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 flow in the neostriatum. The present study was designed to examine some of the age-induced alterations in the interaction of these two neurotransmitter systems. First, responsiveness of neostriatal neurons to glutamate and N-methyl-D-aspartate was compared in neurons from young and in aged animals. N-Methyl-D-aspartate function was chosen for emphasis because declines in cognitive processes during aging are thought to involve changes in this excitatory amino acid receptor. Second, the age-related changes in dopamine's ability to modulate responses mediated by excitatory amino acid receptors was examined. Specifically, the ability of dopamine to differentially modulate responses induced by N-methyl-D-aspartate and glutamate was assessed. There is considerable evidence for alterations in dopamine receptors and behavioral responses to 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 dopamine as well as changes in synaptic responses mediated by activation of N-methyl-D-aspartate receptors were assessed in 69 neurons obtained from 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 indicated that populations of aged neurons from both rats and cats displayed qualitative and quantitative alterations in responses to iontophoretic application of excitatory amino acid receptor agonists. These alterations included lack of response, unusual responses consisting of depolarizations without action potentials or combinations of prepotentials and full amplitude action potentials. Threshold currents for induction of responses were also significantly elevated in neurons from aged animals. Synaptic response components mediated by activation of N-methyl-D-aspartate receptors in aged rats were reduced as well. Exposure to Mg(2+)-free artificial cerebrospinal fluid resulted in marked increases in the size of responses evoked by local stimulation in young neurons from rats. These increases, which are mediated by activation of N-methyl-D-aspartate receptors, were significantly attenuated in aged neurons. The ability of dopamine to modulate responses mediated by activation of excitatory amino acid receptors was reduced in cells from both aged rats and cats. Subpopulations of cells were either unresponsive 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 dopamine 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 during aging. The present findings are supported by data from the literature indicating decreases in N-methyl-D-aspartate receptor function during aging. Furthermore, the decreases in excitatory amino acid function during aging suggest that therapeutic interventions designed to prevent or retard the deleterious effects of age in the neostriatum might be directed toward enhancing excitatory amino acid receptor function.
Cepeda
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Mental Retardation Research Center, University of California at Los Angeles 90024, USA.
Li
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Levine
M S
MS
D000367:Age Factors; D000375:Aging / Q000502:physiology*; D000818:Animals; D002415:Cats; D004298:Dopamine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005071:Evoked Potentials / Q000187:drug effects*; D018698:Glutamic Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D017072:Neostriatum / Q000187:drug effects*; D051381:Rats; D011916:Rats, Inbred F344
D018698:Glutamic Acid; D016202:N-Methylaspartate; D004298:Dopamine