Alleviation of parkinsonism by antagonism of excitatory amino acid transmission in the medial segment of the globus pallidus in rat and primate

Authors

  • Jonathan M. Brotchie,

    1. Experimental Neurology Group, Department of Cell and Structural Biology, University of Manchester, Manchester, England
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  • Dr. Ian J. Mitchell,

    Corresponding author
    1. Experimental Neurology Group, Department of Cell and Structural Biology, University of Manchester, Manchester, England
    • Experimental Neurology Group, Department of Cell and Structural Biology, University of Manchester, Manchester M13 9PT, England
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  • Michael A. Sambrook,

    1. Experimental Neurology Group, Department of Cell and Structural Biology, University of Manchester, Manchester, England
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  • Alan R. Crossman

    1. Experimental Neurology Group, Department of Cell and Structural Biology, University of Manchester, Manchester, England
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Abstract

Recent experimental data has made possible the description of the pathophysiological circuitry that mediates parkinsonism. This work has shown that dopamine-denervated striatal cells discharge abnormally and that this ultimately causes cells in the medial segment of the globus pallidus to become abnormally overactive. The main driving force behind the overactive cells in the medial pallidal segment appears to be excess activity in the afferent pathway to it from the subthalamic nucleus. This pathway is known to use an excitatory amino acid (EAA) as its transmitter. It was therefore hypothesized that local blockade of EAA transmission in the medial segment of the globus pallidus should reverse parkinsonism. This hypothesis was tested in rat and primate models of parkinsonism by the direct injection of the EAA antagonist, kynurenic acid, into the medial segment of the globus pallidus. The results demonstrate that this procedure can reverse parkinsonism in a dose-dependent manner, and suggest that manipulation of EAA transmission in the medial segment of the globus pallidus may have therapeutic potential for treating parkinsonism.

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