Heterogeneity of the N-methyl-D-aspartate receptor ionophore complex in rat brain, as revealed by ligand binding techniques.

The polyamine spermidine markedly potentiated the binding of (+)-[3H]5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imi ne (MK-801) to open ion channels associated with an N-methyl-D-aspartate (NMDA)-sensitive subclass of brain excitatory amino acid receptors, in the presence of a maximally effective concentration of L-glutamic acid (Glu) and glycine (Gly), in Triton-treated preparations of synaptic membranes from the cerebral cortex as well as hippocampus of rat brain, without significantly affecting that in cerebellar synaptic membranes. Among several ligands for the binding sites of [3H]MK-801, the binding was most potently displaced by (+)-MK-801, followed by N-[1-(2-thienyl)cyclohexyl]piperidine, (-)-MK-801, phencyclidine, cyclazocine, ketamine, ketocyclazocine, N-allylnormetazocine and pentazocine, in a rank order of decreasing potency, in hippocampal synaptic membranes. However, the abilities of these ligands to displace the binding were much lower in cerebellar membranes than in hippocampal membranes. Competitive NMDA antagonists induced a much more potent inhibition of [3H] MK-801 binding in the hippocampus than in the cerebellum, whereas competitive Gly antagonists elicited a similarly potent inhibition of the binding in both structures. Moreover, NMDA antagonists caused a greater than 10 times more potent displacement of [3H]Glu binding to the NMDA recognition site in hippocampal membranes than in cerebellar membranes, whereas NMDA agonists similarly displaced [3H]Glu binding in both central regions. Gly agonists elicited an equivalent displacement of strychnine-insensitive [3H]Gly binding in both membrane preparations, whereas Gly antagonists more potently displaced [3H]Gly binding in the hippocampus than in the cerebellum. These results suggest possible heterogeneity of the respective domains within the NMDA receptor ionophore complex, in terms of differential sensitivity to isosteric and allosteric ligands.