A syndrome similar to idiopathic parkinsonism developed after intravenous self-administration of an illicit drug preparation in which N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP) might have been responsible for the toxicity. In the present study we show that intravenous administration of NMPTP to the rhesus monkey produces a disorder like parkinsonism (akinesia, rigidity, postural tremor, flexed posture, eyelid closure, drooling) that is reversed by the administration of L-dopa. NMPTP treatment decreases the release of dopamine and dopamine accumulates in swollen, distorted axons in the nigrostriatal pathway just above the substantia nigra, followed by severe nerve cell loss in the pars compacta of the substantia nigra and a marked reduction in the dopamine content of the striatum. The pathological and biochemical changes produced by NMPTP are similar to the well-established changes in patients with parkinsonism. Thus, the NMPTP-treated monkey provides a model that can be used to examine mechanisms and explore therapies of parkinsonism.The most prominent pathological change in idiopathic parkinsonism is degeneration of the nigrostriatal dopaminergic pathway with nerve cell loss in the substantia nigra (1). A neurochemical consequence of this loss of dopaminergic neurons is a marked decrease in the concentrations of dopamine and its major metabolite homovanillic acid (HVA) in the caudate nucleus and putamen (2). The effectiveness of L-dopa and directacting dopamine agonists in reversing akinesia, rigidity, resting tremor, and postural abnormalities in patients with idiopathic parkinsonism (3, 4) reflects the pathophysiology of these clinical signs.In 1979 a single case of parkinsonism occurring after intravenous self-administration of an illicit narcotic analgesic was described (5). Recently, a series of similar cases has been reported (6). We had the opportunity to examine two patients included in the later study. In both instances there was evidence that the method of Ziering et al. (7) had been used to synthesize the reverse ester of meperidine, 4-propionoxy-4-phenyl-N-methylpiperidine. The injected mixture also contained the side product N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP). After intravenous administration of multiple doses of the drug mixture over several days, the patients gradually developed persistent symptoms of parkinsonism, with a syndrome characterized by severe akinesia, rigidity, a flexed posture, and a resting tremor associated with low concentrations of HVA in the lumbar cerebrospinal fluid (5-6.7 ng/ml). The clinical signs were reversed by the administration of L-dopa or bromocriptine. A marked loss of pigmented cells in the substantia nigra with minimal changes in the locus ceruleus was found in the one patient who died of other causes 18 months after the onset of symptoms (5).In the present study we show that repeated intravenous administration of NMPTP to the rhesus monkey over a period of 5-8 days produces a chronic disorder with neurological, biochemical, pa...

The compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces an irreversible neurological syndrome in man and monkey which is similar to idiopathic Parkinson's disease in its clinical, pathological, neurochemical and pharmacological response properties. MPTP is selectively neurotoxic to the dopaminergic regions of the brain, destroying neurones in the substantia nigra (A8 and A9 cells, nigrostriatal system) but not the ventral tegmental area (A10 cells, mesolimbic system). Selective dopamine depletion and nigral cell loss after MPTP treatment has also been reported recently in the mouse. The mechanism by which a peripherally administered, low-molecular weight compound exerts permanent but selective toxic effects on dopamine systems in the brain may be relevant to parkinsonian syndromes induced by other toxins and to the disease process in idiopathic Parkinson's disease. We report here that MPTP is oxidized in the brain to a pyridinium species (a compound with potent herbicidal activity) and, in the monkey, is trapped intraneuronally. Furthermore, we demonstrate that this enzymatic oxidation is blocked in vivo in the mouse by a monoamine oxidase inhibitor, a condition which also blocks the neurotoxicity, indicating that the oxidative metabolism of MPTP is required for its neurotoxic effect.

Pharmacological intervention was largely ineffective in the management of corticobasal degeneration, and new treatments are needed for ameliorating the symptoms of this syndrome.

Blink rate, a putative noninvasive marker of central dopamine activity, was assessed in medication-free patients with Parkinson's disease, progressive supranuclear palsy, Huntington's disease, and dystonia. The normal control rate of 24 blinks per minute was significantly higher than the rate of 12 and 4 blinks per minute recorded for patients with Parkinson's disease and progressive supranuclear palsy, respectively. The rates for patients with Huntington's disease and dystonia did not differ significantly from those of controls (36 and 26 blinks per minute, respectively).

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