Alteration of glutamate receptors in the striatum of dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys following dopamine agonist treatment.
The effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal lesion and dopaminomimetic treatment on parameters of glutamatergic activity within the basal ganglia of monkeys were studied in relation with the development of dyskinesias. Drug-naive controls, saline-treated MPTP monkeys, as well as MPTP monkeys treated with either a long-acting D2 agonist (cabergoline) or a D1 agonist (SKF-82958) given by intermittent injections or continuous infusion, were included in this study. 3H-L-glutamate, 3H-alpha-amino-3-hydroxy-5-methylisoxasole-4-propionate (AMPA), 3H-glycine, 3H-CGP39653 (an N-methyl-D-aspartate, NMDA, antagonist selective for NR1/NR2A assembly) and 3H-Ro 25-6981 (an NMDA antagonist selective for NR1/NR2B assembly), specific binding to glutamate receptors, the expression of the NR1 subunit of NMDA receptors and glutamate, glutamine and glycine concentrations were studied by autoradiography, in situ hybridization and high-performance liquid chromatography (HPLC), respectively. Pulsatile SKF-82958 and cabergoline treatment relieved parkinsonian symptoms, whereas animals continuously treated with SKF-82958 remained akinetic. Pulsatile SKF-82958 induced dyskinesias in two of the three animals tested, whereas cabergoline did not. MPTP induced no significant changes of striatal specific binding of the radioligands used, NR1 mRNA expression and amino acid concentrations. In the putamen, pulsatile SKF-82958 treatment was associated with decreased content of glycine and glutamate, whereas only glycine was decreased in cabergoline-treated monkeys. Cabergoline and continuous administration of SKF-82958 led to lower levels of NR1 mRNA in the caudate in comparison to pulsatile SKF-82958 administration. The development of dyskinesias following a D1 agonist treatment was associated with an upregulation of 3H-glutamate [+49%], 3H-AMPA [+38%], 3H-CGP39653 [+ 111%], 3H-glycine [+ 26%, nonsignificant] and 3H-Ro 25-6981 [+ 33%] specific binding in the striatum in comparison to nondyskinetic MPTP monkeys. Our data suggest that supersensitivity to glutamatergic input in the striatum might play a role in the pathogenesis of dopaminomimetic-induced dyskinesias and further support the therapeutic potential of glutamate antagonists in Parkinson's disease.
Calon
Frédéric
F
Oncology and Molecular Endocrinology Research Center Laval University Medical Center (CHUL), Quebec, Canada.
Morissette
Marc
M
Ghribi
Othman
O
Goulet
Martin
M
Grondin
Richard
R
Blanchet
Pierre J
PJ
Bédard
Paul J
PJ
Di Paolo
Thérèse
T
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D008252:Macaca fascicularis; D010052:Ovariectomy; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values
D001552:Benzazepines; D018491:Dopamine Agonists; D017470:Receptors, Glutamate; D005973:Glutamine; D018698:Glutamic Acid; C071262:SK&F 82958; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D005998:Glycine