The Anxiolytic-and Anti-depressant-like Effects Of ATPM-ET And The Underlying Mechanism

Background:Opioid receptors are implicated in the regulation of motivation and emotion.However,animal studies show that activation of κ opioid receptor produces contrasting mood-altering effects in models of anxiety-like and depressive-like behaviors,and consequently,the role of κ receptor in mood control remains unsettled.The effect of κ/μ opioid combination in emotion regulation was unexplored.Objective:The aim of the study was to investigate the effects of(-)-3-Nethylaminothiazolo [5,4-b]-N-cyclopropylmethylmorphinan hydrochloride(ATPMET),a novel κ agonist and μ partial agonist,in regulating emotional responses.Method:(1)To evaluate the effect of ATPM-ET on anxious-like behavior.EPM(Elevated Plus Maze)and OPF(Open Field)was used in this part to evaluate the effect of ATPM-ET on anxious-like behavior.Groups: Control(Saline,Tool Drug),ATPMET;Dose: Tool Drug(Diazepam,1 mg/kg),ATPM-ET(2 mg/kg,1 mg/kg,0.5 mg/kg);Administration: Subcutaneous Injection.(2)To evaluate the effect of ATPM-ET on Depression-like behavior.FST(Force Swim Test)and TST(Tail Suspension Test)were used in this part to evaluate the effect of ATPM-ET on anxious-like behavior.Groups: Control(Saline,Tool Drug),ATPM-ET;Dose: Tool Drug(Fluoxetine,10mg/kg),ATPM-ET(1 mg/kg,0.5 mg/kg,0.05 mg/kg);Administration: Subcutaneous Injection.(3)To detect the opioid receptor subtypes which involved in ATPM-ET regulation of anxiety and depression.The κ receptor blocking agent nor-BNI(nor-Binaltorphimine)and μ receptor blocking agent β-FBA(β-Funaltrexamine)were used to block the corresponding receptor subtype activity,and combined ATPM-ET to evaluate the emotional index,the analyze the relationship between the drug and the corresponding subtype.Groups: Antagonists(Saline,Drug),Control(Saline,Drug);Dose: nor-BNI(10 mg/kg),β–Funaltrexamine(20 mg/kg),ATPM-ET(2 mg/kg);Administration: Antagonists(Intraperitoneal Injection),Others(Subcutaneous Injection).(4)To evaluate the effect of ATPM-ET on the spontaneous activity of animals.In this part,the effect of ATPM-ET on locomotor activity of animals was detected by locomotor activity test.Groups: Saline,Drug;Dose: ATPM-ET(0.05 mg/kg,0.1 mg/kg,0.5 mg/kg,1 mg/kg,2 mg/kg);Administration: Subcutaneous Injection.(5)To evaluate the effect of ATPM-ET on conditioned place aversion.This part detected the influence of ATPMET on disgust behavior by the model of conditional disgust.Groups: Control(Saline,Tool Drug),ATPM-ET;Dose: Tool Drug(U50,488 H,5 mg/kg),ATPM-ET(2 mg/kg);Administration: Subcutaneous Injection.Results: In the EPM and OFT,ATPM-ET(1 and 2 mg/kg)significantly increased the time spent in the open arm and in the central area,respectively.In the FST and TST,ATPM-ET(0.5 and 1 mg/kg)significantly reduced the duration of immobility.The anxiolytic-and antidepressant-like effects of ATPM-ET were inhibited by nor-BNI(10 mg/kg),but not by β-FNA(10 mg/kg)pretreatment.Furthermore,at the dose of 2 mg/kg,ATPM-ET did not induce aversive emotion.Conclusion: ATPM-ET,at doses from 0.5 to 2 mg/kg,produced anxiolytic-like effect and antidepressant-like effect,and these effects were more closely mediated by activation of κ receptor than μ receptor.