Metabotropic glutamate receptor II in the brains of Parkinsonian patients.
Modulation of basal ganglia group II metabotropic glutamate receptors (mGluR2/3) is a potential therapeutic alternative to levodopa in Parkinson disease (PD). We used receptor-binding autoradiography of the mGluR2/3-selective radioligand [H]LY341495 in postmortem brain specimens from PD patients (n = 14) and controls (n=11) to investigate possible contributions of changes in ligand binding of this receptor to levodopa-associated motor complications experienced premortem in PD patients. The PD patients included those with and without histories of dyskinesias and those with and without "wearing off," which is defined as a reduced period of benefit from levodopa. Specific binding of [H]LY341495 to mGluR2/3 in the basal ganglia was higher in the caudate nucleus than the putamen and lower by approximately half in the external and internal globus pallidus (GPi) in controls. [H]LY341495-specific binding was reduced in the caudate and GPi in patients without wearing-off (-22% caudate, -30% GPi), compared with controls and with patients who had experienced wearing-off; there were no differences among PD patients with or without dyskinesias. These data suggest that an adaptive downregulation of mGluR2/3 in PD patients without wearing-off may compensate for increased glutamate. They indicate a key role for mGluR2/3 in control of movement and the potential for mGluR2/3-targeted drugs in the management of wearing-off fluctuations in PD.
Samadi
Pershia
P
Molecular Endocrinology and Oncology Research Centre, Laval University Medical Centre, Quebec, Canada.
Rajput
Alex
A
Calon
Frédéric
F
Grégoire
Laurent
L
Hornykiewicz
Oleh
O
Rajput
Ali H
AH
Di Paolo
Thèrèse
T
D000368:Aged; D000369:Aged, 80 and over; D000596:Amino Acids / Q000494:pharmacology; D000978:Antiparkinson Agents / Q000009:adverse effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003042:Cocaine / Q000031:analogs & derivatives; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000473:pathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D007980:Levodopa / Q000009:adverse effects; D008297:Male; D020734:Parkinsonian Disorders / Q000188:drug therapy / Q000473:pathology*; D011180:Postmortem Changes; D011869:Radioligand Assay; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D014316:Tritium / Q000494:pharmacology; D014966:Xanthenes / Q000494:pharmacology
D000596:Amino Acids; D000978:Antiparkinson Agents; D018691:Excitatory Amino Acid Antagonists; D007457:Iodine Radioisotopes; C114624:LY 341495; D018094:Receptors, Metabotropic Glutamate; D014966:Xanthenes; C108822:metabotropic glutamate receptor 2; D014316:Tritium; C079213:RTI 121; D007980:Levodopa; D003042:Cocaine