Striatal Overexpression of ΔFosB Reproduces Chronic Levodopa-Induced Involuntary Movements
Open Access
- 26 May 2010
- journal article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 30 (21), 7335-7343
- https://doi.org/10.1523/jneurosci.0252-10.2010
Abstract
Long-term dopamine replacement therapy in Parkinson's disease leads to the development of disabling involuntary movements named dyskinesias that are related to adaptive changes in striatal signaling pathways. The chronic transcription factor ΔFosB, which is overexpressed in striatal neurons after chronic dopaminergic drug exposure, is suspected to mediate these adaptive changes. Here, we sought to demonstrate the ability of ΔFosB to lead directly to the abnormal motor responses associated with chronic dopaminergic therapy. Using rAAV (recombinant adenoassociated virus) viral vectors, high levels of ΔFosB expression were induced in the striatum of dopamine-denervated rats naive of chronic drug administration. Transgenic ΔFosB overexpression reproduced the entire spectrum of altered motor behaviors in response to acute levodopa tests, including different types of abnormal involuntary movements and hypersensitivity of rotational responses that are typically associated with chronic levodopa treatment. JunD, the usual protein partner of ΔFosB binding to AP-1 (activator protein-1) sites of genes, remained unchanged in rats with high ΔFosB expression induced by viral vectors. These findings demonstrate that the increase of striatal ΔFosB in the evolution of chronically treated Parkinson's disease may be a trigger for the development of abnormal responsiveness to dopamine and the emergence of involuntary movements.Keywords
This publication has 48 references indexed in Scilit:
- Striatal Overexpression of ΔJunD Resets L-DOPA-Induced Dyskinesia in a Primate Model of Parkinson DiseaseBiological Psychiatry, 2009
- Quantitative autoradiographic study on receptor regulation in the basal ganglia in rat model of levodopa-induced motor complicationsJournal of Huazhong University of Science and Technology [Medical Sciences], 2009
- Dysregulation of CalDAG-GEFI and CalDAG-GEFII predicts the severity of motor side-effects induced by anti-parkinsonian therapyProceedings of the National Academy of Sciences of the United States of America, 2009
- Inversion of Dopamine Responses in Striatal Medium Spiny Neurons and Involuntary MovementsJournal of Neuroscience, 2008
- Critical Involvement of cAMP/DARPP-32 and Extracellular Signal-Regulated Protein Kinase Signaling in L-DOPA-Induced DyskinesiaJournal of Neuroscience, 2007
- Role of AP‐1 in ethanol‐induced N‐methyl‐d‐aspartate receptor 2B subunit gene up‐regulation in mouse cortical neuronsJournal of Neurochemistry, 2005
- Loss of bidirectional striatal synaptic plasticity in L-DOPA–induced dyskinesiaNature Neuroscience, 2003
- Striatal fosB Expression Is Causally Linked with l-DOPA-Induced Abnormal Involuntary Movements and the Associated Upregulation of Striatal Prodynorphin mRNA in a Rat Model of Parkinson's DiseaseNeurobiology of Disease, 1999
- L‐DOPA‐induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin‐ and glutamic acid decarboxylase mRNAEuropean Journal of Neuroscience, 1998
- Motor fluctuations in Parkinson's disease: Central pathophysiological mechanisms, Part IAnnals of Neurology, 1988