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

作　　者：Yong-mei Zhang Lu-yu Ye Tian-yu Li Fan Guo Fei Guo Yang Li Yun-feng Li 

机构地区：[1]CAS Key Laboratory of Receptor Research,Center for Neurological and Psychiatric Research and Drug Discovery,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China [2]University of Chinese Academy of Sciences,Beijing 100049,China [3]Beijing Institute of Pharmacology and Toxicology,State Key Laboratory of Toxicology and Medical Countermeasures,Beijing Key Laboratory of Neuropsychopharmacology,Beijing 100850,China

出　　处：《Acta Pharmacologica Sinica》2022年第7期1699-1709,共11页中国药理学报（英文版）

基　　金：This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDA12040220);the National Natural Science Foundation of China(31671049,81773708,81072624,and 81173036);the National Key New Drug Creation Program of China(No.2017ZX09309012,2018ZX09739008,and 2018ZX09711002-002-012).

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-3βin 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.

关 键 词：YL-0919 medial prefrontal cortex GABAergic neurons 5-HT1A receptor GAD67-GFP transgenic mice DISINHIBITION FLUOXETINE electrophysiological recording 

分 类 号：R96[医药卫生—药理学]