The missing, the short, and the long: Levodopa responses and dopamine actions.

We attempt to correlate the clinical pharmacology of dopamine replacement therapy (DRT) in Parkinson Disease with known features of striatal dopamine actions. Despite its obvious impact, DRT does not normalize motor function, likely due to disrupted phasic dopaminergic signaling. The DRT Short Duration Response is likely a permissive-paracrine effect, possibly resulting from dopaminergic support of corticostriate synaptic plasticity. The DRT Long Duration Response may result from mimicry of tonic dopamine signaling regulation of movement vigor. Our understanding of dopamine actions does not explain important aspects of DRT clinical pharmacology. Reducing these knowledge gaps provides opportunities to improve understanding of dopamine actions and symptomatic treatment of Parkinson disease.