The psychostimulant properties of methamphetamine (METH) are associated with an increase in extracellular dopamine (DA) levels in the brain, via facilitation of DA's release from pre-synaptic nerve terminals and inhibition of its reuptake through DA transporter. Recently, we have demonstrated that tumor necrosis factor-α (TNF-α) increases DA uptake and inhibits METH dependence. Moreover, we have clarified 'shati' identified in the nucleus accumbens of mice treated with METH is involved in METH dependence. In the present study, we investigated the effects of TNF-α on DA uptake in PC12 cells and established a PC12 cell line transfected with a vector containing shati cDNA to examine the precise mechanism behind the role of shati in DA uptake. Moreover, we examined the relationship between shati and TNF-α. TNF-α increased DA uptake via the mitogen-activated protein kinase kinase pathway and inhibited the METH-induced decrease in DA uptake in PC12 cells. Transfection of the vector containing shati cDNA into PC12 cells, induced the expression of shati and TNF-α mRNA, accelerated DA uptake, and inhibited the METH-induced decrease in DA uptake. These results suggest that the functional roles of shati in METH-regulated behavioral changes are mediated through inhibition of the METH-induced decrease in DA uptake via TNF-α. © 2008 The Authors.