Drug insight: Continuous dopaminergic stimulation in the treatment of Parkinson's disease

Continuous dopaminergic stimulation is a therapeutic strategy for the management of Parkinson's disease, which proposes that dopaminergic agents that provide continuous stimulation of striatal dopamine receptors will delay or prevent the onset of levodopa-related motor complications. Dopaminergic neurons in the basal ganglia normally fire in a random but continuous manner, so that striatal dopamine concentrations are maintained at a relatively constant level. In the dopamine-depleted state, however, intermittent oral doses of levodopa induce discontinuous stimulation of striatal dopamine receptors. This pulsatile stimulation leads to molecular and physiologic changes in basal ganglia neurons and the development of motor complications. These effects are reduced or avoided when dopaminergic therapies are delivered in a more continuous and physiologic manner. Studies in primate models and patients with Parkinson's disease have shown that continuous or long-acting dopaminergic agents are associated with a decreased risk of motor complications compared with short-acting dopamine agonists or levodopa formulations. Continuous dopaminergic stimulation can be achieved with a continuous infusion, but infusion therapies are cumbersome and not likely to be acceptable to patients with early disease. The current challenge is to develop a long-acting oral formulation of levodopa that provides comparable anti-parkinsonian benefits without motor complications.