COMPARISON OF THE POTENCY OF COMPETITIVE NMDA ANTAGONISTS AGAINST THENEUROTOXICITY OF GLUTAMATE AND NMDA

The object of this investigation was to determine whether glutamate up take affects the apparent potency of the competitive antagonists DL-2- amino-5-phosphonovalerate and CGS-19755 in blocking NMDA receptor-medi ated neurotoxicity. In astrocyte-rich rat cortical cultures we observe d that DL-2-amino-5-phosphonovalerate and CGS-19755 were 24 and 16 tim es more potent against NMDA than against glutamate-induced toxicity. I n contrast, DL-2-amino-5-phosphonovalerate was equipotent against the two agonists in astrocyte-poor cultures, in which dendrites are direct ly exposed to the ex tracellular medium. With the noncompetitive NMDA antagonist MK-801, similar potencies were observed against glutamate ( 212 +/- 16 nM) and against NMDA (155 +/- 9 nM) neurotoxicity. These re sults may be explained if we assume that the neuronal cell body is les s susceptible than the dendrites to NMDA receptor-mediated toxicity, a nd that the action of glutamate in astrocyte-rich cultures is confined to the cell body. In this case, one would expect that higher concentr ations of glutamate would be needed to produce toxicity in astrocyte-r ich cultures, and that higher concentrations of competitive antagonist s would be needed to overcome this toxicity. Our observations help exp lain the pharmacology of the competitive NMDA antagonists against NMDA receptor-mediated neurotoxicity but also suggest the possibility that , because the cell body and dendrites may be distinct sites for neurot oxicity, they might also involve different mechanisms of toxicity.