Effect of the NMDA antagonist MK-801 on MPTP-induced parkinsonism in the monkey.
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 exits, therefore, that excitatory amino acid antagonists might have an anti-parkinson 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 parkinsonism. When administered after a therapeutic dose of L-DOPA it antagonised the anti-parkinson action of L-DOPA. The results suggest that any potential anti-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).(ABSTRACT TRUNCATED AT 250 WORDS)
Crossman
A R
AR
Department of Cell and Structural Biology, Medical School, University of Manchester, U.K.
Peggs
D
D
Boyce
S
S
Luquin
M R
MR
Sambrook
M A
MA
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D003986:Dibenzocycloheptenes / Q000494:pharmacology*; D016291:Dizocilpine Maleate; D007273:Injections, Intramuscular; D007980:Levodopa / Q000494:pharmacology; D020267:MPTP Poisoning; D008252:Macaca fascicularis; D008297:Male; D016202:N-Methylaspartate; D010302:Parkinson Disease, Secondary / Q000139:chemically induced* / Q000503:physiopathology
D003986:Dibenzocycloheptenes; D001224:Aspartic Acid; D007980:Levodopa; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate