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 language | English (US) |
---|---|
Pages (from-to) | 1002-1008 |
Number of pages | 7 |
Journal | Neuropharmacology |
Volume | 58 |
Issue number | 7 |
DOIs | |
State | Published - Jun 2010 |
Externally published | Yes |
Keywords
- 6-Hydroxydopamine
- Dyskinesia
- NMDA
- Parkinson's disease
- Rats
ASJC Scopus subject areas
- Pharmacology
- Cellular and Molecular Neuroscience