SELECTIVE REDUCTION IN DOMOIC ACID TOXICITY IN-VIVO BY A NOVEL NON-N-METHYL-D-ASPARTATE RECEPTOR ANTAGONIST

Our objective was to characterize the neurotoxic actions of systemical ly administered domoic acid on different excitatory amino acid recepto rs, and to compare the receptor selectivity of domoate with the relate d compound kainic acid. Groups of mice were injected with various liga nds selective for N-methyl-D-aspartate (NMDA) and amino-3-(3-hydroxy-5 -methylisoxazol-4-yl)propionic acid - kainate (AMPA/kainate) receptors prior to injection of equitoxic doses of domoic acid or kainic acid. Domoic acid toxicity was not significantly altered by pretreatment wit h any NMDA receptor selective antagonists, with the exception of 3-(2- carboxypiperazine-4-yl)propyl-1-phosphonic acid. Consistent with its c haracterization as an AMPA/kainate agonist, domoate toxicity was signi ficantly antagonized by all non-NMDA receptor antagonists tested. Non- NMDA receptor antagonists that do not distinguish between high- and lo w-affinity [H-3]kainic acid binding (i.e., quinoxalinediones) were equ ally effective at reducing domoic acid and kainic acid toxicity. Howev er, the novel isatinoxime NS-102, which has been shown to interact sel ectively with low-affinity [3H]kainic acid binding sites, produced a s elective dose-related antagonism of domoic acid toxicity relative to k ainic acid. NS-102 produced significant reductions in overall toxicity , onset of motor seizures, and hippocampal CA3 cell damage induced by domoic acid at NS-102 doses that did not antagonize kainic acid induce d toxicity. We conclude that domoic acid toxicity in vivo is mediated largely by a subclass of non-NMDA receptors that are selectively antag onized by NS-102.