ERK Phosphorylation and FosB Expression Are Associated with L-DOPA-Induced Dyskinesia in Hemiparkinsonian Mice

Background The dopamine precursor 3,4-dihydroxyphenyl-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 ΔFosB and prodynorphin expression. L-DOPA also induces activation of ERK1/2 in the dopamine-depleted striatum. Interestingly, elevated FosB/ΔFosB 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.