1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced acute transient dystonia in monkeys associated with low striatal dopamine.
Unilateral intracarotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in baboons produces transient contralateral dystonia lasting 2-3 weeks followed by chronic hemiparkinsonism. We now extend this model to Macaca nemestrina and Macaca fascicularis. MPTP was infused unilaterally into the internal carotid artery of two M. nemestrina and 11 M. fascicularis. Effects were assessed with blinded clinical ratings of dystonia and Parkinsonism; [18F]-6-fluoro-DOPA (FDOPA) positron emission tomography; and postmortem measurements of striatal dopamine content. In two M. nemestrina, MPTP 0.4 mg/kg intracarotid produced acute dystonia within 24 h then chronic Parkinsonism starting 3 weeks later. In three M. fascicularis, MPTP 0.4 mg/kg produced acute dystonia within 3-8 h but two others died from large hemispheric infarcts within 1 day. A much lower dose, MPTP 0.1 mg/kg produced no clinical manifestations (n=1), whereas MPTP 0.25 mg/kg produced consistent transient dystonia and ipsiversive turning within 1-3 days followed by chronic Parkinsonism at 3 weeks (n=5). One week after MPTP, striatal FDOPA uptake decreased an average of 69% in M. nemestrina (0.4 mg/kg); and decreased an average of 70+/-21% in M. fascicularis (0.25 mg/kg). Striatal dopamine was reduced an average 66% in the first day (n=2) during acute dystonia, 98% at 3 days (n=1) and 99%+/-2.3% at 2-4 months (n=5). M. nemestrina had a clinical response similar to baboons whereas M. fascicularis seemed more sensitive to MPTP. These findings extend the model of MPTP-induced transient dystonia followed by chronic hemiparkinsonism to M. nemestrina and M. fascicularis and demonstrate that the early dystonic phase is accompanied by striatal dopamine deficiency.
Tabbal
S D
SD
Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110-1093, USA.
Mink
J W
JW
Antenor
J A V
JA
Carl
J L
JL
Moerlein
S M
SM
Perlmutter
J S
JS
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002452:Cell Count; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D020821:Dystonic Disorders / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000473:pathology*; D008252:Macaca fascicularis; D008254:Macaca nemestrina; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods; D013997:Time Factors
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine