Effect of the NMDA antagonist MK-801 on MPTP-induced parkinsonism in the monkey

A. R. Crossman, D. Peggs, S. Boyce, M. R. Luquin, M. A. Sambrook

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    Abstract

    Current evidence suggests that the motor symptoms of parkinsonism are due to abnormal overactivity of the medial segment of the globus pallidus, brought about by overactivity of the subthalamic nucleus, from which it receives an excitatory amino acid-mediated projection. The possibility exists, therefore, that excitatory amino acid antagonists might have an antiparkinson effect by normalising medial pallidal activity. The NMDA antagonist MK-801 was administered i.m. to a single cynomolgus monkey with parkinsonism induced by the neurotoxin MPTP. In fact, MK-801 exacerbated the symptoms of parkinsonisB. When administered after a therapeutic dose of L-DOPA it antagonised the anti-parkinson action of L-DOPA. The results suggest that any potential antl-parkinson action of excitatory amino acid antagonists will depend upon an action at non-NMDA sites. The administration of the selective neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to produce a primate model of Parkinson's disease is well-documented (Burns, Markey, Phillips & Chiuch, 1984; Crossman, 1987; Langston, Forno, Rebert & Irwin, 1984). Intravenous injection of MPTP, titrated judiciously over a period of several weeks, can produce a stable manifestation of the Motor disability seen in the idiopathic disease of man, with a remarkable correspondence of both symptoms and pathology. Additionally, primates rendered parkinsonian by MPTP respond well to L-DOPA treatment. As in human Parkinson's disease, long-term L-DOPA therapy of MPTP-induced parkinsonism tends to be complicated by the emergence of choreiform movements and dystonic postures (Boyce, Clarke, Luquin, Peggs, Robertson, Mitchell, Sambrook & Crossman, 1989; Clarke, Sambrook, Mitchell & Crossman, 1987). Recent studies of the neural mechanisms mediating the expression of parkinsonian symptoms have suggested that disturbances in the reciprocal relationship between the globus pallidus and the subthalamic nucleus play a crucial role (Crossman, 1987; Mitchell, Clarke, Boyce, Robertson, Peggs, Sambrook & Crossman, 1989). In particular, 2-deoxyglucose uptake studies have shown that parkinsonism is associated with abnormally increased neuronal activity in both the subthalamic nucleus and the medial segment of the globus pallidus. Increased activity of medial pallidal output neurones projecting to the ventral lateral and ventral anterior thalamic nuclei and to the caudal brainstem probably represent an important mechanism by which parkinsonian symptoms are mediated (Crossman, 1987). An increasing body of evidence indicates that transmission in the subthalamopallidal pathway is mediated by an excitatory amino acid, probably glutamate (Kitai and Kita, 1988; Robertson, Farmery, Sambrook & Crossman, 1989). It is possible, therefore, that an amelioration of parkinsonian symptoms might be achieved by antagonism of the subthalamopallidal transmitter, thereby reducing neuronal activity in the medial pallidal segment. The purpose of the present study was to investigate the effect of (+)-5-niethyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine, (MK-801), a selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor channel complex (Wong, Kemp, Priestly, Knight, Woodruff and Iversen, 1988), upon parkinsonian symptoms in the MPTP-exposed monkey. © 1989.
    Original languageEnglish
    Pages (from-to)1271-1273
    Number of pages2
    JournalNeuropharmacology
    Volume28
    Issue number11
    Publication statusPublished - Nov 1989

    Keywords

    • Animals
    • analogs & derivatives: Aspartic Acid
    • pharmacology: Dibenzocycloheptenes
    • Dizocilpine Maleate
    • Injections, Intramuscular
    • pharmacology: Levodopa
    • MPTP Poisoning
    • Macaca fascicularis
    • Male
    • N-Methylaspartate
    • chemically induced: Parkinson Disease, Secondary
    • Support, Non-U.S. Gov't

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