Methamphetamine-induced rapid decrease in dopamine transporter function: Role of dopamine and hyperthermia

Single and multiple high-dose administrations of methamphetamine (METH) dif ferentially decrease dopamine (DA) transporter (DAT) function, as assessed by measuring [H-3] DA uptake into rat striatal synaptosomes prepared 1 h af ter treatment. Prevention of METH-induced hyperthermia attenuated the decre ase in DAT activity induced by multiple injections of the stimulant. Likewi se, this decrease was attenuated by previous depletion of striatal DA level s using alpha -methyl-p-tyrosine ( alpha MT) or pretreatment with the D1 an d D2 antagonists SCH-23390 and eticlopride, respectively. However, METH-ind uced hyperthermia was also blocked by alpha MT and eticlopride. Reinstateme nt of hyperthermia to alpha MT- or eticlopride-pretreated rats partially re stored the METH-induced decrease in DAT activity. In contrast, neither prev ention of METH-induced hyperthermia depletion of DA, nor DA antagonists alt ered the decrease in DAT function induced by a single administration of MET H. Pretreatment with the antioxidant N-t-butyl-alpha -phenylnitrone prevent ed part of the decrease in DAT function associated with multiple, but not a single, METH injections. Although not tested directly, additional data pre sented here suggest that the reduction in DAT activity induced by a single METH administration constitutes a part of the total reduction observed imme diately after multiple administrations. Taken together, the results indicat e that DA, hyperthermia, and oxygen radicals contribute to a component of t he rapid decrease in DAT function induced by multiple injections of METH bu t do not appear to be associated with the reduction induced by a single adm inistration of the stimulant.