Research ReportsEvaluation of the antidepressive property of β-hydroxybutyrate in micePan, Shengyinga,,*; Hu, Peilib,,*; You, Qingshengc,,*; Chen, Jinliangd,,*; Wu, Jingjinge; Zhang, Yarub; Cai, Zixuanb; Ye, Tingb; Xu, Xingb; Chen, Zhuof; Tong, Lijuanb; Huang, Chaob; He, Haiyand Author Information aDepartment of Neurology, Danyang People’s Hospital of Nantong University, Danyang bDepartment of Pharmacology, School of Pharmacy, Nantong University cDepartment of Cardiothoracic Surgery, Affiliated Hospital of Nantong University dDepartment of Respiratory Medicine, Nantong First People’s Hospital, the Second Affiliated Hospital of Nantong University, Nantong eDepartment of Cardiology, Suzhou Kowloon Hospital of Shanghai Jiaotong University School of Medicine, Suzhou fInvasive Technology Department, Nantong First People’s Hospital, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu, China *Dr. Shengying Pan, Dr. Peili Hu, Dr. Qingsheng You and Dr. Jinliang Chen contributed equally to the writing of this article. Received 26 February 2019 Accepted as revised 30 October 2019 Correspondence to Haiyan He, Department of Respiratory Medicine, Nantong First People’s Hospital, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, China, E-mail: [email protected] Behavioural Pharmacology: June 2020 - Volume 31 - Issue 4 - p 322-332 doi: 10.1097/FBP.0000000000000535 Buy Metrics Abstract β-hydroxybutyrate, a ketone body metabolite, has been shown to suppress depression-like behavior in rodents. In this study, we examined its antidepressive property in acute and chronic administration modes in mice by using forced swim test and tail suspension test. Results showed that the decrease effect of β-hydroxybutyrate (300 mg/kg) on immobility time in the tail suspension test and forced swim test in stress-naive mice began to be significant at day 11. In a dose-dependent experiment, β-hydroxybutyrate treatment (11 days) showed significant antidepressant activities at the dose of 200 and 300 mg/kg. Unlike fluoxetine, β-hydroxybutyrate treatment (300 mg/kg) showed no antidepressant activities in the acute (1 hour before the test) and three times administration mode within 24 hours (1, 5, and 24 hours before the test). But in a co-administration mode, β-hydroxybutyrate (100 mg/kg) -fluoxetine (2.5 mg/kg) co-administration exhibited an obvious antidepressant activity in the tail suspension test and forced swim test. Further analysis showed that the antidepressant effects of β-hydroxybutyrate and fluoxetine were not associated with the change in mouse locomotor activity. Furthermore, both chronic β-hydroxybutyrate treatment and β-hydroxybutyrate-fluoxetine co-treatment suppressed chronic unpredictable stress-induced increase in immobility time in the tail suspension test and forced swim test as well as chronic unpredictable stress-induced decrease in mouse body weight. Taken together, these results indicate that β-hydroxybutyrate (1) needs a relatively long time to show comparable behavioral activity to that of fluoxetine in assays that are sensitive to the behavioral effects of established antidepressant compounds and (2) can augment the antidepressant action of a sub-therapeutic dose of fluoxetine. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.