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Maladaptive plasticity of serotonin axon terminals in levodopa-induced dyskinesia

Authors

  • Daniella Rylander PhD,

    1. Basal Ganglia Pathophysiology Laboratory, Department of Experimental Medical Science, Lund University, Lund, Sweden
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  • Martin Parent PhD,

    1. Laboratoire de Neurobiologie, Centre de Recherche Université Laval Robert-Giffard, Faculty of Medicine, Laval University, Beauport, Quebec, Canada
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  • Sean S. O'Sullivan MB, MRCPI,

    1. Queen Square Brain Bank for Neurological Disorders and Institute of Neurology, University College, London, United Kingdom
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  • Sandra Dovero PhD,

    1. Victor Segalen Bordeaux 2 University, Centre National de la Recherche Scientifique (CNRS), Bordeaux Institute of Neuroscience, Bordeaux, France
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  • Andrew J. Lees MD, FRCP,

    1. Queen Square Brain Bank for Neurological Disorders and Institute of Neurology, University College, London, United Kingdom
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  • Erwan Bezard PhD,

    1. Victor Segalen Bordeaux 2 University, Centre National de la Recherche Scientifique (CNRS), Bordeaux Institute of Neuroscience, Bordeaux, France
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  • Laurent Descarries MD, FRCP(C),

    1. Department of Pathology and Cell Biology, Groupe de recherche sur le système nerveux central, Faculty of Medicine; Université de Montreal, Montreal, Quebec, Canada
    2. Department of Physiology, Groupe de recherche sur le système nerveux central, Faculty of Medicine; Montreal University, Montreal, Quebec, Canada
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  • M. Angela Cenci MD, PhD

    Corresponding author
    1. Basal Ganglia Pathophysiology Laboratory, Department of Experimental Medical Science, Lund University, Lund, Sweden
    • Wallenberg Neuroscience Center, Division of Neurobiology, Lund, Sweden
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Abstract

Objective:

Striatal serotonin projections have been implicated in levodopa-induced dyskinesia by providing an unregulated source of dopamine release. We set out to determine whether these projections are affected by levodopa treatment in a way that would favor the occurrence of dyskinesia.

Methods:

As an index of terminal serotonin innervation density, we measured radioligand binding to the plasma membrane serotonin transporter (SERT) in levodopa-treated dyskinetic and nondyskinetic subjects, using brain tissue from both rat and monkey models of Parkinson disease as well as parkinsonian patients. In addition, striatal tissue from dyskinetic rats was used for morphological and ultrastructural analyses of serotonin axon terminals, and for studies of stimulated [3H]dopamine release.

Results:

Across all conditions examined, striatal levels of SERT radioligand binding were significantly elevated in dyskinetic subjects compared to nondyskinetic cases. In the rat striatum, dyskinesiogenic levodopa treatment had induced sprouting of serotonin axon varicosities having a relatively high synaptic incidence. This response was associated with increased depolarization-induced [3H]dopamine release and with a stronger release potentiation by brain-derived neurotrophic factor.

Interpretation:

This study provides the first evidence that L-dopa treatment induces sprouting of serotonin axon terminals, with an increased incidence of synaptic contacts, and a larger activity-dependent potentiation of dopamine release in the dopamine-denervated striatum. Treatment-induced plasticity of the serotonin innervation may therefore represent a previously unappreciated cause of altered dopamine dynamics. These results are important for understanding the mechanisms by which L-dopa pharmacotherapy predisposes to dyskinesia, and for defining biomarkers of motor complications in Parkinsons disease. Ann Neurol 2010

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