Hemiparkinsonism in monkeys after unilateral caudate nucleus infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): behavior and histology.

Systematically administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is biotransformed into 1-methyl-4-phenylpyridinium ion (MPP+), which enters dopaminergic neurons via the dopamine uptake system to destroy nigral cells. Either MPP+ is retrogradely transported to the cell body after being taken up at the nerve terminals, or the dopamine uptake sites on the cell body and its dendritic processes are responsible for the toxin directly entering the neuron. Using a 200 microliter osmotic minipump, we administered 4 mg of MPTP HCl directly into the unilateral caudate nucleus, i.e., the dopamine nerve terminal area, of monkeys for 14 days. Persistent hemiparkinsonism began to appear in a week. Each monkey exhibited a flexed posture and hypokinesia of the contralateral limbs and circling toward the MPTP-treated side. These disturbances developed within 3 months and maintained a plateau for 3 months until the day of sacrifice. After treatment with apomorphine, there appeared a striking circling away from the MPTP-treated side. Selective cell loss in the MPTP-treated side of the substantia nigra pars compacta was found along the entire rostrocaudal extent relative to the untreated side. In conclusion, MPP+ uptake only at the dopamine nerve terminals and retrograde axonal transport to the cell body seemed sufficient to destroy nigral dopamine cells in the monkey.