Molecular Mechanisms of l-DOPA-Induced Dyskinesia

The dopamine (DA) precursor, 3,4-dihydroxyphenyl- l -alanine ( l -DOPA), is the most effective treatment for Parkinson's disease (PD), but causes dyskinesias (abnormal involuntary movements) in the vast majority of patients. There is a wide consensus that l -DOPA-induced dyskinesia (LID) depends on both pre- and postsynaptic disturbances of the nigrostriatal DA transmission. Presynaptically, LID is associated with abnormal DA release and defective DA clearance, which converge to cause large swings in brain DA levels concomitant with the medication. Postsynaptically, LID is associated with a dysregulation of intracellular signaling and gene expression downstream of the D1 DA receptor. These phenomena are particularly well studied in the striatum and are thus the main topic of this chapter. In addition, the chapter reviews studies that have revealed associations between LID and different types of abnormalities in glutamatergic and GABAergic transmission within cortico-basal ganglia circuits.