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Review ArticleReview Article

The Pharmacology of l-DOPA-Induced Dyskinesia in Parkinson’s Disease

Philippe Huot, Tom H. Johnston, James B. Koprich, Susan H. Fox and Jonathan M. Brotchie
David R. Sibley, ASSOCIATE EDITOR
Pharmacological Reviews January 2013, 65 (1) 171-222; DOI: https://doi.org/10.1124/pr.111.005678
Philippe Huot
Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada (P.H., T.H.J, J.B.K, S.H.F., J.M.B.); and Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada (P.H., S.H.F.)
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Tom H. Johnston
Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada (P.H., T.H.J, J.B.K, S.H.F., J.M.B.); and Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada (P.H., S.H.F.)
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James B. Koprich
Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada (P.H., T.H.J, J.B.K, S.H.F., J.M.B.); and Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada (P.H., S.H.F.)
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Susan H. Fox
Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada (P.H., T.H.J, J.B.K, S.H.F., J.M.B.); and Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada (P.H., S.H.F.)
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Jonathan M. Brotchie
Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada (P.H., T.H.J, J.B.K, S.H.F., J.M.B.); and Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada (P.H., S.H.F.)
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David R. Sibley
Toronto Western Research Institute, University Health Network, Toronto, Ontario, Canada (P.H., T.H.J, J.B.K, S.H.F., J.M.B.); and Division of Neurology, Movement Disorder Clinic, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada (P.H., S.H.F.)
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Abstract

l-3,4-Dihydroxyphenylalanine (l-DOPA) remains the most effective symptomatic treatment of Parkinson’s disease (PD). However, long-term administration of l-DOPA is marred by the emergence of abnormal involuntary movements, i.e., l-DOPA-induced dyskinesia (LID). Years of intensive research have yielded significant progress in the quest to elucidate the mechanisms leading to the development and expression of dyskinesia and maintenance of the dyskinetic state, but the search for a complete understanding is still ongoing. Herein, we summarize the current knowledge of the pharmacology of LID in PD. Specifically, we review evidence gathered from postmortem and pharmacological studies, both preclinical and clinical, and discuss the involvement of dopaminergic and nondopaminergic systems, including glutamatergic, opioid, serotonergic, γ-aminobutyric acid (GABA)-ergic, adenosine, cannabinoid, adrenergic, histaminergic, and cholinergic systems. Moreover, we discuss changes occurring in transcription factors, intracellular signaling, and gene expression in the dyskinetic phenotype. Inasmuch as a multitude of neurotransmitters and receptors play a role in the etiology of dyskinesia, we propose that to optimally alleviate this motor complication, it may be necessary to develop combined treatment approaches that will target simultaneously more than one neurotransmitter system. This could be achieved via three ways as follows: 1) by developing compounds that will interact simultaneously to a multitude of receptors with the required agonist/antagonist effect at each target, 2) by targeting intracellular signaling cascades where the signals mediated by multiple receptors converge, and/or 3) to regulate gene expression in a manner that has effects on signaling by multiple pathways

Footnotes

  • This work was supported by The Cure Parkinson’s Trust and Krembil Neuroscience Fund. P.H. was supported by Fellowships from the Edmond J. Safra Philanthropic Foundation, the Parkinson Society Canada, and the Canadian Institutes of Health Research.

  • ↵1Current affiliation: Baycrest Centre for Geriatric Care, Toronto, Ontario, Canada.

  • There are no conflicts of interest. S.H.F. received consultancy fees from Merck, Merck Serono, and Teva. T.H.J., J.B.K., and J.M.B. received consultancy fees from Atuka Ltd. and Atuka Inc., and hold equity positions in Atuka Inc. P.H. received consultancy fees from Atuka Ltd. and Atuka Inc.

  • dx.doi.org/10.1124/pr.111.005678.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 65 (1)
Pharmacological Reviews
Vol. 65, Issue 1
1 Jan 2013
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Review ArticleReview Article

l-DOPA-Induced Dyskinesia Pharmacology

Philippe Huot, Tom H. Johnston, James B. Koprich, Susan H. Fox and Jonathan M. Brotchie
Pharmacological Reviews January 1, 2013, 65 (1) 171-222; DOI: https://doi.org/10.1124/pr.111.005678

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Review ArticleReview Article

l-DOPA-Induced Dyskinesia Pharmacology

Philippe Huot, Tom H. Johnston, James B. Koprich, Susan H. Fox and Jonathan M. Brotchie
Pharmacological Reviews January 1, 2013, 65 (1) 171-222; DOI: https://doi.org/10.1124/pr.111.005678
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  • Article
    • Abstract
    • I. Introduction
    • II. Review Terms of Reference and Presentation
    • III. The Classic Model of the Functional Organization of the Basal Ganglia
    • IV. The Dopaminergic System
    • V. The Glutamatergic System
    • VI. The Opioid System
    • VII. The Serotonergic System
    • VIII. The GABAergic System
    • IX. The Adenosine System
    • X. Cannabinoid Neurotransmission
    • XI. Adrenergic Neurotransmission
    • XII. Histaminergic Neurotransmission
    • XIII. Cholinergic Neurotransmission
    • XIV. Tachykinin Neurotransmission
    • XV. Transcription Factors and Intracellular Signaling
    • XVI. Emerging Concepts in Dyskinesia
    • XVII. Concluding Remarks
    • Authorship contributions
    • Footnotes
    • Abbreviations
    • References
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