Pathophysiology of motor fluctuations in Parkinson's disease

Loss of dopamine neurons in Parkinson's disease (PD) initiates a complex stream of effects that results in the development of tremor, bradykinesia, and rigidity. While levodopa remains the most effective drug for the symptomatic treatment of PD, its chronic administration is associated with the development of motor fluctuations and dyskinesias. The risk of developing motor fluctuations has been linked to disease severity, dosage of levodopa, and the age of the patient. A recent body of preclinical data has demonstrated that alterations in dopaminergic tone as well as in treatment patterns results in cellular adaptations, including alterations in gene expression. This body of preclinical data suggests that nonphysiological, pulsatile stimulation of dopamine receptors induces the development of motor fluctuations and dyskinesias and raises the possibility that nonpulsatile stimulation of dopamine receptors (continuous dopaminergic stimulation) might induce fewer fluctuations. We discuss the theory of continuous dopaminergic stimulation and its implications for the management of motor fluctuations in patients with advanced and early PD.