Differential stimulation of [³H]MK-801 binding to subpopulations of NMDA receptors

The potency of l-glutamate in enhancing [³H]MK-801 binding to N-methyl-d-aspartate (NMDA) receptor ion channels was evaluated by quantitative autoradiography. In the presence of saturating concentrations of spermine, glycine and 20 μM d-2-amino-5-phosphonopentanoate (d-AP5), low concentrations of l-glutamate selectively increased [³H]MK-801 binding in the medial striatum and dorsal lateral septum. In comparison to these regions, EC₅₀ values for l-glutamate stimulation of [³H]MK-801 binding were significantly higher in the cerebral cortex and thalamus. Regions displaying greater sensitivity to l-glutamate correlate to those regions where NMDA receptors are preferentially labelled by l-[³H]glutamate; regions less sensitive to l-glutamate correspond to regions selectively labelled by the NMDA antagonist [³H]CPP ([³H]3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate). Since l-glutamate stimulation of [³H]MK-801 binding appears to reflect channel activation, these results suggest that it is possible to pharmacologically (or pathologically) activate anatomically-distinct subpopulations of NMDA receptors.