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

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.

Figure 1

The cortico-striatal-thalamic-cortical circuits, including the indirect and direct pathways; ENK = enkephalin; GPe = globus pallidus, external segment; GPi = globus pallidus, internal segment; SNc = substantia nigra, pars compacta; SNr = substantia nigra, pars reticulata; SP/DYN = substance P/dynorphin; STh = subthalamic nucleus; D1 or D2: medium-sized spiny neurons with D1 or D2 receptors.

Figure 2

Simplified representation of the corticostriatal processing unit in which cortical information leading to a movement is processed in an intracortical and (parallel) extrapyramidal fashion; (A) sensory input, (B) projections to brainstem and spinal cord, and (C) projection to and from ipsilateral and contralateral cortical areas. NS = nonspecific part; S = specific part.