MK-801 inhibits L-DOPA-induced abnormal involuntary movements only at doses that worsen parkinsonism.
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.
Paquette
Melanie A
MA
Department of Veterans Affairs Medical Center, Portland, OR 97239, USA. paquettem@uthscsa.edu
Anderson
Akari M
AM
Lewis
Jason R
JR
Meshul
Charles K
CK
Johnson
Steven W
SW
Paul Berger
S
S
D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000627:therapeutic use; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology*; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007980:Levodopa / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012399:Rotation; D013997:Time Factors
D000978:Antiparkinson Agents; D018691:Excitatory Amino Acid Antagonists; D007980:Levodopa; D016291:Dizocilpine Maleate; D016627:Oxidopamine