Relationship among nigrostriatal denervation, parkinsonism, and dyskinesias in the MPTP primate model

Presynaptic denervation is likely to play an important role in the pathophy siology of dyskinesias that develop after levodopa administration to patien ts with Parkinson's disease. In this study, the thresholds of nigrostriatal damage necessary for the occurrence of parkinsonism and levodopa-induced i nvoluntary movements were compared in squirrel monkeys lesioned with 1-meth yl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Animals treated with a regim en of MPTP that caused parkinsonism displayed greater than or equal to 95% striatal dopamine depletion, 90% reduction of striatal dopamine uptake site s, and 70% nigral neuronal loss. Levodopa administration ameliorated the pa rkinsonian signs of these monkeys but also induced dyskinesias. A separate group of animals was treated with a milder MPTP regimen that caused 60%-70% striatal dopamine depletion, a 50% decrease in dopamine transporter, and 4 0% loss of dopaminergic nigral neurons. While these monkeys displayed no be havioral signs of parkinsonism, they all became dyskinetic after levodopa a dministration. The priming effect of levodopa, that is, the recurrence of d yskinesias in animals previously exposed to the drug, was compared in sever ely versus mildly lesioned monkeys. When severely injured parkinsonian anim als underwent a second cycle of levodopa treatment, they immediately and co nsistently developed involuntary movements. In contrast, the recurrence of dyskinesias in primed monkeys with a partial nigrostriatal lesion required several levodopa administrations and remained relatively sporadic. The data indicate that moderate nigrostriatal damage which does not induce clinical parkinsonism predisposes to levodopa-induced dyskinesias. Once dyskinesias have been induced, the severity of denervation may enhance the sensitivity to subsequent levodopa exposures.