title: SKF83959 produces antidepressant effects in a chronic social defeat stress model of depression through BDNF-TrkB pathway.
abstract: BACKGROUND
  SKF83959 stimulates the phospholipase Cβ/inositol phosphate 3 pathway, resulting in the activation of Ca(2+)/calmodulin-dependent kinase IIα, which affects the synthesis of brain-derived neurotrophic factor, a neurotrophic factor critical for the pathophysiology of depression. Previous reports showed that SKF83959 elicited antidepressant activity in the forced swim test and tail suspension test as a novel triple reuptake inhibitor. However, there are no studies showing the effects of SKF83959 in a chronic stress model of depression and the role of phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIα/brain-derived neurotrophic factor pathway in SKF83959-mediated antidepressant effects.
  
  
  METHODS
  In this study, SKF83959 was firstly investigated in the chronic social defeat stress model of depression. The changes in hippocampal neurogenesis, dendrite spine density, and brain-derived neurotrophic factor signaling pathway after chronic social defeat stress and SKF83959 treatment were then investigated. Pharmacological inhibitors and small interfering RNA/short hairpin RNA methods were further used to explore the antidepressive mechanisms of SKF83959.
  
  
  RESULTS
  We found that SKF83959 produced antidepressant effects in the chronic social defeat stress model and also restored the chronic social defeat stress-induced decrease in hippocampal brain-derived neurotrophic factor signaling pathway, dendritic spine density, and neurogenesis. By using various inhibitors and siRNA/shRNA methods, we further demonstrated that the hippocampal dopamine D5 receptor, phospholipase C/inositol phosphate 3/ calmodulin-dependent kinase IIα pathway, and brain-derived neurotrophic factor system are all necessary for the SKF83959 effects.
  
  
  CONCLUSIONS
  These results suggest that SKF83959 can be developed as a novel antidepressant and produces antidepressant effects via the hippocampal D5/ phospholipase C/inositol phosphate 3/calmodulin-dependent kinase IIα/brain-derived neurotrophic factor pathway.
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Drs Jiang, Wang, Yang, Fang, Deng, Xiao, and Chen); Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Hubei, China (Drs Wang, Hu, and Chen); The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China (Drs Wang, Hu, and Chen); The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China (Drs Wang and Chen).
authors.forename: Bo
authors.initials: B
authors.lastname: Jiang
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Drs Jiang, Wang, Yang, Fang, Deng, Xiao, and Chen); Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Hubei, China (Drs Wang, Hu, and Chen); The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China (Drs Wang, Hu, and Chen); The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China (Drs Wang and Chen).
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Drs Jiang, Wang, Yang, Fang, Deng, Xiao, and Chen); Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Hubei, China (Drs Wang, Hu, and Chen); The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China (Drs Wang, Hu, and Chen); The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China (Drs Wang and Chen).
authors.forename: Si
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Drs Jiang, Wang, Yang, Fang, Deng, Xiao, and Chen); Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Hubei, China (Drs Wang, Hu, and Chen); The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China (Drs Wang, Hu, and Chen); The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China (Drs Wang and Chen).
authors.forename: Peng
authors.initials: P
authors.lastname: Fang
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Drs Jiang, Wang, Yang, Fang, Deng, Xiao, and Chen); Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Hubei, China (Drs Wang, Hu, and Chen); The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China (Drs Wang, Hu, and Chen); The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China (Drs Wang and Chen).
authors.forename: Zhi-Fang
authors.initials: ZF
authors.lastname: Deng
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Drs Jiang, Wang, Yang, Fang, Deng, Xiao, and Chen); Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Hubei, China (Drs Wang, Hu, and Chen); The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China (Drs Wang, Hu, and Chen); The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China (Drs Wang and Chen).
authors.forename: Jun-Li
authors.initials: JL
authors.lastname: Xiao
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Drs Jiang, Wang, Yang, Fang, Deng, Xiao, and Chen); Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Hubei, China (Drs Wang, Hu, and Chen); The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China (Drs Wang, Hu, and Chen); The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China (Drs Wang and Chen).
authors.forename: Zhuang-Li
authors.initials: ZL
authors.lastname: Hu
authors.affiliation: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (Drs Jiang, Wang, Yang, Fang, Deng, Xiao, and Chen); Key Laboratory of Neurological Diseases (HUST), Ministry of Education of China, Wuhan, Hubei, China (Drs Wang, Hu, and Chen); The Key Laboratory for Drug Target Researches and Pharmacodynamic Evaluation of Hubei Province, Wuhan, China (Drs Wang, Hu, and Chen); The Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, China (Drs Wang and Chen). chenj@mails.tjmu.edu.cn.
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Chen
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002908:Chronic Disease; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D011505:Protein-Tyrosine Kinases / Q000187:drug effects* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D050641:Receptors, Dopamine D5 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D012919:Social Behavior; D013315:Stress, Psychological / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D010738:Type C Phospholipases / Q000378:metabolism; D020813:Receptor, trkB
chemical_list: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D018491:Dopamine Agonists; D015544:Inositol 1,4,5-Trisphosphate; D008562:Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; D034741:RNA, Small Interfering; D050641:Receptors, Dopamine D5; D010738:Type C Phospholipases; C080703:SK&F 83959; C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB; C517671:Camk2a protein, mouse
keywords: SKF83959; brain-derived neurotrophic factor; chronic social defeat stress; depression