Neuropsychiatric behaviors in the MPTP marmoset model of Parkinson's disease.
OBJECTIVE
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.
Fox
Susan H
SH
Division of Neurology, Toronto Western Research Institute, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada.
Visanji
Naomi
N
Reyes
Gaby
G
Huot
Philippe
P
Gomez-Ramirez
Jordi
J
Johnston
Tom
T
Brotchie
Jonathan M
JM
D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001526:Behavioral Symptoms / Q000139:chemically induced*; D002144:Callithrix; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000209:etiology*; D005260:Female; D006948:Hyperkinesis / Q000139:chemically induced*; D007980:Levodopa / Q000009:adverse effects / Q000627:therapeutic use*; D020734:Parkinsonian Disorders / Q000188:drug therapy; D015203:Reproducibility of Results
D000978:Antiparkinson Agents; D007980:Levodopa