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 stimu lated [H-3]MK-801 binding in the presence of low concentrations of glu tamate (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 concentratio ns of glutamate and glycine. 5,7-Dichlorokynurenic acid, CGS-19755, an d arcaine completely inhibited the stimulated [H-3]MK-801 binding, the re was an apparent decreased potency of the [H-3]MK-801 binding inhibi tion curve for 5,7-dichlorokynurenic acid, but not CGS-19755 or arcain e, in the presence of either beta-amyloid (25-35) or substance P. The compounds do not appear to act through the strychnine-insensitive glyc ine 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 mu M could not be tested because they formed large aggregate precipitates in the assay. The data indicate that beta-amyloid (25-35) or substanc e P does not stimulate [H-3]MK-801 binding at either the N-methyl-D-as partate, glycine, or polyamine binding sites. Furthermore, the nonpept ide substance P receptor (NK1) antagonist, CP-96,345, did not block be ta-amyloid (25-35)- or substance P-stimulated [H-3]MK-801 binding. The refore, 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 re cording techniques, they may have implications in the pattern of selec tive neuronal loss observed in patients with neurodegenerative process es such as Alzheimer's, Parkinson's, and Huntington's diseases.