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Effect of pulsatile administration of levodopa on dyskinesia induction in drug-naïve MPTP-treated common marmosets: Effect of dose, frequency of administration, and brain exposure

Authors

  • Lance A. Smith MSc, PhD,

    1. Division of Pharmacology and Therapeutics, 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. Division of Pharmacology and Therapeutics, 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, PhD,

    1. Division of Pharmacology and Therapeutics, Guy's, King's, and St Thomas' School of Biomedical Sciences, King's College, London, United Kingdom
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  • Eleni Maratos MSc, PhD,

    1. Division of Pharmacology and Therapeutics, Guy's, King's, and St Thomas' School of Biomedical Sciences, King's College, London, United Kingdom
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  • Peter Jenner PhD, FRPharmS, DSc

    Corresponding author
    1. Division of Pharmacology and Therapeutics, 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

Levodopa (L-dopa) consistently primes basal ganglia for the appearance of dyskinesia in parkinsonian patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP) -treated primates. This finding may reflect its relatively short duration of effects resulting in pulsatile stimulation of postsynaptic dopamine receptors in the striatum. We have compared the relationship between L-dopa dose and frequency of administration on dyskinesia initiation in drug-naïve, MPTP-treated common marmosets. We have also studied the effect of increased brain exposure to pulsatile administration by combining a low-dose of L-dopa with the peripheral catechol-O-methyltransferase inhibitor (COMT-I), entacapone. Pulsatile administration of a low (dose range, 5.0–7.5 mg/kg p.o.) or a high (12.5 mg/kg) dose of L-dopa plus carbidopa b.i.d. produced a dose-related reversal of motor deficits. Repeated administration of low and high doses of L-dopa for 26 days to drug-naïve, MPTP-treated animals also caused a dose-related induction of peak-dose dyskinesia. Repeated administration of high-dose L-dopa b.i.d. compared to once daily caused a frequency-related improvement of motor symptoms, resulting in a more rapid and initially more intense appearance of peak-dose dyskinesia. Administration of low-dose L-dopa b.i.d. for 26 days in combination with entacapone enhanced the increase in locomotor activity and reversal of disability produced by L-dopa alone, but with no obvious change in duration of L-dopa's effect. However, combining entacapone with L-dopa resulted in the more rapid appearance of dyskinesia, which was initially more severe than occurred with L-dopa alone. Importantly, increasing pulsatile exposure of brain to L-dopa by preventing its peripheral breakdown also increases dyskinesia induction. © 2003 Movement Disorder Society

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