N-METHYL-D-ASPARTATE MEDIATED RESPONSES DECREASE WITH AGE IN FISCHER-344 RAT-BRAIN

N-Methyl-D-aspartate (NMDA) receptor-mediated responses were studied in hippocampus, cortex, and striatum of Fischer 344 rats of various ages (3-5, 12-14, or 24-28 months old; young, middle-aged, and senescent or old, respectively) to determine whether aging alters the function of NMDA receptors. NMDA-induced inhibition of muscarinic-stimulated phosphoinositide hydrolysis in hippocampus, and NMDA-stimulated release of [H-3]norepinephrine (NE) or [H-3]dopamine (DA) were used as indices of NMDA receptor function. The muscarinic agonist carbachol (1 mM) stimulated PI hydrolysis in hippocampi from all three age groups with no significant differences between the groups. NMDA inhibited the carbachol-evoked PI response in a concentration-dependent manner (10-100-mu-M) in all age groups. However, the NMDA-induced (100-mu-M) inhibition of the carbachol-stimulated response was markedly reduced in an age-dependent manner with losses of 25% and 53% in middle-aged and senescent rats compared to young. Concentration-effect curves for NMDA-stimulated [H-3]NE release were determined uisng hippocampal and cortical slices from rats of the three age groups. In the hippocampus the maximal response for NMDA was significantly decreased from 6.55 fractional [H-3]NE release in young to 4.51 and 4.18 in middle-aged and old rats, respectively, with no age-related changes in the potency of NMDA or slope of the curves. In cortical slices the maximal response was significantly reduced in an age-dependent manner by 23% in the senescent rats compared to the young rats. NMDA-stimulated [H-3]DA release from striatal slices was significantly lower in the senescent rats at concentrations of NMDA from 500-2000-mu-M. Our results demonstrate that NMDA-mediated responses in rat cortex, hippocampus, and striatum are attenuated with increasing age. These age-dependent decrements in the responses mediated by NMDA receptors may underlie, at least in part, some of the cognitive or motor-behavioral impairments seen with advanced age.