C. Cepeda et al., AGING REDUCES NEOSTRIATAL RESPONSIVENESS TO N-METHYL-D-ASPARTATE AND DOPAMINE - AN IN-VITRO ELECTROPHYSIOLOGICAL STUDY, Neuroscience, 73(3), 1996, pp. 733-750
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