Effect of temperature on dopamine transporter function and intracellular accumulation of methamphetamine: Implications for methamphetamine-induced dopaminergic neurotoxicity

Hyperthermia exacerbates and hypothermia attenuates methamphetamine (METH)- induced dopamine (DA) neurotoxicity. The mechanisms underlying these temper ature effects are unknown. Given the essential role of the DA transporter ( DAT) in the expression of METH-induced DA neurotoxicity, we hypothesized th at the effect of temperature on METH-induced DA neurotoxicity is mediated, at least in part, at the level of the DAT. To test this hypothesis, the eff ects of small, physiologically relevant temperature changes on DAT function were evaluated in two types of cultured neuronal cells: (1) a neuroblastom a cell line stably transfected with human DAT cDNA and (2) rat embryonic me sencephalic primary cells that naturally express the DAT. Temperatures for studies of DAT function were selected based on core temperature measurement s in animals exposed to METH under usual ambient (22 degrees C) and hypothe rmic (6 degrees C) temperature conditions, where METH neurotoxicity was ful ly expressed and blocked, respectively. DAT function, determined by measuri ng accumulation of radiolabeled DA and 1-methyl-4-phenylpyridinium (MPP+), was found to directly correlate with temperature, with higher levels of sub strate uptake at 40 degrees C, intermediate levels at 37 degrees C, and low er levels at 34 degrees C. DAT-mediated accumulation of METH also directly correlated with temperature, with greater accumulation at higher temperatur es. These findings indicate that relatively small, physiologically relevant changes in temperature significantly alter DAT function and intracellular METH accumulation, and suggest that the effect of temperature on METH-induc ed DA neurotoxicity is mediated, at least in part, at the level of the DAT.