Normalization of GABAA receptor specific binding in the substantia nigra reticulata and the prevention of L-dopa-induced dyskinesias in MPTP parkinsonian monkeys.
L-Dopa therapy in Parkinson's disease (PD) is counfounded by the development of involuntary movements such as L-Dopa-induced dyskinesias (LIDs). In this study GABA(A) receptor autoradiography was assessed using [(3)H]flunitrazepam binding to the benzodiazepine site of the GABA(A) receptor and [(35)S]t-butylbicyclophosphorothionate (TBPS) binding to the chloride channel of GABA(A) receptors in the substantia nigra reticulata (SNr) and subthalamic nucleus (STN). L-Dopa-treated parkinsonian monkeys experiencing LIDs were compared to animals in which LIDs was 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 results demonstrated a decrease of GABA(A) receptor specific binding in the posterior part of the SNr in dyskinetic monkeys compared to nondyskinetic animals, while no modulation has been observed in the STN. These results provide evidence for the first time that pharmacological treatments preventing LIDs in nonhuman primate model of PD are associated with normalization of GABA(A) receptor-mediated signalling in the SNr.
Samadi
Pershia
P
Molecular Endocrinology and Oncology Research Centre, Laval University Medical Centre, Quebec, Canada.
Morissette
Marc
M
Calon
Fréderic
F
Hadj Tahar
Abdallah
A
Dridi
Mehdi
M
Belanger
Nancy
N
Meltzer
Leonard T
LT
Bédard
Paul J
PJ
Di Paolo
Thérèse
T
D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D001345:Autoradiography / Q000379:methods; D001522:Behavior, Animal; D001583:Benzoxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001667:Binding, Competitive / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D003292:Convulsants / Q000378:metabolism; D004195:Disease Models, Animal; D004409:Dyskinesia, Drug-Induced / Q000473:pathology* / Q000517:prevention & control*; D005260:Female; D005445:Flunitrazepam / Q000378:metabolism; D018757:GABA Modulators / Q000378:metabolism; D007554:Isotopes / Q000378:metabolism; D007980:Levodopa / Q000009:adverse effects*; D008252:Macaca fascicularis; D010052:Ovariectomy / Q000379:methods; D020734:Parkinsonian Disorders / Q000188:drug therapy; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D011485:Protein Binding / Q000187:drug effects; D011859:Radiography; D018079:Receptors, GABA / Q000378:metabolism*; D013378:Substantia Nigra / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000473:pathology
D000978:Antiparkinson Agents; D001583:Benzoxazoles; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D018757:GABA Modulators; D007554:Isotopes; D010880:Piperidines; D018079:Receptors, GABA; D007980:Levodopa; C481484:besonprodil; D005445:Flunitrazepam; C037476:tert-butylbicyclophosphorothionate