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The monoamine reuptake inhibitor BTS 74 398 fails to evoke established dyskinesia but does not synergise with levodopa in MPTP-treated primates

Authors

  • Matthew J. Hansard BSc, PhD,

    1. Neurodegenerative Disease Research Centre, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College, London, United Kingdom
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  • Lance A. Smith MSc, PhD,

    1. Neurodegenerative Disease 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 Disease Research Centre, Guy's, King's and St. Thomas' School of Biomedical Sciences, King's College, London, United Kingdom
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  • Sharon C. Cheetham MSc, PhD,

    1. RenaSci Consultancy Ltd., Nottingham, United Kingdom
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  • Peter Jenner FRPharm, DSc

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

Long-term treatment of Parkinson's disease (PD) with levodopa (L-dopa) induces dyskinesia that, once established, is provoked by each dose of L-dopa or a dopamine (DA) agonist. In contrast, monoamine reuptake inhibitors may reverse motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates without provoking established involuntary movements. We now examine whether the potent monoamine reuptake blocker BTS 74 398 induces established dyskinesia in MPTP-treated common marmosets primed previously with L-dopa and whether co-administration of BTS 74 398 with L-dopa potentiates motor behaviour and dyskinesia induced by acute L-dopa treatment. Administration of BTS 74 398 (2.5, 5.0, or 10.0 mg/kg, p.o.) in MPTP-treated common marmosets increased locomotor activity and reduced motor disability in a dose-related manner but did not provoke involuntary movements. BTS 74 398 (2.5, 5.0, or 10.0 mg/kg p.o.) co-administered with a threshold dose of L-dopa (2.5 mg/kg p.o.) did not evoke a motor response or induce dyskinesia. Similarly, concomitant administration of BTS 74 398 (5.0 mg/kg p.o.) with a submaximal L-dopa dose (12.5 mg/kg p.o.) did not potentiate the motor response produced by L-dopa alone and there was no alteration in the dyskinesia provoked by L-dopa challenge. BTS 74 398 reverses motor abnormalities in MPTP-treated marmosets without evoking established dyskinesia but no additive improvement occurs when administered in combination with L-dopa. The lack of synergy with L-dopa may suggest different sites of drug action. © 2003 Movement Disorder Society

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