Electrophysiological Mechanism Underlying The Rapid Antidepressant Actions Of Hypidone Hydrochloride(YL-0919)

Objective:Hypidone hydrochloride(YL-0919),a novel small-molecule compound which is identified as a potential selective serotonin reuptake inhibitor(SSRI),5-hydroxytryptamine(5-HT)1A receptor agonist and 5-HT 6 receptor agonist.Our previous studies revealed that hypidone hydrochloride(YL-0919)exerted a significant antidepressant effect in various animal models,but further research is needed on its antidepressant mechanism.This research will use behavioral pharmacology and neurobiological means to study the rapid onset of antidepressant effect of hypidone hydrochloride(YL-0919)and possible electrophysiological mechanisms.Method(1)The forced swimming test(FST)and Chronic unpredictable stress model(CUS)in rats were used to evaluate the antidepressant activity of YL-0919.(2)The multi-channel in vivo recording system was used to observe the effects of YL-0919 on the excitability of mPFC pyramidal neurons in normal rats and depression rats and to explore the possible mechanism.Result(1)YL-0919(0.625、1.25、2.5 mg/kg i.p.)significantly decreased the immobility time in the TST;Compared to fluoxetine,YL-0919(2.5mg/kg,i.g.)significantly improved depression-like behavior in CUS rats 4 days after administration.Including decrease in sucrose preference and increase in the latency to Novelty suppressed feeding behavior.(2)In multi-channel in vivo recording,a single intraperitoneal injection of YL-0919(2.5 mg/kg,i.p.)can rapidly stimulate mPFC pyramidal neurons,but fluoxetine does not have this effect;5-HT1A receptor antagonists WAY100635(0.1,0.3 mg/kg I.P.)can antagonize this stimulatory effect of YL-0919,5-HT6 receptor antagonists SB271046(3,10 mg/kg I.P.)do not have this effect;GABAA receptor antagonist bicuculline(2 mg/kg i.p.)can significantly reduce the excitotoxicity of YL-0919 on pyramidal neurons;CUS reduces spontaneous firing frequency of pyramidal neurons in the medial prefrontal cortex,and a single administration of YL-0919 for 1 h reversed this phenomenon,but there was no significant change after FLX treatment.In addition;there was no significant effect on the excitability of mPFC pyramidal neurons after continuous administration of YL-0919 and FLX for 4 days.Conclusion(1)YL-0919 has a significant antidepressant effect in rat acute and chronic stress models,and chronic unpredictable stress results suggest that YL-0919 has a rapid onset antidepressant effect.(2)YL-0919 can rapidly stimulate mPFC pyramidal neurons and 5-HT1A receptor activation may be an important link.GABAergic interneurons may be involved in the rapid excitation of pyramidal neurons induced by YL-0919.The excitatory effect of YL-0919 on pyramidal neurons may be an important starting point for its rapid antidepressant.