Fenfluramine-induced serotonergic neurotoxicity in mice: Lack of neuroprotection by inhibition/ablation of nNOS

Yossef Itzhak, Syed F. Alit, Karen L. Anderson

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Previous studies have implicated a role for nitric oxide (NO) and peroxynitrite in methamphetamine-induced dopaminergic neuro-toxicity. The present study was undertaken to investigate whether NO is involved in serotonergic neurotoxicity caused by fenflur-amine. In the first experiment, the effect of the neuronal nitric oxide synthase (nNOS) inhibitor 7-nitroindazole (7-NI; 25 mg/kg × 4) on fenfluramine (25 mg/kg × 4)-induced serotonergic neurotoxicity in Swiss Webster mice was investigated. In the second experiment, the effect of fenfluramine (25 mg/kg × 4) on nNOS (-/-) and wild-type (WT) mice was investigated. Fenfluramine induced hypothermia in all three mouse strains, and 7-NI had no thermoregulatory effect. Selective depletion of 5-HT and 5-HT transporter binding sites in the striatum, frontal cortex and hippocampus in all three mouse strains was observed, with no evidence of dopaminergic neurotoxicity. In the first experiment, 7-NI did not attenuate serotonergic neurotoxicity in Swiss Webster mice. In the second experiment, nNOS(-/-) and WT mice were equally sensitive to serotonergic neurotoxicity. These findings suggest that NO and peroxynitrite do not mediate fenfluramine-induced serotonergic neurotoxicity, and that NO is a selective mediator of amphetamines-induced dopaminergic neurotoxicity.

Original languageEnglish (US)
Pages (from-to)268-271
Number of pages4
JournalJournal of neurochemistry
Volume87
Issue number1
DOIs
StatePublished - Oct 2003

Keywords

  • 7-nitroindazole
  • Fenfluramine
  • Methamphetamine
  • Nitric oxide
  • Serotonergic and dopaminergic neurotoxicity

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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