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Prevention of levodopa-induced dyskinesias by a selective NR1A/2B N-methyl-D-aspartate receptor antagonist in parkinsonian monkeys: Implication of preproenkephalin

Authors

  • Marc Morissette PhD,

    Corresponding author
    1. Molecular Endocrinology and Oncology Research Centre, Laval University Medical Centre, Quebec, Canada
    2. Faculty of Pharmacy, Laval University, Quebec, Canada
    • Molecular Endocrinology and Oncology Research Center, Laval University Medical Center, CHUL, 2705 Laurier Blvd, Quebec, QC, Canada G1V 4G2
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  • Mehdi Dridi MSc,

    1. Molecular Endocrinology and Oncology Research Centre, Laval University Medical Centre, Quebec, Canada
    2. Faculty of Pharmacy, Laval University, Quebec, Canada
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  • Frédéric Calon PhD,

    1. Molecular Endocrinology and Oncology Research Centre, Laval University Medical Centre, Quebec, Canada
    2. Faculty of Pharmacy, Laval University, Quebec, Canada
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  • Abdallah Hadj Tahar PhD,

    1. Neuroscience Research Unit, Laval University Medical Centre, Quebec, Canada
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  • Leonard T. Meltzer PhD,

    1. Pfizer Global Research & Development, Ann Arbor Laboratories, Ann Arbor, Michigan, USA
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  • Paul J. Bédard PhD,

    1. Neuroscience Research Unit, Laval University Medical Centre, Quebec, Canada
    2. Faculty of Medicine, Laval University, Quebec, Canada
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  • Thérèse Di Paolo PhD

    1. Molecular Endocrinology and Oncology Research Centre, Laval University Medical Centre, Quebec, Canada
    2. Faculty of Pharmacy, Laval University, Quebec, Canada
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Abstract

Enkephalin is reported to play an important role in the pathophysiology of levodopa (LD) -induced dyskinesias. The present study investigated the effect of chronic treatment with a selective NR1A/2B N-methyl-D-aspartate (NMDA) receptor antagonist, CI-1041, on the expression of preproenkephalin-A (PPE-A) in brains of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -treated monkeys in relation to the development of LD-induced dyskinesias. Four MPTP-monkeys received LD/benserazide alone; they all developed dyskinesias. Four other MPTP-monkeys received LD/benserazide plus CI-1041; only one of them developed mild dyskinesias at the end of the fourth week of treatment. Four normal monkeys and four saline-treated MPTP monkeys were also included. MPTP-treated monkeys had extensive and similar striatal dopamine denervation. An increase of PPE-A mRNA levels assayed by in situ hybridization was observed in the lateral putamen (rostral and caudal) and caudate nucleus (rostral) of saline-treated MPTP monkeys compared to controls, whereas no change or a small increase was observed in their medial parts. Striatal PPE-A mRNA levels remained elevated in LD-treated MPTP monkeys, whereas cotreatment with CI-1041 brought them back to control values. These findings suggest that chronic blockade of striatal NR1A/2B NMDA receptors with CI-1041 normalizes PPE-A mRNA expression and prevents the development of LD-induced dyskinesias in an animal model of Parkinson disease. © 2005 Movement Disorder Society

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