PMID- 28625859 OWN - NLM STAT- MEDLINE DCOM- 20180612 LR - 20181101 IS - 1878-4216 (Electronic) IS - 0278-5846 (Linking) VI - 79 IP - Pt B DP - 2017 Oct 3 TI - Harmine produces antidepressant-like effects via restoration of astrocytic functions. PG - 258-267 LID - S0278-5846(17)30239-7 [pii] LID - 10.1016/j.pnpbp.2017.06.012 [doi] AB - Depression is a world-wide disease with no effective therapeutic methods. Increasing evidence indicates that astrocytic pathology contributes to the formation of depression. In this study, we investigated the effects of harmine, a natural beta-carboline alkaloid and potent hallucinogen, known to modulate astrocytic glutamate transporters, on chronic unpredictable stress (CUS)-induced depressive-like behaviors and astrocytic dysfunctions. Results showed that harmine treatment (10, 20mg/kg) protected the mice against the CUS-induced increases in the immobile time in the tail suspension test (TST) and forced swimming test (FST), and also reversed the reduction in sucrose intake in the sucrose preference experiment. Harmine treatment (20mg/kg) prevented the reductions in brain-derived neurotrophic factor (BDNF) protein levels and hippocampal neurogenesis induced by CUS. In addition, harmine treatment (20mg/kg) increased the protein expression levels of glutamate transporter 1 (GLT-1) and prevented the CUS-induced decreases in glial fibrillary acidic protein (GFAP) protein expressions in the prefrontal cortex and hippocampus, suggesting that restoration of astrocytic functions may be a potential mechanism underlying the antidepressant-like effects of harmine. This opinion was proved by the results that administration of mice with l-Alpha-Aminoadipic Acid (L-AAA), a gliotoxin specific for astrocytes, attenuated the antidepressant-like effects of harmine, and prevented the improvement effects of harmine on BDNF protein levels and hippocampal neurogenesis. These results provide further evidence to confirm that astrocytic dysfunction contributes critically to the development of depression and that harmine exerts antidepressant-like effects likely through restoration of astrocytic functions. CI - Copyright (c) 2017 Elsevier Inc. All rights reserved. FAU - Liu, Fengguo AU - Liu F AD - Department of Neurology, Danyang People's Hospital, #2 Xinmin Western Road, Danyang 212300, Jiangsu, China. FAU - Wu, Jingjing AU - Wu J AD - Department of Cardiology, Suzhou Kowloon Hospital of Shanghai Jiaotong University School of Medicine, #118 Wansheng Street, Suzhou 215021, Jiangsu, China. FAU - Gong, Yu AU - Gong Y AD - Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong 226001, Jiangsu, China. FAU - Wang, Peng AU - Wang P AD - Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong 226001, Jiangsu, China. FAU - Zhu, Lei AU - Zhu L AD - Department of Pharmacy, First People's Hospital of Yancheng, Yulong Western Road, Yancheng 224006, Jiangsu, China. FAU - Tong, Lijuan AU - Tong L AD - Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong 226001, Jiangsu, China. FAU - Chen, Xiangfan AU - Chen X AD - Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong 226001, Jiangsu, China. FAU - Ling, Yong AU - Ling Y AD - Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong 226001, Jiangsu, China. FAU - Huang, Chao AU - Huang C AD - Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu, China; Key Laboratory of Inflammation and Molecular Drug Target of Jiangsu Province, #19 Qixiu Road, Nantong 226001, Jiangsu, China. Electronic address: huachao@ntu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170615 PL - England TA - Prog Neuropsychopharmacol Biol Psychiatry JT - Progress in neuro-psychopharmacology & biological psychiatry JID - 8211617 RN - 0 (Antidepressive Agents) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Excitatory Amino Acid Transporter 2) RN - 0 (Slc1a2 protein, mouse) RN - 01K63SUP8D (Fluoxetine) RN - 4FHH5G48T7 (Harmine) SB - IM MH - Anhedonia/drug effects/physiology MH - Animals MH - Antidepressive Agents/*pharmacology MH - Astrocytes/*drug effects/metabolism/pathology MH - Brain-Derived Neurotrophic Factor/metabolism MH - Chronic Disease MH - Depressive Disorder/*drug therapy/metabolism/pathology MH - Disease Models, Animal MH - Dose-Response Relationship, Drug MH - Excitatory Amino Acid Transporter 2/metabolism MH - Fluoxetine/pharmacology MH - Harmine/*pharmacology MH - Hippocampus/drug effects/metabolism/pathology MH - Male MH - Mice, Inbred C57BL MH - Neurogenesis/drug effects/physiology MH - Prefrontal Cortex/drug effects/metabolism/pathology MH - Stress, Psychological/drug therapy/metabolism/pathology MH - Uncertainty OTO - NOTNLM OT - Astrocyte OT - Chronic unpredictable stress OT - Depression OT - Glutamate transporter 1 OT - Harmine EDAT- 2017/06/20 06:00 MHDA- 2018/06/13 06:00 CRDT- 2017/06/20 06:00 PHST- 2017/03/26 00:00 [received] PHST- 2017/06/14 00:00 [revised] PHST- 2017/06/14 00:00 [accepted] PHST- 2017/06/20 06:00 [pubmed] PHST- 2018/06/13 06:00 [medline] PHST- 2017/06/20 06:00 [entrez] AID - S0278-5846(17)30239-7 [pii] AID - 10.1016/j.pnpbp.2017.06.012 [doi] PST - ppublish SO - Prog Neuropsychopharmacol Biol Psychiatry. 2017 Oct 3;79(Pt B):258-267. doi: 10.1016/j.pnpbp.2017.06.012. Epub 2017 Jun 15.