The N‐Methyl‐D‐Aspartate Antagonist MK‐801 Fails to Protect Dopaminergic Neurons from 1‐Methyl‐4‐ Phenylpyridinium Toxicity In Vitro

Abstract: Recent reports suggest that NMDA receptor antagonists when administered in vivo can protect dopaminergic neurons from the toxic actions of MPP⁺. In the present study the possible neuroprotective effects against MPP⁺ toxicity of the noncompetitive NMDA receptor antagonist MK‐801 was studied in primary cultures of fetal rat mesencephalic dopamine neurons. MK‐801 failed to protect dopaminergic neurons from MPP⁺ toxicity at concentrations that completely block NMDA‐induced toxicity of these same neurons. In contrast to work carried out in cerebellar granule cells, MPP⁺ toxicity of mesencephalic dopamine neurons was unaffected by preexposure to subtoxic concentrations of either NMDA or cycloheximide. Our findings suggest that the toxic effects of MPP⁺ on dopaminergic neurons are not mediated through a direct interaction with the NMDA subtype of glutamate receptor.