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

In order to examine differential strain susceptibility to neurotoxic effect s of amphetamine and to assess the potential role of superoxide radicals in am phetamine-induced dopaminergic damage, the drug was injected to mice wi th different levels or 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-I and C57BL/6J mice caused significant decreas es in dopamine and 3,4-dihydroxyphenylacetic acid levels, in [I-125]RTI-121 -labeled dopamine transporters as well as a significant depletion in the co ncentration of dopamine transporter and vesicular monoamine transporter 2 p roteins. 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 leve ls of Cu/Zn SOD 2.57 and 1.67 units/mg of protein, respectively, showed sig nificant protection against all the toxic effects of amphetamine. The atten uation of toxicity observed in transgenic mice was not caused by difference s 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 amp hetamine in CD-I and C57BL/6J mice, which show some differences in Cu/Zn SO D activity and in their thermic responses to amphetamine administration. Th us, these observations provide evidence for possible complex interactions b etween thermoregulation and free radical load in the long-term neurotoxic e ffects of this illicit drug of abuse. Published by Elsevier Science Ltd on behalf of IBRO.