Glutamate-mediated striatal dysregulation and the pathogenesis of motor response complications in Parkinson's disease.
Chronically administered levodopa to Parkinson's disease (PD) patients ultimately produces alterations in motor response. Similarly, in 6-hydroxydopamine lesioned hemi-parkinsonian rats, chronic twice-daily administration of levodopa progressively shortens the duration of contralateral turning, an index of, the wearing-off fluctuations that occur in parkinsonian patients. The pathogenesis of these response alterations involves, in part, upregulation of corticostriatal glutamatergic synaptic transmission. Changes involving kinase and phosphatase signaling pathways within striatal dopaminoceptive medium-spiny neurons now appear to contribute to increased synaptic efficacy of glutamatergic receptors in these neurons. Glutamate-mediated striatal sensitization subsequently modifies basal ganglia output in ways that favor the appearance of parkinsonian motor complications. At the molecular level, transcriptional activation of striatal CREB and cdk5 may contribute to the persistent expression of these levodopa-induced response alterations. Conceivably, a safer and more effective therapy for PD can be provided by drugs that target signaling proteins within striatal spiny neurons or those that interact extracellularly with non-dopaminergic receptors such as AMPA and NMDA, adenosine, adrenergic, opioid, and serotonergic.
Oh
J D
JD
Department of Psychology, Central Michigan University, Mount Pleasant, Michigan, USA.
Chase
T N
TN
D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000627:therapeutic use; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology*; D004409:Dyskinesia, Drug-Induced / Q000209:etiology*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D007980:Levodopa / Q000009:adverse effects / Q000627:therapeutic use; D009043:Motor Activity / Q000502:physiology; D010300:Parkinson Disease / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology*; D011956:Receptors, Cell Surface / Q000378:metabolism
D000978:Antiparkinson Agents; D011956:Receptors, Cell Surface; D018698:Glutamic Acid; D007980:Levodopa