The therapeutic concept of continuous dopaminergic stimulation (CDS) in the treatment of Parkinson's disease

Abstract

Continuous dopaminergic stimulation is a therapeutic concept for the management of Parkinson's disease (PD) that proposes that continuous, as opposed to discontinuous or pulsatile, stimulation of striatal dopamine receptors will delay or prevent the onset of levodopa-related motor complications. This hypothesis has arisen from studies of the normal basal ganglia demonstrating that nigral dopaminergic neurons normally fire continuously and striatal dopamine levels are relatively constant. In MPTP monkeys, pulsatile stimulation of striatal dopamine receptors with short-acting agents is associated with the induction of molecular and physiologic changes in basal ganglia neurons and the development of motor complications. These are avoided when dopaminergic therapies are delivered in a more continuous manner. Studies in animal models support this hypothesis, demonstrating that long-acting dopamine agonists are associated with a decreased risk of motor complications in comparison to short-acting formulations of levodopa. Similarly, continuous infusion of dopamine agonists ropinirole and rodigotine reduces dyskinesia associated with intermittent doses of oral formulations of the same drug. The current challenge is to develop a long-acting formulation of levodopa that simulates the pharmacokinetic pattern seen with infusions of levodopa in attempt to provide comparable benefits with an oral levodopa treatment strategy.