Repeated administration of piribedil induces less dyskinesia than L-dopa in MPTP-treated common marmosets: A behavioural and biochemical investigation

Authors

  • Lance A. Smith MSc, PhD, PGCE,

    1. Neurodegenerative Diseases Research Centre, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College, London, United Kingdom
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  • Banu C. Tel MSc,

    1. Neurodegenerative Diseases Research Centre, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College, London, United Kingdom
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  • Michael J. Jackson BSc,

    1. Neurodegenerative Diseases Research Centre, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College, London, United Kingdom
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  • Matthew J. Hansard BSc,

    1. Neurodegenerative Diseases Research Centre, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College, London, United Kingdom
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  • Rogelio Braceras MSc, MD,

    1. Neurodegenerative Diseases Research Centre, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College, London, United Kingdom
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  • Céline Bonhomme PhD,

    1. Institut de Recherches Internationales Servier, Direction de la Recherche et du Développement, Courbevoie, France
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  • Claire Chezaubernard DPharm,

    1. Institut de Recherches Internationales Servier, Direction de la Recherche et du Développement, Courbevoie, France
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  • Susanna Del Signore MD,

    1. Institut de Recherches Internationales Servier, Direction de la Recherche et du Développement, Courbevoie, France
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  • Sarah Rose BSc, PhD,

    1. Neurodegenerative Diseases Research Centre, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College, London, United Kingdom
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  • Peter Jenner PhD, DSc, FRPharmS

    Corresponding author
    1. Neurodegenerative Diseases Research Centre, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College, London, United Kingdom
    • Neurodegenerative Diseases Research Centre, Hodgkin Building, GKT School of Biomedical Sciences, King's College London, London SE1 1UL, United Kingdom
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Abstract

Piribedil ([1-(3,4-methylenedioxybenzyl)-4-(2-pyrimidinyl)piperazine]; S 4200) is a dopamine agonist with equal affinity for D2/D3 dopamine receptors effective in treating Parkinson's disease as monotherapy or as an adjunct to levodopa (L-dopa). However, its ability to prime basal ganglia for the appearance of dyskinesia is unknown. We now report on the ability of repeated administration of piribedil to induce dyskinesia in drug naïve 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -lesioned common marmosets compared with L-dopa and its actions on the direct and indirect striatal outflow pathways. Administration of piribedil (4.0–5.0 mg/kg orally) or L-dopa (12.5 mg/kg orally plus carbidopa 12.5 mg/kg orally twice daily) produced equivalent increases in locomotor activity and reversal of motor deficits over a 28-day study period. Administration of L-dopa resulted in the progressive development of marked dyskinesia over the period of study. In contrast, administration of piribedil produced a significantly lower degree and intensity of dyskinesia. Surprisingly, piribedil caused an increase in vigilance and alertness compared to L-dopa, which may relate to the recently discovered α2-noradrenergic antagonist properties of piribedil. The behavioural differences between piribedil and L-dopa are reflected in the biochemical changes associated with the direct striatal output pathway. Administration of L-dopa or piribedil did not reverse the MPTP-induced up-regulation of preproenkephalin A mRNA in rostral or caudal areas of the putamen or caudate nucleus. In contrast, administration of either piribedil or L-dopa reversed the downregulation of preprotachykinin mRNA induced by MPTP in rostral and caudal striatum. L-dopa, but not Piribedil, reversed the decrease in preproenkephalin B mRNA produced by MPTP treatment. © 2002 Movement Disorder Society

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