Inhibitors of Na+/H+ and Na+/Ca2+ exchange potentiate methamphetamine-induced dopamine neurotoxicity: Possible role of ionic dysregulation in methamphetamine neurotoxicity

Brian T. Callahan, Branden J. Cord, Jie Yuan, Una D. McCann, George A. Ricaurte

Research output: Contribution to journalArticlepeer-review

Abstract

Although the neurotoxic potential of methamphetamine (METH) is well established, underlying mechanisms have yet to be identified. In the present study, we sought to determine whether ionic dysregulation was a feature of METH neurotoxicity. In particular, we reasoned that if METH impairs the function of Na+/H+ and/or Na+/Ca2+ antiporters by compromising the inward Na+ gradient [via prolonged DA transporter (DAT) activation and Na+/K+ ATPase inhibition], then amiloride (AMIL) and other inhibitors of Na+/H+ and/or Na+/Ca2+ exchange would potentiate METH neurotoxicity. To test this hypothesis, mice were treated with METH alone or in combination with AMIL or one of its analogs; 1 week later, the animals were killed for studies of dopamine (DA) neuronal integrity. AMIL markedly potentiated the toxic effect of METH on DA neurons. Potentiation was not caused by increased core temperature, enhanced DAT activity or higher METH brain levels. The DAT inhibitor, WIN-35,428, protected completely against METH-induced DA neurotoxicity in AMIL pretreated animals, suggesting that the potentiating effects of AMIL require a METH/DAT interaction. Findings with METH and AMIL were extended to six other AMIL analogs (MIA, EIPA, DIMA, BENZ, BEP, DiCBNZ), another species (rats), and neuronal type (5-HT neurons). These results support the notion that ionic dysregulation may play a role in METH neurotoxicity.

Original languageEnglish (US)
Pages (from-to)1348-1362
Number of pages15
JournalJournal of Neurochemistry
Volume77
Issue number5
DOIs
StatePublished - 2001

Keywords

  • Amiloride
  • Amphetamines
  • Dopamine
  • Na/ H and Na/Ca exchangers
  • Transporter

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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