1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonian syndrome in Macaca fascicularis: Which midbrain dopaminergic neurons are lost?

German, Dwight C.; Dubach, Mark; Askari, Samaneh; Speciale, Samuel G.; Bowden, Douglas M.

doi:10.1016/0306-4522(88)90320-x

Cited by 193 publications

(101 citation statements)

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“…In one monkey (Sq8, given 2.5 mg/kg), there was nearly total depletion of [3H]mazindol binding in the caudate-putamen, even rostrally. This pattern resembled the patterns reported for experiments in which large or repeated doses of MPTP were given (13)(14)(15)(16). In a second monkey (Sql4, given 1.5 mg/kg), the MPTP treatment was nearly ineffective in reducing [3H]mazindol binding sites except in the posterior putamen.…”

Section: Resultssupporting

confidence: 81%

“…This pattern has not been found consistently in MPTP-treated monkeys (13)(14)(15)(16). Instead, MPTP is capable of depleting dopaminergic markers from nearly the entire caudate nucleus as well as from the putamen, leaving only the ventral striatum (nucleus accumbens and olfactory tubercle) and the adjoining ventral caudoputamen relatively spared.…”

mentioning

confidence: 93%

“…Ten days after the treatment, these animals and three untreated control squirrel monkeys were deeply anesthetized with sodium pentobarbital (12 mg/kg), and their brains were removed, quickly cut into blocks, and frozen in powdered dry ice. Serial transverse sections [10][11][12][13][14][15] Am thick were cut on a cryostat, thaw-mounted onto gelatincoated slides, air dried, and stored in 20 sets of regularly spaced sections at -20'C until use.[3H]Mazindol Binding. Binding incubations were performed as described previously (19,24) on two complete sets of sections for each brain and on additional control and trial sections.…”

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confidence: 99%

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Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Moratalla

Quinn

DeLanney

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

135

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The meperidine analogue derivative l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces nigrostriatal fiber damage and severe parkinsonism in humans and animals. MPTP-induced parkinsonism has been proposed as a model ofParkinson disease, but doubts have been raised about whether the patterns of nigrostriatal fiber loss in the two conditions are similar. We report here observations on [3H]mazindol monoamine (principally dopamine) uptake-site binding in the striatum of monkeys (Saimiri sciureus) exposed to low doses of MPTP. We show that this treatment can produce a pattern of nigrostriatal degeneration characteristic of that seen in Parkinson disease, in which there is greater depletion of dopaminergic markers in the putamen than in the caudate nucleus, especially posteriorly. Moreover, within the regions of diminished uptake-site binding in the MPTP-treated monkeys, there is differential preservation of binding in striosomes relative to the surrounding matrix. We suggest that both regional and striosome/matrix patterns of nigrostriatal depletion are key features of MPTP-induced neurodegeneration and that both patterns may provide dues to the mechanisms underlying neurodegeneration in Parkinson disease as well.Exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces a behavioral state in humans and other primates that strongly resembles idiopathic Parkinson disease (1, 2). MPTP-induced parkinsonism is highly responsive to L-dopa therapy, and in the brains of MPTP-treated primates (including one human) it has been shown that there is a concomitant loss of dopamine-containing neurons of the nigrostriatal tract, also a hallmark of pathology in Parkinson disease (3-8). These characteristics suggest that MPTPinduced parkinsonism may be similar to the idiopathic disease and have motivated a large body of work aimed at understanding the molecular mechanisms underlying MPTPinduced neurotoxicity (8-11).A key feature of the neurodegeneration in Parkinson disease is a characteristic gradient of dopamine loss in the striatum, with greater defects in the putamen than in the caudate nucleus and greater defects posteriorly than anteriorly in the putamen (4)(5)(6)(7)12). This pattern has not been found consistently in MPTP-treated monkeys (13-16). Instead, MPTP is capable of depleting dopaminergic markers from nearly the entire caudate nucleus as well as from the putamen, leaving only the ventral striatum (nucleus accumbens and olfactory tubercle) and the adjoining ventral caudoputamen relatively spared. This more global deficit has been interpreted as suggesting that MPTP-induced parkinsonism, for all its similarities to Parkinson disease, may not be a suitable model for the disease (14,15,17). This is a fundamentally important issue, because the MPTP model not only implicates environmental toxins as possible etiologic factors in Parkinson disease (11) but also, if correct, could greatly enhance efforts to understand the molecular basis of cell death in Parkinson disease (18).To address this issue ...

