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Brain Advance Access originally published online on August 25, 2004
Brain 2004 127(12):2747-2754; doi:10.1093/brain/awh290
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Brain Vol. 127 No. 12 © Guarantors of Brain 2004; all rights reserved

Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson's disease: implications for dyskinesias

Raúl de la Fuente-Fernández, Vesna Sossi, Zhigao Huang, Sarah Furtado, Jian-Qiang Lu, Donald B. Calne, Thomas J. Ruth and A. Jon Stoessl

Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, BC, Canada

Correspondence: Dr A. Jon Stoessl, Pacific Parkinson's Research Centre, Vancouver Hospital and Health Sciences Centre, University of British Columbia, Purdy Pavilion, 2221 Wesbrook Mall, Vancouver, BC, Canada V6T 2B5 E-mail: jstoessl{at}interchange.ubc.ca

Peak-dose dyskinesias are abnormal movements that usually occur 1 h after oral administration of levodopa, and often complicate chronic treatment of Parkinson's disease. We investigated by PET with [11C]raclopride whether Parkinson's disease progression modifies the striatal changes in synaptic dopamine levels induced by levodopa administration, and whether this modification, if present, could have an impact on the emergence of dyskinesias. We found that, 1 h after oral administration of standard-release 250/25 mg of levodopa/carbidopa, levodopa-induced increases in synaptic dopamine levels (as estimated by striatal changes in [11C]raclopride binding potential) correlated positively with duration of Parkinson's disease symptoms (for the caudate nucleus, r = 0.79, P < 0.001; for the putamen, r = 0.88, P < 0.0001). Patients with peak-dose dyskinesias had larger 1-h increases in synaptic dopamine levels than stable responders, but there were no between-group differences in [11C]raclopride binding 4 h post-levodopa. The corresponding (time x group) interaction term in the repeated measures analysis of covariance was significant, even after adjusting for between-group differences in duration of Parkinson's disease symptoms (for the caudate nucleus, P = 0.030; for the putamen, P = 0.021). Our results indicate that, at the synaptic level, an identical dose of levodopa induces increasingly larger 1-h changes in dopamine levels as Parkinson's disease progresses. Large levodopa-induced increases in synaptic dopamine concentration can lead to dramatic changes in receptor occupancy, which may be responsible for the emergence of peak-dose dyskinesias in Parkinson's disease.


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