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New monoamine antidepressant, hypidone hydrochloride (YL-0919), enhances the excitability of medial prefrontal cortex in mice via a neural disinhibition mechanism

文献类型：期刊论文

作者Zhang, Yong-Mei1,2; Ye, Lu-Yu1,2; Li, Tian-Yu1,2; Guo, Fan1,2; Guo, Fei1,2; Li, Yang1,2; Li, Yun-Feng3
刊名ACTA PHARMACOLOGICA SINICA
出版日期2021-11-22
页码11
ISSN号1671-4083
关键词YL-0919 medial prefrontal cortex GABAergic neurons 5-HT1A receptor GAD67-GFP transgenic mice disinhibition fluoxetine electrophysiological recording
DOI10.1038/s41401-021-00807-0
通讯作者Guo, Fei(guofei@simm.ac.cn) ; Li, Yang(liyang@simm.ac.cn) ; Li, Yun-Feng(lyf619@aliyun.com)
英文摘要Hypidone hydrochloride (YL-0919) is a novel antidepressant in clinical phase II trial. Previous studies show that YL-0919 is a selective 5-HT (serotonin) reuptake inhibitor, 5-HT1A receptor partial agonist, and 5-HT6 receptor agonist, which exerts antidepressant effects in various animal models, but its effects on neural function remain unclear. Medial prefrontal cortex (mPFC), a highly evolved brain region, controls highest order cognitive functions and emotion regulation. In this study we investigated the effects of YL-0919 on the mPFC function, including the changes in neuronal activities using electrophysiological recordings. Extracellular recording (in vivo) showed that chronic administration of YL-0919 significantly increased the spontaneous discharges of mPFC neurons. In mouse mPFC slices, whole-cell recording revealed that perfusion of YL-0919 significantly increased the frequency of sEPSCs, but decreased the frequency of sIPSCs. Then we conducted whole-cell recording in mPFC slices of GAD67-GFP transgenic mice, and demonstrated that YL-0919 significantly inhibited the excitability of GABAergic neurons. In contrast, it did not alter the excitability of pyramidal neurons in mPFC slices of normal mice. Moreover, the inhibition of GABAergic neurons by YL-0919 was prevented by pre-treatment with 5-HT1A receptor antagonist WAY 100635. Finally, chronic administration of YL-0919 significantly increased the phosphorylation levels of mTOR and GSK-3 beta in the mPFC as compared with vehicle. Taken together, our results demonstrate that YL-0919 enhances the excitability of mPFC via a disinhibition mechanism to fulfill its rapid antidepressant neural mechanism, which was accomplished by 5-HT1A receptor-mediated inhibition of inhibitory GABAergic interneurons.
WOS关键词MAJOR DEPRESSIVE DISORDER ; 5-HT1A ; STRESS ; RECEPTORS ; VILAZODONE ; AGONISTS ; AMYGDALA
资助项目Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040220] ; National Natural Science Foundation of China[31671049] ; National Natural Science Foundation of China[81773708] ; National Natural Science Foundation of China[81072624] ; National Natural Science Foundation of China[81173036] ; National Key New Drug Creation Program of China[2017ZX09309012] ; National Key New Drug Creation Program of China[2018ZX09739008] ; National Key New Drug Creation Program of China[2018ZX09711002-002-012]
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
出版者NATURE PUBL GROUP
WOS记录号WOS:000721428700001
源URL[http://119.78.100.183/handle/2S10ELR8/298988]  
专题中国科学院上海药物研究所
通讯作者Guo, Fei; Li, Yang; Li, Yun-Feng
作者单位1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
2.Chinese Acad Sci, Ctr Neurol & Psychiat Res & Drug Discovery, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
3.Beijing Inst Pharmacol & Toxicol, State Key Lab Toxicol & Med Countermeasures, Beijing Key Lab Neuropsychopharmacol, Beijing 100850, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Yong-Mei,Ye, Lu-Yu,Li, Tian-Yu,et al. New monoamine antidepressant, hypidone hydrochloride (YL-0919), enhances the excitability of medial prefrontal cortex in mice via a neural disinhibition mechanism[J]. ACTA PHARMACOLOGICA SINICA,2021:11.
APA Zhang, Yong-Mei.,Ye, Lu-Yu.,Li, Tian-Yu.,Guo, Fan.,Guo, Fei.,...&Li, Yun-Feng.(2021).New monoamine antidepressant, hypidone hydrochloride (YL-0919), enhances the excitability of medial prefrontal cortex in mice via a neural disinhibition mechanism.ACTA PHARMACOLOGICA SINICA,11.
MLA Zhang, Yong-Mei,et al."New monoamine antidepressant, hypidone hydrochloride (YL-0919), enhances the excitability of medial prefrontal cortex in mice via a neural disinhibition mechanism".ACTA PHARMACOLOGICA SINICA (2021):11.

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来源：上海药物研究所

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