Continuous dopamine-receptor treatment of Parkinson's disease: scientific rationale and clinical implications.
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.
Olanow
C Warren
CW
Department of Neurology, Mount Sinai School of Medicine, New York, NY 10029, USA. warren.olanow@mssm.edu
Obeso
Jose A
JA
Stocchi
Fabrizio
F
D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001479:Basal Ganglia / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004409:Dyskinesia, Drug-Induced / Q000209:etiology; D006801:Humans; D007980:Levodopa / Q000008:administration & dosage* / Q000009:adverse effects; D016571:Neural Networks, Computer; D010300:Parkinson Disease / Q000188:drug therapy*; D011954:Receptors, Dopamine / Q000502:physiology*
D000978:Antiparkinson Agents; D015259:Dopamine Agents; D011954:Receptors, Dopamine; D007980:Levodopa