AUTORADIOGRAPHIC EVIDENCE FOR METHAMPHETAMINE-INDUCED STRIATAL DOPAMINERGIC LOSS IN MOUSE-BRAIN - ATTENUATION IN CUZN-SUPEROXIDE DISMUTASE TRANSGENIC MICE

Methamphetamine (METH) has long-lasting neurotoxic effects on the nigr ostriatal dopamine (DA) system of rodents. METH-induced neurotoxicity is thought to involve release of DA in presynaptic DA terminals, which is associated with increased formation of oxygen-based free radicals. We have recently shown that METH-induced striatal DA depletion is att enuated in transgenic (Tg) mice that express the human CuZn-superoxide dismutase (SOD) enzyme. That study did not specifically address the i ssue of loss of DA terminals. In the present study, we have used recep tor autoradiographic studies of [I-125]RTI-121-labeled DA uptake sites to evaluate the effects of several doses of METH on striatal DA termi nals of Non-Tg as well as of heterozygous and homozygous SOD-Tg mice. In Non-Tg mice, METH caused decreases in striatal DA uptake sites in a dose-dependent fashion. The loss of DA terminals was more prominent i n the lateral region than in the medial subdivisions of the striatum. In SOD-Tg mice, the loss of DA terminals caused by METH was attenuated in a gene dosage-dependent fashion, with the homozygous mice showing the greatest protection. Female mice were somewhat more resistant than male mice against these deleterious effects of METH. These results pr ovide further evidence for a role of superoxide radicals in the long-t erm effects of METH. They also suggest the notion of a gender-specific handling of oxidative stress.