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Section: Resultssupporting

confidence: 81%

mentioning

confidence: 93%

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confidence: 99%

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Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Moratalla

Quinn

DeLanney

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

135

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“…Saccadic eye movement in MPTP (1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced dopamine deficient animals should be ideal for this purpose. MPTP is known to destroy dopaminergic neurons in the SNc, thus producing clinical symptoms quite similar to Parkinson's disease (Langston, 1985;German et al, 1988;Graham et al, 1990). As in Parkinson's disease the level of dopamine is decreased in the Cd of monkeys treated with MPTP (Mitchell et al, 1986;Elsworth et al, 1989;Schneider and Kovelowski, 1990).…”

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confidence: 99%

Eye movements in monkeys with local dopamine depletion in the caudate nucleus. I. Deficits in spontaneous saccades

et al. 1995

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The basal ganglia contribute to the suppression and initiation of saccadic eye movements through the inhibitory connection from the substantia nigra pars reticulata (SNr) to the superior colliculus. This mechanism consists of serial and parallel connections, which are mostly inhibitory and GABAergic. Dopamine is known to exert powerful modulatory effects on the basal ganglia function, but its nature and mechanism are still unclear, especially in relation to voluntary behavior. The purpose of this series of investigation was to study the role of dopamine in the control of saccadic eye movements. We examined, in the monkey, whether and how the deficiency of the nigrostriatal dopaminergic innervation affects saccadic eye movements. The present article is focused on spontaneous saccades that the monkey made with no incentive to obtain reward; the next paper will describe task-specific saccades. Using an osmotic minipump we infused 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) unilaterally into the head-body junction of the caudate nucleus of monkeys where presaccadic neurons were clustered. Tyrosine hydroxylase activity, visualized using an immunohistochemical method, decreased locally around the injection site with some effects extending into the ipsilateral putamen and locally in the ipsilateral substantia nigra. Changes of eye movements started to appear 3–5 d after starting the infusion. Spontaneous saccades became less frequent. The area scanned by the saccades became narrower and shifted to the hemifield ipsilateral to the infusion site. The saccade amplitudes and peak velocities decreased; durations were prolonged. These effects were more prominent for saccades directed toward the side contralateral to the infusion site. These monkeys showed no obvious skeletomotor symptoms. These results suggest that the local deprivation of the dopaminergic innervation in the caudate nucleus facilitates neuronal activity of the SNr leading to suppression of saccadic eye movements.

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“…The neurotoxin 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively destroys dopamine (DA)-containing neurons in the ventral mesencephalon, and in particular those lo-cated in the substantia nigra pars compacta in cats and monkeys (Bums et al, 1983;Schneider et al, 1987;German et al, 1988). The loss of neurons and the subsequent reduction in striatal DA leads to Parkinson-like motor deficits in these species.…”

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confidence: 99%

Response of caudate neurons to stimulation of intrinsic and peripheral afferents in normal, symptomatic, and recovered MPTP-treated cats

Rothblat

Schneider

1993

J. Neurosci.

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Cat caudate nucleus (CD) neurons were tested for changes in spontaneous activity, response to peripheral sensory stimuli (tactile, auditory, and visual), and electrical stimulation of monosynaptic afferents (pericruciate cortex and nucleus centralis lateralis) in normal cats and in the same cats after induction of and spontaneous recovery from parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). After normal baseline data were collected, cats were given MPTP (7.5 mg/kg, 5–7 d) to induce a parkinsonian syndrome consisting of rigidity, akinesia, and decreased orienting to sensory stimuli. During this symptomatic period, the mean spontaneous activity of CD units increased (6.20 spikes/sec vs 2.25 spikes/sec in normal cats). In these same animals, the percentage of units responding to peripheral sensory stimulation was significantly decreased (compared to normal) while the percentage of units responding to electrical stimulation of monosynaptic afferents increased. By 6 weeks after MPTP administration, cats had recovered gross motor and sensorimotor function and CD unit recordings were reinitiated. In functionally recovered animals, all electrophysiological measures returned to levels resembling those seen in normal animals. These data suggest that the processing of peripheral sensory information is an important part of basal ganglia function and that the sensory responsiveness of the CD may reflect the overall motor condition of the animal. The changes observed in the responsiveness of CD neurons to direct electrical stimulation of monosynaptic afferents may indicate that the defect in the processing of polysynaptic sensory information observed in the striatum in parkinsonian animals may be occurring, at least in part, extrastriatally.

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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonian syndrome in Macaca fascicularis: Which midbrain dopaminergic neurons are lost?

Cited by 193 publications

References 30 publications

Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Differential vulnerability of primate caudate-putamen and striosome-matrix dopamine systems to the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Eye movements in monkeys with local dopamine depletion in the caudate nucleus. I. Deficits in spontaneous saccades

Response of caudate neurons to stimulation of intrinsic and peripheral afferents in normal, symptomatic, and recovered MPTP-treated cats

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