BETA-AMYLOID (25-35) OR SUBSTANCE-P STIMULATES [H-3] MK-801 BINDING TO RAT CORTICAL MEMBRANES IN THE PRESENCE OF GLUTAMATE AND GLYCINE

Micromolar concentrations of beta-amyloid (25-35) or substance P stimulated [H-3]MK-801 binding in the presence of low concentrations of glutamate (1 muM) and glycine (0.02 muM). Unlike polyamines spermine and spermidine, neither beta-amyloid (25-35) nor substance P increased [H-3]MK-801 binding in the presence of maximally stimulating concentrations of glutamate and glycine. 5,7-Dichlorokynurenic acid, CGS-19755, and arcaine completely inhibited the stimulated [H-3]MK-801 binding, there was an apparent decreased potency of the [H-3]MK-801 binding inhibition curve for 5,7-dichlorokynurenic acid, but not CGS-19755 or arcaine, in the presence of either beta-amyloid (25-35) or substance P. The compounds do not appear to act through the strychnine-insensitive glycine binding site because neither beta-amyloid (25-35) nor substance P displaced [H-3]glycine binding. Full-length beta-amyloid (1-40), up to 10 muM, did not stimulate [H-3]MK-801 binding. Concentrations > 10 muM could not be tested because they formed large aggregate precipitates in the assay. The data indicate that beta-amyloid (25-35) or substance P does not stimulate [H-3]MK-801 binding at either the N-methyl-D-aspartate, glycine, or polyamine binding sites. Furthermore, the nonpeptide substance P receptor (NK1) antagonist, CP-96,345, did not block beta-amyloid (25-35)- or substance P-stimulated [H-3]MK-801 binding. Therefore, the effect is not due to an interaction between the substance P receptors and the N-methyl-D-aspartate receptor-operated ionophore. Finally, if these observations can be verified using single-channel recording techniques, they may have implications in the pattern of selective neuronal loss observed in patients with neurodegenerative processes such as Alzheimer's, Parkinson's, and Huntington's diseases.