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Topography of dyskinesias and torticollis evoked by inhibition of substantia nigra pars reticulata

Authors

  • David Dybdal,

    1. Department of Pharmacology & Physiology, Georgetown University Medical Center, Washington, DC, USA
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  • Patrick A. Forcelli,

    1. Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, USA
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  • Mark Dubach,

    1. Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA
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  • Michael Oppedisano,

    1. Department of Pharmacology & Physiology, Georgetown University Medical Center, Washington, DC, USA
    2. Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, USA
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  • Angela Holmes,

    1. Department of Pharmacology & Physiology, Georgetown University Medical Center, Washington, DC, USA
    2. Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, USA
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  • Ludise Malkova,

    1. Department of Pharmacology & Physiology, Georgetown University Medical Center, Washington, DC, USA
    2. Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, USA
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  • Karen Gale

    Corresponding author
    1. Interdisciplinary Program in Neuroscience, Georgetown University, Washington, DC, USA
    • Department of Pharmacology & Physiology, Georgetown University Medical Center, Washington, DC, USA
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  • Funding agencies: This work was supported by the National Institutes of Health (grant nos.: NS20576 and F31MH10812).

  • Relevant conflicts of interest/financial disclosures: Nothing to report.

  • Full financial disclosures and author roles may be found in the online version of this article.

Correspondence to: Dr. Karen Gale, Department of Pharmacology & Physiology, Georgetown University Medical Center, 3900 Reservoir Road NW, Washington, DC 20007, USA; Galek@Georgetown.edu

Abstract

GABAergic neurons of the substantia nigra pars reticulata (SNpr) and globus pallidus pars interna (GPi) constitute the output pathways of the basal ganglia. In monkeys, choreiform limb dyskinesias have been described after inhibition of the GPi, but not the SNpr. Given the anatomical and functional similarities between these structures, we hypothesized that choreiform dyskinesias could be evoked by inhibition of an appropriate region within the SNpr. The GABAA receptor agonist, muscimol, was infused into various sites within the SNpr and the adjacent STN of freely moving macaques. The effect of the GABAA antagonist, bicuculline (BIC), was also examined. Muscimol (MUS) in SNpr evoked the following: (1) choreiform dyskinesias of the contralateral arm and/or leg from central and lateral sites; (2) contralaterally directed torticollis from central and posterior sites; and (3) contraversive quadrupedal rotation from anterior and lateral sites. MUS infusions into the adjacent SN pars compacta or STN were without effect, ruling out a contribution of drug spread to adjacent structures. BIC in SNpr induced ipsiversive postures without choreiform dyskinesia or torticollis, whereas in the STN, it evoked ballistic movements. This is the first report of choreiform dyskinesia evoked by inhibition of the SNpr. This highly site-specific effect was obtained from a restricted region within the SNpr distinct from that responsible for inducing torticollis. These results suggest that overactivity of different SNpr outputs mediates choreiform dyskinesia and torticollis. These abnormalities are symptoms of dystonia, Huntington's disease, and iatrogenic dyskinesias, suggesting that these conditions may result, in part, from a loss of function in SNpr efferent projections. © 2012 Movement Disorder Society

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