Alteration of glutamate receptors in the striatum of dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys following dopamine agonist treatment

Frédéric Calon, Marc Morissette, Othman Ghribi, Martin Goulet, Richard Grondin, Pierre J. Blanchet, Paul J. Bédard, Thérèse DiPaolo

Research output: Contribution to journalArticle

79 Citations (Scopus)

Abstract

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-α-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.

Original languageEnglish (US)
Pages (from-to)127-138
Number of pages12
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
Volume26
Issue number1
DOIs
StatePublished - Jan 18 2002

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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Dopamine Agonists
Glutamate Receptors
Haplorhini
Glycine
Dyskinesias
Glutamic Acid
N-Methylaspartate
Propionates
Therapeutics
Corpus Striatum
Excitatory Amino Acid Antagonists
Messenger RNA
Drug and Narcotic Control
Putamen
SK&F 82958
Basal Ganglia
Glutamine
Autoradiography
In Situ Hybridization

Keywords

  • AMPA
  • Autoradiography
  • Dyskinesias
  • MPTP
  • NMDA
  • NR1 subunit
  • Parkinson

ASJC Scopus subject areas

  • Pharmacology
  • Biological Psychiatry

Cite this

Alteration of glutamate receptors in the striatum of dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys following dopamine agonist treatment. / Calon, Frédéric; Morissette, Marc; Ghribi, Othman; Goulet, Martin; Grondin, Richard; Blanchet, Pierre J.; Bédard, Paul J.; DiPaolo, Thérèse.

In: Progress in Neuro-Psychopharmacology and Biological Psychiatry, Vol. 26, No. 1, 18.01.2002, p. 127-138.

Research output: Contribution to journalArticle

Calon, Frédéric ; Morissette, Marc ; Ghribi, Othman ; Goulet, Martin ; Grondin, Richard ; Blanchet, Pierre J. ; Bédard, Paul J. ; DiPaolo, Thérèse. / Alteration of glutamate receptors in the striatum of dyskinetic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys following dopamine agonist treatment. In: Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2002 ; Vol. 26, No. 1. pp. 127-138.
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AU - Ghribi, Othman

AU - Goulet, Martin

AU - Grondin, Richard

AU - Blanchet, Pierre J.

AU - Bédard, Paul J.

AU - DiPaolo, Thérèse

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N2 - 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-α-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.

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