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

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.

• Authors: Melanie A Paquette, Akari M Anderson, Jason R Lewis, Charles K Meshul, Steven W Johnson, S Paul Berger
• Journal: Neuropharmacology (Neuropharmacology) Vol. 58 Issue 7 Pg. 1002-8 (Jun 2010) ISSN: 1873-7064 [Electronic] England
• PMID: 20079362 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: (c) 2010 Elsevier Ltd. All rights reserved.

Chemical References

• Antiparkinson Agents
• Excitatory Amino Acid Antagonists
• Levodopa
• Dizocilpine Maleate
• Oxidopamine

Topics

• Animals
• Antiparkinson Agents (administration & dosage, therapeutic use)
• Disease Models, Animal
• Dizocilpine Maleate (administration & dosage, pharmacology)
• Dyskinesia, Drug-Induced (drug therapy)
• Excitatory Amino Acid Antagonists (administration & dosage, pharmacology)
• Levodopa (adverse effects, therapeutic use)
• Male
• Motor Activity (drug effects)
• Oxidopamine
• Parkinsonian Disorders (chemically induced, drug therapy)
• Rats
• Rats, Sprague-Dawley
• Rotation
• Time Factors