Contribution of brain serotonin subtype 1B receptors in levodopa-induced motor complications

Abstract

l-DOPA-induced dyskinesias (LID) are abnormal involuntary movements limiting the chronic use of l-DOPA, the main pharmacological treatment of Parkinson's disease. Serotonin receptors are implicated in the development of LID and modulation of basal ganglia 5-HT1B receptors is a potential therapeutic alternative in Parkinson's disease. In the present study, we used receptor-binding autoradiography of the 5-HT1B-selective radioligand [3H]GR125743 to investigate possible contributions of changes in ligand binding of this receptor in LID in post-mortem brain specimens from Parkinson's disease patients (n = 14) and control subjects (n = 11), and from 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys treated with saline (n = 5), l-DOPA (n = 4) or l-DOPA + 2-methyl-6-(phenylethynyl)pyridine (MPEP) (n = 5), and control monkeys (n = 4). MPEP is the prototypal metabotropic glutamate 5 (mGlu5) receptor antagonist and has been shown to reduce the development of LID in these monkeys in a chronic treatment of one month. [3H]GR125743 specific binding to striatal and pallidal 5-HT1B receptors respectively were only increased in l-DOPA-treated MPTP monkeys (dyskinetic monkeys) as compared to controls, saline and L-DOPA + MPEP MPTP monkeys; dyskinesias scores correlated positively with this binding. Parkinson's disease patients with motor complications (l-DOPA-induced dyskinesias and wearing-off) had higher [3H]GR125743 specific binding compared to those without motor complications and controls in the basal ganglia. Reduction of motor complications was associated with normal striatal 5-HT1B receptors, suggesting the potential of this receptor for the management of motor complications in Parkinson's disease.