ERK phosphorylation and FosB expression are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice

Biol Psychiatry. 2006 Jan 1;59(1):64-74. doi: 10.1016/j.biopsych.2005.05.044. Epub 2005 Sep 1.


Background: The dopamine precursor 3,4-dihydroxyphenyl-L-alanine (L-DOPA) is currently the most efficacious noninvasive therapy for Parkinson's disease. A major complication of this therapy, however, is the appearance of the abnormal involuntary movements known as dyskinesias. We have developed a model of L-DOPA-induced dyskinesias in mice that reproduces the main clinical features of dyskinesia in humans.

Methods: Dyskinetic symptoms were triggered by repetitive administration of a constant dose of L-DOPA (25 mg/kg, twice a day, for 25 days) in unilaterally 6-hydroxydopamine (6-OHDA) lesioned mice. Mice were examined for behavior, expression of FosB, neuropeptides, and externally regulated kinase (ERK) phosphorylation.

Results: Dyskinetic symptoms appear toward the end of the first week of treatment and are associated with L-DOPA-induced changes in DeltaFosB and prodynorphin expression. L-DOPA also induces activation of ERK1/2 in the dopamine-depleted striatum. Interestingly, elevated FosB/DeltaFosB expression occurs exclusively within completely lesioned regions of the striatum, displaying an inverse correlation with remaining dopaminergic terminals. Following acute L-DOPA treatment, FosB expression occurs in direct striatal output neurons, whereas chronic L-DOPA also induces FosB expression in nitric oxide synthase-positive striatal interneurons.

Conclusions: This model provides a system in which genetic manipulation of individual genes can be used to elucidate the molecular mechanisms responsible for the development and expression of dyskinesia.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antiparkinson Agents / adverse effects*
  • Behavior, Animal
  • Blotting, Western / methods
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Disease Models, Animal
  • Dopamine / metabolism
  • Drug Administration Schedule
  • Dyskinesia, Drug-Induced / etiology
  • Dyskinesia, Drug-Induced / metabolism*
  • Dyskinesias / etiology
  • Dyskinesias / physiopathology
  • Enkephalins / genetics
  • Enkephalins / metabolism
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Gene Expression / drug effects*
  • Immunohistochemistry / methods
  • In Situ Hybridization / methods
  • Levodopa / adverse effects*
  • Locomotion / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Oxidopamine
  • Parkinsonian Disorders / chemically induced
  • Parkinsonian Disorders / drug therapy
  • Phosphorylation / drug effects
  • Protein Precursors / genetics
  • Protein Precursors / metabolism
  • Proto-Oncogene Proteins c-fos / metabolism*
  • RNA, Messenger / metabolism
  • Statistics, Nonparametric
  • Time Factors


  • Antiparkinson Agents
  • Enkephalins
  • Protein Precursors
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Levodopa
  • Oxidopamine
  • preproenkephalin
  • Extracellular Signal-Regulated MAP Kinases
  • Dopamine