Abstract Repeated administration of large doses of methamphetamine depresses both neostriatal tyrosine hydroxylase and tryptophan hydroxylase activity. Neostriatal concentrations of dopamine, serotonin and their acidic metabolites are similarly reduced by methamphetamine. Coadministration of the dopamine uptake inhibitor, amfonelic acid, selectively prevented the methamphetamine-induced decrease in tyrosine hydroxylase activity while not altering the depression of tryptophan hydroxylase activity. In vitro, amfonelic acid blocked methamphetamine-induced [ 3H]dopamine release from neostriatal slices but had no effect on [ 3H]serotonin release. In experiments conducted with [ 3H]amphetamine and amfonelic acid, no evidence was found for carrier-mediated transport of amphetamine. The results demonstrate a role for the dopamine uptake carrier in the neurochemical effects of high doses of methamphetamine. Furthermore, the ability of amfonelic acid to antagonize the neurochemical effects of methamphetamine appears to be due to an inhibition of carrier-mediated dopamine efflux rather than carrier-mediated uptake of methamphetamine.