Basal ganglia group II metabotropic glutamate receptors specific binding in non-human primate model of L-Dopa-induced dyskinesias.
L-Dopa-induced dyskinesias (LIDs), the disabling abnormal involuntary movements induced by chronic use of L-Dopa, limit the quality of life in Parkinson's disease (PD) patients. Modulation of group II metabotropic glutamate receptors (mGluR2/3) in the basal ganglia, a brain region critically involved in motor control, is considered as an alternative approach in therapy of PD. In this study, receptor binding autoradiography of [3H]LY341495, a mGluR2/3 selective radioligand, was used to investigate possible changes in mGluR2/3 in the basal ganglia of L-Dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys having developed LIDs compared to animals in which LIDs were prevented by adjunct treatments with CI-1041, a selective antagonist of the NR1A/2B subtype of NMDA receptor, or low doses of the dopamine D2 receptor agonist, cabergoline. Our study is the first to provide evidence of: (1) the similar localization of [3H]LY341495 specific binding to mGluR2/3 in the primate basal ganglia as compared to receptor distribution measured by immunohistochemistry in human and rat as well as this ligand binding in intact rat brain; (2) no change of [3H]LY341495 specific binding in basal ganglia after nigrostriatal denervation by MPTP; and (3) a widespread reduction of [(3)H]LY341495 specific binding to mGluR2/3 in the caudate nucleus (-17% to -31%), putamen (-12% to -45%) and globus pallidus (-56 to -59%) of non-dyskinetic animals treated with L-Dopa+cabergoline as compared to controls, MPTP monkeys treated with saline, L-Dopa alone (dyskinetic) or L-Dopa+CI-1041 (non-dyskinetic). This study is the first to propose a close interaction between mGluR2/3 and dopamine D2 receptors activation in the basal ganglia.
Samadi
Pershia
P
Molecular Endocrinology and Oncology Research Centre, Laval University Medical Centre, Quebec, Canada.
Grégoire
Laurent
L
Morissette
Marc
M
Calon
Fréderic
F
Hadj Tahar
Abdallah
A
Bélanger
Nancy
N
Dridi
Mehdi
M
Bédard
Paul J
PJ
Di Paolo
Thérèse
T
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000378:metabolism*; D001345:Autoradiography; D001479:Basal Ganglia / Q000378:metabolism*; D001522:Behavior, Animal / Q000187:drug effects; D000077465:Cabergoline; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D003627:Data Interpretation, Statistical; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D004873:Ergolines / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D007980:Levodopa / Q000009:adverse effects* / Q000378:metabolism*; D008252:Macaca fascicularis; D010052:Ovariectomy; D011699:Putamen / Q000187:drug effects / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects / Q000378:metabolism*; D014966:Xanthenes / Q000494:pharmacology
D000596:Amino Acids; D000978:Antiparkinson Agents; D004873:Ergolines; D018691:Excitatory Amino Acid Antagonists; C114624:LY 341495; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D007980:Levodopa; D000077465:Cabergoline