Changes of GABA receptors and dopamine turnover in the postmortem brains of parkinsonians with levodopa-induced motor complications.
Brain samples from 14 Parkinson's disease patients, 10 of whom developed motor complications (dyskinesias and/or wearing-off) on dopaminomimetic therapy, and 11 controls were analyzed. Striatal 3beta-(4-(125)I-iodophenyl)tropane-2beta-carboxylic acid isopropyl ester ([(125)I]RTI-121) -specific binding to dopamine transporter and concentration of dopamine were markedly decreased, but no association between level of denervation and development of motor complications was observed. The homovanillic acid/dopamine ratio of concentrations was higher in putamen of patients with wearing-off compared to those without. Striatal (35)S-labeled t-butylbicyclophosphorothionate ([(35)S]TBPS) and [(3)H]flunitrazepam binding to GABA(A) receptors were unchanged in patients with Parkinson's disease, whereas [(125)I]CGP 64213 -specific binding to GABA(B) receptors was decreased in the putamen and external segment of the globus pallidus of parkinsonian patients compared with controls. [(3)H]Flunitrazepam binding was increased in the putamen of patients with wearing-off compared to those without. [(35)S]TBPS-specific binding was increased in the ventral internal globus pallidus of dyskinetic subjects. These data suggest altered dopamine metabolism and increased GABA(A) receptors in the putamen related to the pathophysiology of wearing-off. The present results also suggest that an up-regulation of GABA(A) receptors in the internal globus pallidus is linked to the pathogenesis of levodopa-induced dyskinesias.
Calon
Frédéric
F
Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (CHUL), and Faculty of Pharmacy, Laval University, Québec, Canada.
Morissette
Marc
M
Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (CHUL), and Faculty of Pharmacy, Laval University, Québec, Canada.
Rajput
Ali H
AH
Division of Neurology, University of Saskatchewan, Royal University Hospital, Saskatoon, Canada.
Hornykiewicz
Oleh
O
Division of Neurology, University of Saskatchewan, Royal University Hospital, Saskatoon, Canada.|Institute for Brain Research, Faculty of Medicine, University of Vienna, Vienna, Austria.
Bédard
Paul J
PJ
Neuroscience Research Unit, Laval University Medical Center (CHUL), and Department of Medicine, Faculty of Medicine, Laval University, Québec, Canada.
Di Paolo
Thérèse
T
Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (CHUL), and Faculty of Pharmacy, Laval University, Québec, Canada.
D000368:Aged; D000369:Aged, 80 and over; D000978:Antiparkinson Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D016022:Case-Control Studies; D004298:Dopamine / Q000378:metabolism*; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005917:Globus Pallidus / Q000378:metabolism; D006801:Humans; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism*; D011180:Postmortem Changes; D018079:Receptors, GABA / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism
D000978:Antiparkinson Agents; D018079:Receptors, GABA; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D007980:Levodopa; D004298:Dopamine