Zn²⁺ inhibition of [³H]MK-801 binding is different in mouse brain and spinal cord: Effect of glycine and glutamate

Zn²⁺ inhibits NMDA-type excitatory amino acid activity by a non-competitive action. Based on regional differences in the central nervous system (CNS) in binding characteristics of [³H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate ([³H]MK-801) and other non-competitive antagonists of NMDA used to label open channels in the receptor complex, we compared the inhibitory influence of Zn²⁺ on [³H]MK-801 binding in whole mouse brain and spinal cord membranes. Radioligand binding techniques were used in the presence and absence of maximally effective concentrations of glycine and glutamate. Using extensively washed membranes without exogenous glycine and glutamate, Zn²⁺ was found to be a weaker inhibitor of the [³H]MK-801-labeled site in the spinal cord than in the whole brain. In contrast, exogenous glycine and glutamate decreased the inhibitory effect of Zn²⁺ in the brain but dramatically increased the inhibitory effect of Zn²⁺ in the spinal cord. Thus the inhibitory effect of Zn²⁺ in the spinal cord appears to be magnified by glutamatergic and glycinergic activity while that in the brain is not. The different actions of Zn²⁺ may be attributable to the differential distribution of NMDA receptor subunits in the mouse brain and spinal cord.