Amphetamine-induced toxicity in dopamine terminals in CD-1 and C57BL/6J mice: Complex roles for oxygen-based species and temperature regulation

I. N. Krasnova, B. Ladenheim, S. Jayanthi, J. Oyler, T. H. Moran, M. A. Huestis, J. L. Cadet

Research output: Contribution to journalArticle

Abstract

In order to examine differential strain susceptibility to neurotoxic effects of amphetamine and to assess the potential role of superoxide radicals in amphetamine-induced dopaminergic damage, the drug was injected to mice with different levels of copper/zinc superoxide dismutase (Cu/Zn SOD) enzyme. Administration of amphetamine (10 mg/kg, i.p., given every 2 h, a total of four times) to wild-type CD-1 and C57BL/6J mice caused significant decreases in dopamine and 3,4-dihydroxyphenylacetic acid levels, in [125I]RTI-121-labeled dopamine transporters as well as a significant depletion in the concentration of dopamine transporter and vesicular monoamine transporter 2 proteins. The amphetamine-induced toxic effects were less prominent in CD-1 mice, which have much higher levels of Cu/Zn SOD activity (0.69 units/mg of protein) in their striata than C57BL/6J animals (0.007 units/mg of protein). Transgenic mice on CD-1 and C57BL/6J background, which had striatal levels of Cu/Zn SOD 2.57 and 1.67 units/mg of protein, respectively, showed significant protection against all the toxic effects of amphetamine. The attenuation of toxicity observed in transgenic mice was not caused by differences in amphetamine accumulation in wild-type and mutant animals. However, CD-1-SOD transgenic mice showed marked hypothermia to amphetamine whereas C57-SOD transgenic mice did not show a consistent thermic response to the drug. The data obtained demonstrate distinctions in the neurotoxic profile of amphetamine in CD-1 and C57BL/6J mice, which show some differences in Cu/Zn SOD activity and in their thermic responses to amphetamine administration. Thus, these observations provide evidence for possible complex interactions between thermoregulation and free radical load in the long-term neurotoxic effects of this illicit drug of abuse.

Original languageEnglish (US)
Pages (from-to)265-274
Number of pages10
JournalNeuroscience
Volume107
Issue number2
DOIs
StatePublished - Nov 16 2001

Keywords

  • Amphetamine
  • Antioxidant enzymes
  • Caudate-putamen
  • Dopamine
  • Superoxide radicals

ASJC Scopus subject areas

  • Neuroscience(all)

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