| ObjectiveIn this study,we aim to construct non-motor behavioral methods and discuss the non-motor symptoms in MPTP-induced chronic Parkinsonism in cynomolgus monkey,then we will determine the therapeutic effects of pramipexole.MethodsIn this study,10 male non-human primates(cynomolgus monkeys)were used(age 14.9±1.5 years),including chronic Parkinsonism group(a single unilateral intracarotid dose of MPTP to establish PD model,n=5)and normal controls group(n=5).We establish behavioral methods for evaluating non-human primate non-motor symptoms,including the Delayed Matching-to-sample Task(DMTS),Physical Activity Monitoring(PAM),and Progressive Ratio task(PR),Human Intruder Test(HIT),Novel Fruit Test(NFT),Predator Confrontation Test(PCT),Apathy.Feeding Test(AFT),to compare the behavioral metrics of non-motor symptoms like cognitive memory,sleep,motivation,anxiety and depression-like behavior.At the same time,behavioral methods were used to in the treatment of chronic Parkinson’s disease.Pramipexole(PPX)was used to evaluate changes in the non-motor behavioral metrics of MPTP-induced chronic Parkinsonism in cynomolgus monkey.ResultsPD animals were induced by MPTP showed decreased learning ability,and there were significant cognitive memory reduction,sleep disorders,less motivation,and anxiety and depression-like behavior.The PD group was treated by pramipexole showed that sleep and motivation increased,and anxiety and depression-like behavior were alleviated,but cognitive memory did not significantly improve.1.According to the results of learning ability,PD animals showed decreased learning ability(Control group:100%,PD group:60%).2.In DMTS,the correct rate of PD group was significantly lower than that of Control group at the delay of 5s,10s,15s and 30s(5s:u=4.667,P=0.031;10s:u=4.667,P=0.031;15s:u=5.600,P=0.018;30s:u=4.755,P=0.029),there was a significant decrease in cognitive memory in PD group.Pramipexole was used for drug intervention in PD group,with no significant change in the correct rate(5s:u=0.292,P=0.589;10s:u=1.212,P=0.271:15s:u=0.549,P=0.459;30s:u=1.167,P=0.280),and the results showed no significant improvement in cognitive memory.3.In PAM,The nocturnal activity of PD group was higher than that of Control group(Control group:2000.55±1364.78;PD group:2752.40±1906.57,t=-1.466,P=0.151),and PD animals may have sleep disorders.The PD group was by pramipexole and sleep situation was alleviated(PD+PPX group:2042.56±1060.97,t=0.847,P=0.403).4.In PRT,there was a significant decrease in motivation in PD group(Control group:60.77±13.89;PD group:46.88±11.43,t=3.944,P=0.000),the motivation was significantly increased after treatment by pramipexole in the PD group(PD+PPX group:58.21±13.13,t=-3.189,P=0.003).5.In comprehensive anxiety test(HIT,NFT,PCT)(1)In HIT,the movement and standing behavior of the PD group were higher than those of the normal group,and abnormal behaviors such as scratching,grinding,freezing,and shaking cages were observed(P>0.05),while the length of the post-cage was significantly shorter than control group during profile and stare period(Profile period:120(51.77),51.93(61.01);Stare period:111.27(38.94),0.00(64.70));PD group showed behavioral hyperresponsiveness,including freezing,grinding,scratching,yawning(P>0.05),and there were different degrees of anxiety behavior.The results indicating that there was anxiety in the PD group.Treatment with pramipexole showed higher activity,and abnormal behaviors such as scratching,grinding,freezing,and shaking cages were reduced to different extents(P>0.05),and the length of the post-cage in profile period,the length of the freezing in baseline and stare period was reduced(P<0.05).(2)In NFT,the extraction rates of Control group and PD group were 100%,and 80%respectively.There was no significant difference between the Control group and the PD group in the observation of familiar and novel fruits and the duration of extraction(P>0.05).There was no significant change in the treatment of PD group by pramipexole(P>0.05).(3)In PCT,the extraction rates of control group,PD group were 80%and 40%,respectively.The withdrawal rates were 20%and 60%respectively.However,there was no significant difference in the duration of food(Control group:1.18±0.82;PD group:1.13±1.08,t=0.079,P=0.939).There was no significant change in the treatment of PD group by pramipexole(PD+PPX group:0.85±1.16,t=0.396,P=0.702).6.In AFT,PD group had limb disorder on the right side,and the duration of observing and taking food on the left side was longer than that of the control group(Duration of observing food:Control group 0.53(0.17),PD group 0.85(0.53),u=3796.000,P=0.000;Duration of taking food:Control group 0.53(0.13),PD group 0.83(0.24),u=4787.000,P=0·000).After the treatment of pramipexole in PD group,the duration of observing and taking food in PDD+PPX group was significantly lower than that in PD group(Duration of observing food:0.45(0.31),u=599.000,P=0.000.Duration of taking food:0.53(0.14),u=162.000,P=0.000).ConclusionIn this study,a combination of positive reinforcement and negative reinforcement training was adopted to establish and quantify multiple behavioral training methods innovatively,and was adopted a multi-angle and multi-level non-motor behavioral method to comprehensively evaluate the non-human primate model of chronic Parkinson’s disease.The results showed that MPTP-induced chronic Parkinson’s disease in cynomolgus monkeys was similar to Parkinson’s disease in humans,with cognitive decline,sleep disorder,apathy or loss of motivation,anxiety and depression and other non-motor behavior disorders.Pramipexole,as a non-ergonomic dopamine receptor agonist,can relieve non-motor behavior disorders in cynomolgus monkeys with chronic Parkinson’s disease,including sleep,apathy or motivation,and different degrees of anxiety and depressive symptoms.In conclusion,this study of cynomolgus monkey MPTP induced in the model of movement behavior method and evaluation,will provide method basis for determination of non-human primate animal behavior,and as the disease mechanism of laying a foundation for biomedical research at the same time,such as further confirmed from the Angle of the motion behavior of cynomolgus monkey MPTP induced Parkinson’s disease model reliability,offers a new carrier for preclinical study. |
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