MPTP TOXICITY AND ANIMAL MODELS OF PARKINSON'S DISEASE

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1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin which causes selective destruction of dopaminergic neurones of the nigrostriatal pathway in monkeys, but is less specific in mice requiring higher doses and affecting other areas as well. A hemiparkinsonian model has been developed by infusion of MPTP into the internal carotid artery of monkeys. The behavioral effects (turning in the direction of the lesioned side) are used to evaluate agonists (which reverse the turning) and procedures which regenerate or replace by implantation dopamine-producing cells. Dopaminergic neurones and receptor changes have been demonstrated using biochemical techniques for measurement of dopamine, norepinephrine, and serotonin and their metabolites as well as binding of radiolabelled ligands to receptors and immunohistofluorescence of tyrosine hydroxylase. These confirm unilateral destruction of dopamine innervation of the caudate-putamen in hemiparkinsonian monkeys and increased D2 receptors in this area in these animals. PET scanning with 18F-DOPA has demonstrated the deficiency in dopamine formation and storage in the striatum of MPTP treated animals and the restoration of dopamine in transplants of fetal mesencephalic tissue. Tyrosine hydroxylase immunohistochemical studies of the results of tissue implants suggest stimulation of sprouting of surviving dopaminergic neurones rather than fiber ingrowth from the implant as the cause of functional recovery. There are also functional restorations of local cerebral glucose utilization (LCGU) in areas of the cortex and striatum in which LCGU is depressed by MPTP. Using LCGU to examine responses to DOPA, it was found that supersensitivity was evident in that LCGU was markedly elevated in MPTP-treated, but not in normal monkeys by L-DOPA. In hemiparkinsonian monkeys, the ocular dominance columns could be distinguished and those innervated by the MPTP treated-eye reacted to L-DOPA in a similar hyperactive manner, suggesting retinal dopamine receptor supersensitivity.