Competitive (AP7) and non‐competitive (MK‐801) NMDA receptor antagonists differentially alter glucose utilization in rat cortex

Abstract The effects of D, L ‐2‐amino‐7‐phosphonoheptanoic acid (AP7), a competitive N‐methyl‐D‐aspartate (NMDA) receptor antagonist, and MK‐801, a non‐competitive NMDA receptor antagonist, on regional brain metabolism were studied in unanesthetized, freely moving rats by using the quantitative [ 14 C]2‐deoxyglucose autoradiographic procedure. AP7 (338 or 901 mg/kg) produced a dose‐dependent decrease of metabolic activity throughout most of the regions studied including sensory, motor, and limbic cortices. In contrast, MK‐801 (0.1 or 1.0 mg/kg) resulted in a dose‐dependent decrease of metabolic activity in sensory cortices, and an increase in limbic regions such as the hippocampal stratum lacunosum moleculare and entorhinal cortex. MK‐801 also produced a biphasic response in agranular motor cortex, whereby the low dose increased while the high dose decreased labeling. In addition, MK‐801 produced heterogeneous effects on regional cerebral metabolism in sensory cortices. Metabolic activity decreased in layer IV relative to layer Va following MK‐801 treatment in primary somatosensory (S I ) and visual (V I ) cortices, suggesting a shift in activity from afferent fibers innervating layer IV to those innervating layer Va. MK‐801 administration also decreased metabolic activity in granular S I relative to dysgranular S I and in V I relative to secondary visual cortex (V II ), thus providing a relative sparing of activity in dysgranular S I and V II . Thus, the non‐competitive NMDA receptor antagonist suppressed activity form extrinsic neocortical sources, enhancing relative intracortical activity and stimulating limbic regions while the competitive NMDA antagonist depressed metabolic activity in all cortical regions. These selective laminar and regional changes in metabolic activity may be due to an enhanced susceptibility of certain cortical circuits to non‐competitive NMDA receptor antagonists.