Inhibition of [formula omitted] evoked sodium flux by MK-801

Abstract

The inhibition of N- methyl- d-aspartate (NMDA) stimulated 22Na + efflux from rat hippocampal slices was studied using competitive and non-competitive receptor antagonists. There was a good correlation between the abilities of the competitive antagonists to block NMDA evoked 22Na + efflux and their potencies as inhibitors of l-[ 3H]glutamate binding. The recently reported novel NMDA receptor antagonist, (+)-5-methyl-16,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-10-imine (MK-801) was shown to non-competitively inhibit NMDA stimulated 22Na + efflux with an IC 50 value of 0.4 μM. Relatively high (10 μM) concentrations of MK-801 had no effects on quisqualic acid, α-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA), or kainic acid stimulated efflux. However, MK-801 was able to block 22Na + efflux induced by ibotenic acid and l-homocysteic acid, amino acids that act as NMDA receptor agonists. MK-801, (−)-MK-801, and non-competitive NMDA receptor antagonists of the arylcyclohexylamine and dioxolane classes inhibited NMDA stimulated 22Na + efflux with potencies that reflected their abilities to compete for [ 3H]MK-801 binding sites in rat cortical membranes. These results indicate the utility of the 22Na + efflux assay in studying the properties of NMDA receptors and confirm the nature and selectivity of the inhibition of NMDA receptor linked ion channel activation by MK-801.