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

Nicolas Morina, Marc Morissetteb, Laurent Grégoireb, Alex Rajputc, Ali H. Rajputc, Dr. Thérèse Di Paoloa
Faculty of Pharmacy, Université Laval, Quebec City, CANADA, G1K 7P4
Neuroscience Research Unit, Centre de recherche du CHU de Québec, Quebec City, CANADA, G1V 4G2
Division of Neurology, University of Saskatchewan, Royal University Hospital, Saskatoon, SK, Canada, S7N 0W8

Highlights

• Basal ganglia 5-HT1B receptors increased in L-DOPA-induced dyskinetic MPTP monkeys.

• L-DOPA + MPEP treatment left striatal 5-HT1B receptors unchanged in MPTP monkeys.

• Dyskinesias correlated with striatal and pallidal 5-HT1B receptor levels in monkeys.

• Basal ganglia 5-HT1B receptors increased in PD patients with motor complications.

• Striatal 5-HT1B receptors were unchanged in PD patients without 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-HT1Breceptors 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.

“… Slices were thaw-mounted onto SuperFrost Plus slides (Brain Research Laboratories, Newton, MA) and stored at −80 °C until use for assay …”

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