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...

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Human plasma contains several catechols, including the catecholamines norepinephrine, epinephrine, and dopamine, their precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), and their deaminated metabolites, dihydroxyphenylglycol, the main neuronal metabolite of norepinephrine, and dihydroxyphenylacetic acid, a deaminated metabolite of dopamine. Products of metabolism of catechols include 3-methoxytyrosine (from L-DOPA), homovanillic acid and dopamine sulfate (from dopamine), normetanephrine, vanillylmandelic acid, and methoxyhydroxyphenylglycol (from norepinephrine), and metanephrine (from epinephrine). Plasma levels of catechols and their metabolites have related but distinct sources and therefore reflect different functions of catecholamine systems. This article provides an update about plasma levels of catechols and their metabolites and the relevance of those levels to some issues in human health and disease.Near the end of the 19th century, soon after the description of the profound cardiovascular effects of injected adrenal extract and the purification and identification of epinephrine as the vasoactive principal of the adrenal gland, researchers began to develop chemical means to assess activity of what came to be called the sympathoadrenomedullary system. The first chemical method for such measurement was colorimetric, based on the unusual susceptibility of epinephrine to oxidize, forming a brownish compound called "adrenochrome". Early attempts to measure circulating levels of epinephrine and related compounds chemically failed, mainly because the potency of epinephrine corresponds to very low normal concentrations in the bloodstream. Bioassays such as used by the great American physiologist, Walter B. Cannon were the first to detect successfully epinephrine release into the circulation. Cannon later developed and exploited a preparation based on the magnitude of the increase in heart rate in animals with denervated hearts; abolition of the increase by adrenalectomy confirmed the hormone's adrenal source. Subsequent chemical methods depended on fluorescence detection (after the trihydroxyindole reaction or ethylenediamine condensation) or radioenzymatic assays (after methylation with S-adenosylmethionine and catechol-Omethyltransferase). Ironically, current sensitive chemical methods using liquid chromatography with electrochemical detection depend on the same catechol oxidation as did the original colorimetric method.For almost the whole of the first half of the last century, epinephrine was the only catecholamine to receive attention. Cannon proposed-erroneously-that epinephrine was not only the main vasoactive hormone released by the adrenal gland but also the chemical messenger released from sympathetic nerves. This fit with his concept of a unitary sympathoadrenomedullary system, which would help maintain homeostasis (a word he coined) during emergencies but would not be necessary in day-to-day life. Fifty years after the discovery of epinephrine, norepinephrine, rather than epinephrine, was fi...