Methamphetamine (METH) causes deleterious effects in brain monoaminergic systems. Evidence has accumulated to suggest that these effects may be mediated via the overproduction of the superoxide radicals. We have recently shown that METH-induced dopamine (DA) depletion is attenuated in copper-zinc superoxide dismutase (CuZnSOD) transgenic (Tg) mice. In the present study, we have used receptor autoradiographic studies of [125I]RTI-55 labeled serotonin (5-HT) uptake sites to evaluate the effect of a two dosing schedule (5 mg/kg or 10 mg/kg x 4) of METH on striatal 5-HT uptake sites in nontransgenic (Non-Tg), heterozygous (Hetero) and homozygous (Homo) SOD-Tg mice. The low dose caused no significant changes in striatal 5-HT uptake sites in any of the groups. The high dose caused marked decreases (-74%) in striatal 5-HT uptake sites in Non-Tg mice. In contrast, 5-HT uptake sites showed only a 31% decrease in homozygous SOD-Tg mice whereas heterozygous SOD-Tg mice showed 63% depletion. These results show that increased SOD activity can protect against METH-induced neurotoxicity in striatal serotonergic terminals. These data provide further evidence for a role of oxidative stress in the neurotoxic effects of METH.