Non-synaptic release of [3H]noradrenaline in response to oxidative stress combined with mitochondrial dysfunction in rat hippocampal slices

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Brain ischemia is frequently associated with oxidative stress in the reperfusion period. It is known that noradrenaline (NA) is released in excess under energy deprivation by the sodium-dependent reversal of the monoamine carrier. However, it is not known howoxidative stress affects NA release in the brain alone or in combination with energy deprivation. As a model of oxidative stress, the effect of H2O2 (0.1-1.5 mM) perfusion was investigated in superfused rat hippocampal slices. It elicited a dose-dependent elevation of the release of [3H]NA and its tritiated metabolites as well as a simultaneous drop in the tissue energy charge. Mitochondrial inhibitors, i.e. rotenone (10 μM), and oligomycin (10 μM) in combination, also decreased the energy charge, but they had only a mild effect on [3H]NA release. However, when H2O2 was added together with oligomycin and rotenone their effect on [3H]NA release was greatly exacerbated. H2O2 and mitochondrial inhibitors also induced an increase in [Na+]i in isolated nerve terminals, and their effect was additive. The effect of H2O2 on tritium release was temperature-dependent. It was also attenuated by the glutamate receptor antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (30 μM) and (±)-2-amino-5-phosphonopentanoic acid (10 μM), by the nitric oxide synthase inhibitors, Nω-nitro-L-arginine methyl ester (100 μM), or 7-nitroindazole (50 μM) and by the vesicular uptake inhibitor tetrabenazine (1 μM). Our results suggest that oxidative stress releases glutamate followed by activation of postsynaptic ionotropic glutamate receptors that trigger nitric oxide production and results in a flood of NA from cytoplasmic stores. The massive elevation of extracellular NA under conditions of oxidative stress combined with mitochondrial dysfunction may provide an additional source of highly reactive free radicals thus initiating a self-amplifying cycle leading to neuronal degeneration.

Original languageEnglish
Pages (from-to)771-781
Number of pages11
Issue number3
Publication statusPublished - Sep 1 2003


  • Glutamate receptors
  • HO
  • Nitric oxide
  • Oligomycin
  • Rotenone

ASJC Scopus subject areas

  • Neuroscience(all)

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