Striatal mechanisms and pathogenesis of parkinsonian signs and motor complications.
Recent studies suggest that motor dysfunction associated with the chronic nonphysiologic stimulation of dopaminergic receptors on striatal spiny neurons alters the sensitivity of nearby glutamatergic receptors, especially those of the N-methyl-D-aspartate (NMDA) subtype. Lesioning the nigrostriatal dopamine system of rats or nonhuman primates induces parkinsonian signs; subsequent once- or twice-daily treatment with levodopa produces many of the features of the human motor complication syndrome. Some drugs that block NMDA receptors palliate parkinsonian signs in these animal models, as well as in patients with Parkinson's disease. Certain NMDA receptor antagonists injected into the striatum or given systemically also have the ability to act palliatively or prophylactically to alleviate levodopa-induced response alterations. These observations support the view that sensitization of striatal NMDA receptors contributes to the pathogenesis of motor dysfunction in Parkinson's disease. Since protein phosphorylation serves as an important regulatory mechanism for NMDA receptors, differential increases in the phosphorylation state of tyrosine and serine residues, observed as a result of nigrostriatal system destruction as well as response alteration induction, could account for the apparent augmentation in synaptic efficacy. Current evidence thus suggests that the intermittent stimulation of dopaminergic receptors activates signal transduction pathways in striatal neurons, which augment phosphorylation of NMDA receptors and thus their sensitivity to cortical glutamatergic input. As a result, striatal output changes in ways that favor the appearance of parkinsonian signs and motor complications.
Chase
T N
TN
Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
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JD
D000818:Animals; D003342:Corpus Striatum / Q000503:physiopathology*; D015259:Dopamine Agents / Q000009:adverse effects; D006801:Humans; D007980:Levodopa / Q000009:adverse effects; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology*; D010300:Parkinson Disease / Q000209:etiology* / Q000503:physiopathology*; D010302:Parkinson Disease, Secondary / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*
D015259:Dopamine Agents; D007980:Levodopa