics of Education, Department of Laboratory Medicine, Chongqing Medical University, 4Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 5Department of Neurology, The Inner Mongolia Autonomous Region People’s Hospital, Hohhot, Inner Mongolia, 6Department of Neurology, Yongchuan Hospital, Chongqing Medical University, Chongqing, China*These authors contributed equally to this work Purpose: Ginkgo biloba extract (GBE) contains diterpene ginkgolides (DGs), which have been shown to have neuroprotective effects by a number of previous studies. We previously demonstrated part of the action of DG. However, the impact of DG on the prefrontal cortex (PFC) remains unclear. Here, we evaluated the effects of DG and venlafaxine (for comparison) on behavioral and metabolite changes in the PFC using mice models and gas chromatography–mass spectrometry-based metabolomics.Materials and methods: Mice were randomly divided into control (saline), DG (12.18 mg/kg) and venlafaxine (16 mg/kg) groups. After 2 weeks of treatment, depression and anxiety-related behavioral tests were performed. Metabolic profiles of the PFC were detected by gas chromatography–mass spectrometry.Results: The DG group exhibited positive effects in the sucrose preference test. The differential metabolites were mainly related to amino acid metabolism, energy metabolism and lipid metabolism. The results indicated that the DG group exhibited perturbed lipid metabolism, molecular transport and small-molecule biochemistry in the PFC. Compared with the control