Continuous dopamine-receptor treatment of Parkinson's disease: scientific rationale and clinical implications
Olanow CW, Obeso JA, Stocchi F.
Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Levodopa-induced motor complications are a common source of disability for patients with Parkinson's disease.
Evidence suggests that motor complications are associated with non-physiological, pulsatile stimulation of dopamine receptors. In healthy brains, dopamine neurons fire continuously, striatal dopamine concentrations are relatively constant, and there is continuous activation of dopamine receptors. In the dopamine-depleted state, standard levodopa therapy does not normalise the basal ganglia. Rather, levodopa or other short-acting dopaminergic drugs induce molecular changes and altered neuronal firing patterns in basal ganglia neurons leading to motor complications.
The concept of continuous dopaminergic stimulation proposes that continuous delivery of a dopaminergic drug will prevent pulsatile stimulation and avoid motor complications. In monkeys treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and patients with Parkinson's disease, long-acting or continuous infusion of a dopaminergic drug reduces the risk of motor complications.
The current challenge is to develop a long-acting oral formulation of levodopa that provides clinical benefits but avoids motor complications.
CITATION Lancet Neurol. 2006 Aug;5(8):677-87