Changes in Extracellular Concentrations of Glutamate, Aspartate, Glycine, Dopamine, Serotonin, and Dopamine Metabolites After Transient Global Ischemia in the Rabbit Brain

A. J. Baker, M. H. Zornow, M. S. Scheller, T. L. Yaksh, S. R. Skilling, D. H. Smullin, A. A. Larson, R‐ Kuczenski

Research output: Contribution to journalArticle

167 Scopus citations

Abstract

Although considerable evidence supports a role for excitatory amino acids in the pathogenesis of ischemic neuronal injury, few in vivo studies have examined the effect of increasing durations of ischemia on the extracellular concentrations of these agents. Recently, other neurotransmittiers (e.g., glycine and doparaine) have been implicated in the mechanism of ischemic neuronal injury. Accordingly, this study was undertaken to examine the patterns of changes of extracellular glutamate, aspartate, glycine concentrations in the hippocampus, and dopamine, serotonin, and dopamine metabolites in the caudate nucleus with varying durations (5, 10, or 15 minutes) of transient global cerebral ischemia as evidence to support their pathogenetic roles. Microdialysis was used to sample the brain's extracellular space before, during, and after the ischemic period. Glutamate and aspartate concentrations in the dialysate increased from baseline by 1‐, 5‐, and 13‐fold and by 4‐, 9‐, and 31‐fold, respectively, for the three ischemic durations. The concentrations returned to baseline rapidly after reperfusion. The peak concentrations of glutamate and aspartate were significantly higher with increasing ischemic duration. Dopamine concentrations increased by approximately 700‐fold in response to all three ischemic durations and returned to baseline within 10 min of reperfusion. Glycine, in contrast, increased during ischemia by a mean of 4‐fold, but remained elevated throughout the 80‐min period of reperfusion. The final concentrations of glycine were significantly higher than baseline levels (p = 0.0002, Mann‐Whitney test). That glutamate and aspartate concentrations in the hippocampus co‐vary with the duration of global ischemia is taken as supportive evidence of their pathogenetic role in ischemic neuronal injury. The observation that dopamine concentrations increased independently of ischemic duration indicates a maximal release with only S min of ischemia and suggests that dopamine's role in the incremental injury seen with increasing ischemic duration is limited to prolonged high concentrations rather than increasing peak levels as seen with glutamate and aspartate. The sustained elevation of glycine concentrations after ischemia may explain the ability of excitatory amino acids to produce delayed toxicity in the reperfusion phase, as glycine has been shown to facilitate glutamate's activity at the N‐ methyl‐D‐aspartate receptor.

Original languageEnglish (US)
Pages (from-to)1370-1379
Number of pages10
JournalJournal of Neurochemistry
Volume57
Issue number4
DOIs
StatePublished - Oct 1991

Keywords

  • Dopamine
  • Excitatory amino acids
  • Global cerebral ischemia
  • Glycine
  • Microdialysis

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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