Age-related decreases of the N-methyl-d-aspartate receptor complex in the rat cerebral cortex and hippocampus

Binding activities of central excitatory amino acid receptors were examined in Triton-treated membrane preparations of the cerebral cortex and hippocampus from brains of rats at 2, 7 and 29 months after birth. Aged rats exhibited a significant reduction of [³H]glutamate (Glu) binding displaceable by N-methyl-D-aspartate (NMDA), as well as strychnine-insensitive [³H]glycine binding in both central structures, as compared with those in young rats. Binding of [³H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), a non-competitive NMDA antagonist used to label the activated state of ion channels linked to NMDA-sensitive receptors, also decreased with aging irrespective of the experimental conditions employed. Scatchard analysis revealed that reduction of both [³H]Glu binding and [³H]MK-801 binding were due to a significant decrease in the densities of binding sites with aging, with their affinities being unaltered. Binding of [³H]D,L-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), which is a specific agonist for quisqualate-sensitive receptors, was unchanged with aging when determined in the absence of 100 mM potassium thiocyanate (KSCN). However, AMPA binding determined in the presence of added KSCN was about 25% reduced in both brain regions of aged rats. Binding of [³H]kainate to kainate-sensitive receptors was unchanged with aging. These results suggest that glutamatergic neurotransmission mediated by NMDA-sensitive receptors may be selectively impaired with aging in the hippocampus and cerebral cortex among 3 different subclasses of excitatory amino acid receptors in the brain.