Evaluation of Levodopa Dose and Magnitude of Dopamine Depletion as Risk Factors for Levodopa-lnduced Dyskinesia in a Rat Model of Parkinson's Disease

摘要

Levodopa dose and severity of Parkinson's disease(PD)are recognized risk factors for levodopa-induced dyskinesia(LID)in humans.The purpose of the present study was to evaluate the ability of these variables to predict severity of LID in a rat model of PD.Varied concentrations of 6-hydroxy-dopamine were injected into the midbrain to produce wide ranges of dopamine depletion in striatum.Three weeks later,rats were given daily injections of levodopa(2-10 mg/kg i.p.)plus benserazide(12.5 mg/kg i.p.)for 15 days.Abnormal involuntary movements(AIMs)were measured for limb,axial,orolingual,and rotatory movements.Dose-response analysis for total AIM scores yielded a levodopa ED50 value of 3.2 mg/kg on treatment day 15.There were strong interrelated correlations between individual AIM categories(rho>0.7)and for each AIM category in regard to total AIM score(rho>0.7).In rats that received levodopa doses that were greater than the ED50,rates of amphetamine-induced rotation were significantly correlated with total AIM scores(rho=0.413).However,of those rotating>5 times/min,34% had relatively low AIM scores(<8).Likewise,there was a significant correlation between percentages of tyrosine hydroxylase(TH)loss and total AIM scores(rho=0.388).However,in those rats that had>85% TH loss,30% had AIM scores<8.Our results show that given an adequate dose and magnitude of striatal dopamine depletion,levodopa produces dyskinesia with a continuous spectrum of severity.Although levodopa dose and level of dopamine depletion are significant risk factors for LID,we conclude that other factors must contribute to LID susceptibility.