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

Objectives: Neuropsychiatric symptoms are increasingly recognised its 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 inter-rater reliability between three trained raters of differing professional backgrounds. As anticipated, animals exhibited a progressive increase in levodopa-incluced 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 I 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.