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Parkinson’s Disease
Volume 2016 (2016), Article ID 6461907, 5 pages
http://dx.doi.org/10.1155/2016/6461907
Review Article

Levodopa-Induced Dyskinesia Is Related to Indirect Pathway Medium Spiny Neuron Excitotoxicity: A Hypothesis Based on an Unexpected Finding

1Mental Health Research Institute, Tomsk, Russia
2National Research Tomsk Polytechnic University, Tomsk, Russia
3Department of Pharmacy, University of Groningen, Groningen, Netherlands
4GGZ Westelijk Noord-Brabant, Bergen op Zoom, Netherlands

Received 30 November 2015; Accepted 29 March 2016

Academic Editor: Francisco Grandas

Copyright © 2016 Svetlana A. Ivanova and Anton J. M. Loonen. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

A serendipitous pharmacogenetic finding links the vulnerability to developing levodopa-induced dyskinesia to the age of onset of Huntington’s disease. Huntington’s disease is caused by a polyglutamate expansion of the protein huntingtin. Aberrant huntingtin is less capable of binding to a member of membrane-associated guanylate kinase family (MAGUKs): postsynaptic density- (PSD-) 95. This leaves more PSD-95 available to stabilize NR2B subunit carrying NMDA receptors in the synaptic membrane. This results in increased excitotoxicity for which particularly striatal medium spiny neurons from the indirect extrapyramidal pathway are sensitive. In Parkinson’s disease the sensitivity for excitotoxicity is related to increased oxidative stress due to genetically determined abnormal metabolism of dopamine or related products. This probably also increases the sensitivity of medium spiny neurons for exogenous levodopa. Particularly the combination of increased oxidative stress due to aberrant dopamine metabolism, increased vulnerability to NMDA induced excitotoxicity, and the particular sensitivity of indirect pathway medium spiny neurons for this excitotoxicity may explain the observed increased prevalence of levodopa-induced dyskinesia.