title: TREK1 channel blockade induces an antidepressant-like response synergizing with 5-HT1A receptor signaling.
abstract: Current antidepressants often remain the inadequate efficacy for many depressive patients, which warrant the necessary endeavor to develop the new molecules and targets for treating depression. Recently, the two-pore domain potassium channel TREK1 has been implicated in mood regulation and TREK-1 antagonists could be the promising antidepressant. This study has screened a TREK1 blocker (SID1900) with a satisfactory blood-brain barrier permeation and bioavailability. Electrophysiological research has shown that SID1900 and the previously reported TREK1 blocker (spadin) efficiently blocked TREK-1 current in HEK293 cells and specifically blocked two-pore domain potassium channels in primary-cultured rat hippocampal neurons. SID1900 and spadin induced a significant antidepressant-like response in the rat model of chronic unpredictable mild stress (CUMS). Both two TREK1 blockers substantially increased the firing rate of 5-HT-ergic neurons in the dorsal raphe nuclei (DRN) and PFC of CUMS rats. SID1900 and spadin significantly up-regulated the expression of PKA-pCREB-BDNF signaling in DRN, hippocampus and PFC of CUMS rats, which were enhanced and reversed by a 5-HTR1A agonist (8-OH-DPAT) and antagonist (WAY100635) respectively. The present findings suggested that TREK1 channel blockers posses the substantial antidepressant-like effect and have the potential synergistic effect with 5-HT1A receptor activation through the common CREB-BDNF signal transduction.
authors.affiliation: Neurologic Department, Neuropsychiatric Institute, Medical School, Affiliated ZhongDa Hospital, Southeast University, 87 DingJiaQiao Road, Nanjing, 210009 Jiangsu, People׳s Republic of China. Electronic address: dongdong822625@163.com.
authors.forename: Dongqing
authors.initials: D
authors.lastname: Ye
authors.affiliation: Pharmacological laboratory in Shanghai Institute of Materia Medica affiliated Chinese Academy Sciences, Shanghai 201203, People׳s Republic of China. Electronic address: liyang@simm.ac.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Neurologic Department of Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, 210029, Jiangsu, People׳s Republic of China. Electronic address: drxrz@hotmail.com.
authors.forename: Xiangrong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Pharmacological laboratory in Shanghai Institute of Materia Medica affiliated Chinese Academy Sciences, Shanghai 201203, People׳s Republic of China. Electronic address: flyguo82@hotmail.com.
authors.forename: Fei
authors.initials: F
authors.lastname: Guo
authors.affiliation: Neurologic Department, Neuropsychiatric Institute, Medical School, Affiliated ZhongDa Hospital, Southeast University, 87 DingJiaQiao Road, Nanjing, 210009 Jiangsu, People׳s Republic of China. Electronic address: xxx.0351@163.com.
authors.forename: Leiyu
authors.initials: L
authors.lastname: Geng
authors.affiliation: Pharmacological laboratory in Shanghai Institute of Materia Medica affiliated Chinese Academy Sciences, Shanghai 201203, People׳s Republic of China. Electronic address: qiqizhang822@163.com.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Neurologic Department, Neuropsychiatric Institute, Medical School, Affiliated ZhongDa Hospital, Southeast University, 87 DingJiaQiao Road, Nanjing, 210009 Jiangsu, People׳s Republic of China. Electronic address: janemengzhang@vip.163.com.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D018490:Serotonin Agents / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013315:Stress, Psychological / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D014162:Transfection
chemical_list: D000928:Antidepressive Agents; D001643:Bridged Bicyclo Compounds; D010080:Oxazoles; D010455:Peptides; D024683:Potassium Channels, Tandem Pore Domain; C000611224:SID1900; D018490:Serotonin Agents; C103742:potassium channel protein TREK-1; C551795:spadin peptide; D044282:Receptor, Serotonin, 5-HT1A
keywords: 5-HT(1A) receptor; Antidepressant; Brain derived neurotrophic factor (BDNF); Chronic unpredictable mild stress (CUMS); SID1900; TWIK-related mechano-gated K(+) channel (TREK1)