AGING REDUCES NEOSTRIATAL RESPONSIVENESS TO N-METHYL-D-ASPARTATE AND DOPAMINE - AN IN-VITRO ELECTROPHYSIOLOGICAL STUDY

Excitatory amino acids and dopamine interact to control information fl ow in the neostriatum. The present study was designed to examine some of the age-induced alterations in the interaction of these two neurotr ansmitter systems. First, responsiveness of neostriatal neurons to glu tamate and N-methyl-D-aspartate was compared in neurons from young and in aged animals. N-Methyl-D-aspartate function was chosen for emphasi s because declines in cognitive processes during aging are thought to involve changes in this excitatory amino acid receptor. Second, the ag e-related changes in dopamine's ability to modulate responses mediated by excitatory amino acid receptors was examined. Specifically, the ab ility of dopamine to differentially modulate responses induced by N-me thyl-D-aspartate and glutamate was assessed. There is considerable evi dence for alterations in dopamine receptors and behavioral responses t o dopamine in aged animals. It thus becomes important to determine how these alterations are reflected at an electrophysiological level. The responses to application of excitatory amino acid agonists and dopami ne as well as changes in synaptic responses mediated by activation of N-methyl-D-aspartate receptors were assessed in 69 neurons obtained fr om young Fischer 344 rats (3-5 months) and young cats (3-4 years) and 69 neurons obtained from aged Fischer 344 rats (24-26 months) and aged cats (10-16 years) using an in vitro slice preparation. The results i ndicated that populations of aged neurons from both rats and cats disp layed qualitative and quantitative alterations in responses to iontoph oretic application of excitatory amino acid receptor agonists. These a lterations included lack of response, unusual responses consisting of depolarizations without action potentials or combinations of prepotent ials and full amplitude action potentials. Threshold currents for indu ction of responses were also significantly elevated in neurons from ag ed animals. Synaptic response components mediated by activation of N-m ethyl-D-aspartate receptors in aged rats were reduced as well. Exposur e to Mg2+-free artificial cerebrospinal fluid resulted in marked incre ases in the size of responses evoked by local stimulation in young neu rons from rats. These increases, which are mediated by activation of N -methyl-D-aspartate receptors, were significantly attenuated in aged n eurons. The ability of dopamine to modulate responses mediated by acti vation of excitatory amino acid receptors was reduced in cells from bo th aged rats and cars. Subpopulations of cells were either unresponsiv e to dopamine or required higher iontophoretic current intensities to modulate excitatory amino acid-induced responses. The present findings further document age-induced changes in neostriatal electrophysiology indicating that interactions between excitatory amino acids and dopam ine appear to be compromised during aging. They emphasize alterations in N-methyl-D-aspartate receptor function and suggest further than the ability of neostriatal neurons to integrate information is altered du ring aging. The present findings are supported by data from the litera ture indicating decreases in N-methyl-D-aspartate receptor function du ring aging. Furthermore, the decreases in excitatory amino acid functi on during aging suggest that therapeutic interventions designed to pre vent or retard the deleterious effects of age in the neostriatum might be directed toward enhancing excitatory amino acid receptor function. Copyright (C) 1996 IBRO