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

Neuroscience. 2001;107(2):265-74. doi: 10.1016/s0306-4522(01)00351-7.


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 [(125)I]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.

MeSH terms

  • 3,4-Dihydroxyphenylacetic Acid / metabolism
  • Amphetamine / toxicity*
  • Animals
  • Blotting, Western
  • Body Temperature Regulation*
  • Brain / metabolism
  • Caudate Nucleus / metabolism
  • Central Nervous System Stimulants / toxicity*
  • Dopamine / metabolism*
  • Dopamine Plasma Membrane Transport Proteins
  • Free Radicals / metabolism
  • Gas Chromatography-Mass Spectrometry
  • Male
  • Membrane Glycoproteins / metabolism
  • Membrane Transport Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Tissue Proteins*
  • Neuropeptides*
  • Phenotype
  • Presynaptic Terminals / metabolism*
  • Putamen / metabolism
  • Species Specificity
  • Superoxide Dismutase / metabolism*
  • Vesicular Biogenic Amine Transport Proteins
  • Vesicular Monoamine Transport Proteins


  • Central Nervous System Stimulants
  • Dopamine Plasma Membrane Transport Proteins
  • Free Radicals
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Neuropeptides
  • Vesicular Biogenic Amine Transport Proteins
  • Vesicular Monoamine Transport Proteins
  • 3,4-Dihydroxyphenylacetic Acid
  • Amphetamine
  • Superoxide Dismutase
  • Dopamine