Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson's disease

The concept of a threshold of dopamine (DA) depletion for onset of Parkinso n's disease symptoms, although widely accepted, has, to date, not been dete rmined experimentally in nonhuman primates in which a more rigorous definit ion of the mechanisms responsible for the threshold effect might be obtaine d. The present study was thus designed to determine (1) the relationship be tween Parkinsonian symptom appearance and level of degeneration of the nigr ostriatal pathway and (2) the concomitant presynaptic and postsynaptic stri atal response to the denervation, in monkeys treated chronically with 1-met hyl-4-phenyl-1,2,3,6-tetrahydropyridine according to a regimen that produce s a progressive Parkinsonian state. The kinetics of the nigrostriatal degen eration described allow the determination of the critical thresholds associ ated to symptom appearance, these were a loss of 43.2% of tyrosine hydroxyl ase-immunopositive neurons at the nigral level and losses of 80.3 and 81.6% DA transporter binding and DA content, respectively, at the striatal level . Our data argue against the concept that an increase in DA metabolism coul d act as an efficient adaptive mechanism early in the disease progress. Sur prisingly, the D-2-like DA receptor binding showed a biphasic regulation in relation to the level of striatal dopaminergic denervation, i.e., an initi al decrease in the presymptomatic period was followed by an upregulation of postsynaptic receptors commencing when striatal dopaminergic homeostasis i s broken. Further in vivo follow-up of the kinetics of striatal denervation in this, and similar, experimental models is now needed with a view to dev eloping early diagnosis tools and symptomatic therapies that might enhance endogenous compensatory mechanisms.