Striatal dopaminergic correlates of stable parkinsonism and degree of recovery in Old-World primates one year after MPTP treatment

Despite widespread use of the primate 1-methyl-4-phenyl-1,2,3,6-tetrahydrop yridine (MPTP) model of Parkinson's disease, there is a paucity of data con cerning the relationship between striatal dopaminergic function and behavio r over time. This study examines the relationship between markers of dopami ne neuron integrity and dopaminergic metabolic activity in striatal subregi ons with the degree of parkinsonian disability in 32 monkeys treated with M PTP one year earlier. Based on the parkinsonian summary score during the mo nth following MPTP treatment, each monkey was assigned to one of four sever ity categories. We called these categories "Severe", "Moderate", "Mild" and "Asymptomatic". Monkeys in the Severe category were behaviorally stable, a nd loss of dopamine concentration was greater than 98% in all subregions of striatum one year after MPTP treatment. This value was not significantly d ifferent from the level of depletion, reported previously, at one to two mo nths after MPTP in Severe monkeys, and apparently this loss of striatal dop amine is beyond the level from which effective compensations can occur. The parkinsonian disabilities in monkeys of other severity groups (Moderate, M ild, Asymptomatic) improved significantly over the year, despite having mea n dopamine depletion of 75-99% in different subregions of striatum at one t o two months after MPTP treatment. At one year after MPTP treatment, the me an dopamine depletions in different subregions of caudate nucleus and putam en had diminished in Asymptomatics (21-81%), Milds (35-96%), and Moderates (86-97%). Dopamine loss in nucleus accumbens was relatively spared compared with most striatal subregions, yet in Severe monkeys the decrease in this region reached 96%. In addition, at one year after MPTP treatment, there wa s a significant linear relationship between parkinsonian behavioral severit y category and dopamine concentration, and homovanillic acid concentration and homovanillic acid/dopamine ratio in the striatum. The re-establishment of dopamine levels and homovanillic acid/dopamine ratios was most pronounce d in putamen, ventromedial caudate nucleus and nucleus accumbens. Thus the small difference in striatal dopamine loss that distinguishes monk eys with widely different behavior at one to two months after MPTP increase s over time. We suggest that the milder the initial loss, the greater capac ity there is for regeneration or sprouting of dopamine terminals, which is reflected in marked increases in dopamine levels and modest elevations of m etabolic activity (homovanillic acid/dopamine ratio). With greater initial losses, there is less capacity to increase terminal density, which is refle cted later by smaller increases in striatal dopamine levels and more marked increases in metabolic activity. It appears that 5-10% of normal striatal dopamine levels is sufficient for overtly normal motor performance in non-h uman primates. (C) 1999 IBRO. Published by Elsevier Science Ltd.