典型文献
New monoamine antidepressant,hypidone hydrochloride(YL-0919),enhances the excitability of medial prefrontal cortex in mice via a neural disinhibition mechanism
文献摘要：
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-3β 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.
文献关键词：
中图分类号：
作者姓名：
Yong-mei Zhang;Lu-yu Ye;Tian-yu Li;Fan Guo;Fei Guo;Yang Li;Yun-feng Li
作者机构：
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;University of Chinese Academy of Sciences,Beijing 100049,China;Beijing Institute of Pharmacology and Toxicology,State Key Laboratory of Toxicology and Medical Countermeasures,Beijing Key Laboratory of Neuropsychopharmacology,Beijing 100850,China
文献出处：
引用格式：
[1]Yong-mei Zhang;Lu-yu Ye;Tian-yu Li;Fan Guo;Fei Guo;Yang Li;Yun-feng Li-.New monoamine antidepressant,hypidone hydrochloride(YL-0919),enhances the excitability of medial prefrontal cortex in mice via a neural disinhibition mechanism)[J].中国药理学报（英文版）,2022(07):1699-1709
A类：
hypidone,Hypidone,HT6,sEPSCs,sIPSCs
B类：
New,monoamine,antidepressant,hydrochloride,YL,enhances,excitability,medial,prefrontal,cortex,mice,via,neural,disinhibition,mechanism,novel,clinical,phase,trial,Previous,studies,that,selective,serotonin,reuptake,HT1A,receptor,partial,which,exerts,effects,various,animal,models,but,its,remain,unclear,Medial,mPFC,highly,evolved,brain,region,controls,highest,order,cognitive,functions,emotion,regulation,In,this,study,investigated,including,changes,neuronal,activities,using,electrophysiological,recordings,Extracellular,vivo,showed,chronic,administration,significantly,increased,spontaneous,discharges,mouse,slices,whole,revealed,perfusion,frequency,decreased,Then,conducted,GAD67,GFP,transgenic,demonstrated,inhibited,GABAergic,contrast,did,not,alter,pyramidal,normal,Moreover,by,was,prevented,treatment,antagonist,WAY,Finally,phosphorylation,levels,mTOR,GSK,compared,vehicle,Taken,together,our,results,fulfill,rapid,accomplished,mediated,inhibitory,interneurons
AB值：
0.48612
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