Journal
BIOLOGICAL PSYCHIATRY
Volume 59, Issue 1, Pages 64-74Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2005.05.044
Keywords
dopamine; dynorphin; dyskinesia; ERK1/2 phosphorylation; FosB; Parkinson's disease; striatum
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Background: The dopamine precursor 3,4-dihydroxyphenly-l-alanine (L-DOPA) is currently the most efficacious noninvasive therapy for Parkinson's disease. A major complication of this therapy, however, is the appearance of the abnormal involuntary movements. known as dyskinesias. We have developed a model of L-DOPA-induced dyskinesias in mice that reproduces the main clinical features of dyskinesia in humans. Methods. Dyskinetic symptoms were triggered by repetitive administration of a constant dose of L-DOPA (25 mg/kg, twice a day, for 25 days) in unilaterally 6-hydroxydopamine (6-OHDA) lesioned mice. Mice were examined for behavior, expression of FosB, neuropeptides, and externally regulated kinase (ERK) phosphorylation. Results: Dyskinetic symptoms appear toward the end of the first week of treatment and are associated with L-DOPA-induced changes in Delta FosB and prodynorphin expression. L-DOPA also induces activation of ERK1/2 in the dopamine-depleted striatum. Interestingly, elevated FosB/Delta FosB expression occurs exclusively within completely lesioned regions of the striatum, displaying an inverse correlation with remaining dopaminergic terminals. Following acute L-DOPA treatment, FosB expression occurs in direct striatal output neurons, whereas chronic L-DOPA also induces FosB expression in nitric oxide synthase-positive striatal interneurons. Conclusions: This model provides a system in which genetic manipulation of individual genes can be used to elucidate the molecular mechanisms responsible for the development and expression of dyskinesia.
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