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Updated: Aug 16, 2026
Rating L-DOPA-Induced Dyskinesias in the Unilaterally 6-OHDA-Lesioned Rat Model of Parkinson's Disease
Published on: October 4, 2021
ERK phosphorylation and FosB expression are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice
Nancy Pavón1, Ana B Martín, Ainhoa Mendialdua
1Instituto Cajal, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
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 DeltaFosB and prodynorphin expression. L-DOPA also induces activation of ERK1/2 in the dopamine-depleted striatum. Interestingly, elevated FosB/DeltaFosB 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.
Insights
Researchers developed a mouse model for Parkinson's disease dyskinesia, a common side effect of L-DOPA treatment. This model helps study the molecular changes, like FosB expression, linked to these involuntary movements.
Area of Science:
- Neuroscience
- Pharmacology
- Movement Disorders
Background:
- 3,4-dihydroxyphenyl-L-alanine (L-DOPA) is the primary noninvasive treatment for Parkinson's disease.
- Dyskinesias, or abnormal involuntary movements, are a significant complication of L-DOPA therapy.
- A novel mouse model mimicking human L-DOPA-induced dyskinesias has been established.
Purpose of the Study:
- To establish and validate a mouse model for L-DOPA-induced dyskinesias.
- To investigate the molecular mechanisms underlying the development of dyskinesia.
- To provide a platform for genetic studies on dyskinesia.
Main Methods:
- Unilaterally 6-hydroxydopamine (6-OHDA) lesioned mice received daily L-DOPA (25 mg/kg) for 25 days.
- Behavioral assessments were conducted to monitor dyskinetic symptoms.
- Expression of FosB, neuropeptides, and ERK phosphorylation in the striatum was analyzed.
Main Results:
- Dyskinetic symptoms emerged within the first week of chronic L-DOPA treatment.
- L-DOPA induced changes in DeltaFosB and prodynorphin expression, alongside ERK1/2 activation in the dopamine-depleted striatum.
- Elevated FosB/DeltaFosB expression correlated inversely with dopaminergic terminals and occurred in specific neuronal populations.
Conclusions:
- The developed mouse model accurately reproduces key features of human L-DOPA-induced dyskinesias.
- This model facilitates the study of molecular pathways involved in dyskinesia.
- It enables genetic manipulation to elucidate the mechanisms of dyskinesia development and expression.
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