Rapid and Reversible Effects of Methamphetamine on

Reactive oxygen species decrease dopamine transporter (DAT) function in vitro. Because of this, and the finding that METH administration causes oxygen radical formation in vivo, the effects of METH administration on DAT activity in rat striatum were investigated. A single METH injection caused a dose-dependent (0–15 mg/kg) decrease in [3H]dopamine uptake into striatal synaptosomes prepared 1 h after METH administration; an effect attributable to a decreased Vmax of [ 3H]dopamine uptake. Similarly, multiple high-dose administrations of METH (10 mg/kg/dose; four doses at 2-h intervals) decreased DAT function. The decreases in DAT activity after either single or multiple METH administrations were reversed 24 h after treat-ment. [3H]5HT transport into striatal synaptosomes was also affected by METH treatment. Taken together, these data sug-gest that METH decreases DAT activity, perhaps through a reactive oxygen species-mediated mechanism. These findings may have important implications regarding the role of oxidative events in the physiological regulation of monoaminergic sys-tems. Abuse of the amphetamine analog, METH, is a serious world-wide health problem. Hence, there is considerable effort to elucidate mechanisms whereby METH alters central nervous system function. Deleterious effects of high-dose METH admin-istration on monoaminergic neurons in rodents and primates, including decreases in brain levels of dopamine and 5HT, and the activity of their respective synthetic enzymes, tyrosine hy-droxylase and TPH, have been described (Hotchkiss and Gibb