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Neuropsychiatric Behaviors in the MPTP Marmoset Model of Parkinson’s Disease

Published online by Cambridge University Press:  02 December 2014

Susan H. Fox ,
Naomi Visanji ,
Gaby Reyes ,
Philippe Huot ,
Jordi Gomez-Ramirez ,
Tom Johnston  and
Jonathan M. Brotchie
Susan H. Fox*
Affiliation:
Division of Neurology, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada Toronto Western Research Institute, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada
Naomi Visanji
Affiliation:
Toronto Western Research Institute, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada
Gaby Reyes
Affiliation:
Toronto Western Research Institute, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada
Philippe Huot
Affiliation:
Toronto Western Research Institute, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada
Jordi Gomez-Ramirez
Affiliation:
Toronto Western Research Institute, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada
Tom Johnston
Affiliation:
Toronto Western Research Institute, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada
Jonathan M. Brotchie
Affiliation:
Toronto Western Research Institute, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada
*
Division of Neurology, Movement Disorders Clinic MCL7-421, Toronto Western Hospital, 399, Bathurst St, Toronto, Ontario, M5V 2S8,Canada.
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Abstract

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Objectives:

Neuropsychiatric symptoms are increasingly recognised as a significant problem in patients with Parkinson's disease (PD). These symptoms may be due to ‘sensitisation’ following repeated levodopa treatment or a direct effect of dopamine on the disease state. The levodopa-treated MPTP-lesioned marmoset was used as a model of neuropsychiatric symptoms in PD patients. Here we compare the time course of levodopa-induced motor fluctuations and neuropsychiatric-like behaviors to determine the relationship between duration of treatment and onset of symptoms.

Methods:

Marmosets were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (2.0 mg/kg s.c.) for five days, resulting in stable parkinsonism. Levodopa (15 mg/kg and benserazide, 3.75 mg/kg) p.o. b.i.d. was administered for 30 days. Animals were evaluated for parkinsonian disability, dyskinesia and on-time (motor fluctuations) and neuropsychiatric-like behaviors on Day 0 (prior to levodopa) and on Days 1, 7, 13, 27 and 30 of treatment using post hoc DVD analysis by a trained rater, blind to the treatment day.

Results:

The neuropsychiatric-like behavior rating scale demonstrated high interrater reliability between three trained raters of differing professional backgrounds. As anticipated, animals exhibited a progressive increase in levodopa-induced motor fluctuations, dyskinesia and wearing-off, that correlated with the duration of levodopa therapy. In contrast, levodopa-induced neuropsychiatric-like behaviors were present on Day 1 of levodopa treatment and their severity did not correlate with duration of treatment.

Conclusions:

The data suggest that neuropsychiatric disorders in PD are more likely an interaction between levodopa and the disease state than a consequence of sensitisation to repeated dopaminergic therapy.

Résumé:

RÉSUMÉ: Objectifs:

Il est de plus en plus accepté que les symptômes neuropsychiatriques constituent un problème important chez les patients atteints de la maladie de Parkinson (MP). Ces symptômes pourraient être dus à une « sensibilisation » suite au traitement par la lévodopa ou à un effet direct de la dopamine sur la maladie. Le ouistiti, qui a subi une lésion par la MPTP et qui a été traité par la lévodopa, a été utilisé comme modèle des symptômes neuropsychiatriques observés chez les patients atteints de la MP. Nous avons comparé l’évolution dans le temps des fluctuations motrices induites par la lévodopa et des comportements d’aspect neuropsychiatrique pour déterminer la relation entre la durée du traitement et le début des symptômes.

Méthodes:

De la 1-méthyl-4-phényl-1,2,3,6-tétrahydropyridine (2,0 mg/kg s.c.) a été administrée à des ouistitis pendant cinq jours pour induire un parkinsonisme stable. De la lévodopa (15 mg/kg) et du bensérazide (3,75 mg/kg) ont été administrés p.o. bid pendant 30 jours. Nous avons évalué l’invalidité parkinsonienne chez les animaux, les dyskinésies et les fluctuations motrices et les comportements d’aspect neuropsychiatrique au jour 0 (avant l’administration de lévodopa) et aux jours 1, 7, 13, 27 et 30 du traitement au moyen de l’analyse post hoc de DVD par un évaluateur entraîné, en aveugle quant au jour de traitement.

Résultats:

L’échelle d’évaluation des comportements d’aspect neuropsychiatrique a démontré une grande fiabilité inter-évaluateur entre trois évaluateurs entraînés possédant une formation professionnelle différente. Tel que prévu, les animaux présentaient une augmentation progressive des fluctuations motrices induites par la lévodopa, des dyskinésie et de l’épuisement de l’effet en fin de dose qui étaient corrélés à la durée du traitement par la lévodopa. Par contre, les comportements d’aspect neuropsychiatrique étaient présents le premier jour du traitement par la lévodopa et leur sévérité n’était pas corrélée à la durée du traitement.

Conclusions:

Selon nos données, les troubles neuropsychiatriques dans la MP sont vraisemblablement dus à une interaction entre la lévodopa et la maladie et ne sont pas une conséquence de la sensibilisation à l’administration répétée de lévodopa.

Type
Research Article
Information
Canadian Journal of Neurological Sciences , Volume 37 , Issue 1 , January 2010 , pp. 86 - 95
Copyright
Copyright © The Canadian Journal of Neurological 2010

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