MK-801 inhibits l-DOPA-induced abnormal involuntary movements only at doses that worsen parkinsonism

Melanie A. Paquette, Akari M. Anderson, Jason R. Lewis, Charles K. Meshul, Steven W. Johnson, S. Paul Berger

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Amantadine and dextromethorphan suppress levodopa (l-DOPA)-induced dyskinesia in Parkinson's disease patients and abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA) rat model. These medications have been hypothesized to exert their therapeutic effects by a noncompetitive N-methyl-. d-aspartate (NMDA) antagonist mechanism, but they also have known serotonin (5-HT) indirect agonist effects that could suppress AIMs. This raised the possibility that NMDA antagonists lacking 5-HTergic effects would not have the anti-dyskinetic action predicted by previous investigators. To test this hypothesis, we investigated MK-801, the most widely-studied NMDA antagonist. We found that chronic low-dose MK-801 (0.1 mg/kg) had no effect on development of AIMs or contraversive rotation. In addition, in l-DOPA-primed rats, low-dose MK-801 (0.1 mg/kg) had no effect on expression of AIMs, contraversive rotation, or sensorimotor function. Conversely, higher doses of MK-801 (0.2-0.3 mg/kg) suppressed expression of AIMs. However, as we show for the first time, anti-dyskinetic doses of MK-801 also suppressed l-DOPA-induced contralateral rotation and impaired sensorimotor function, likely due to non-specific interference of MK-801 with l-DOPA-induced behavior. We conclude that noncompetitive NMDA antagonists are unlikely to suppress dyskinesia clinically without worsening parkinsonism.

Original languageEnglish (US)
Pages (from-to)1002-1008
Number of pages7
JournalNeuropharmacology
Volume58
Issue number7
DOIs
StatePublished - Jun 2010

Keywords

  • 6-Hydroxydopamine
  • Dyskinesia
  • NMDA
  • Parkinson's disease
  • Rats

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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