Striatal Overexpression of ΔFosB Reproduces Chronic Levodopa-Induced Involuntary Movements

摘要

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.