The mechanisms by which the brain dopamine neuronal transporter is regulated by chronic alteration of dopamine transmission are not well understood. It has been shown previously that chronic inhibition of dopamine synthesis decreases dopamine transporter (DAT) density and function. The purpose of the present study was to determine whether these effects involve dopamine D2 receptors. Chronic treatment with alpha-methyl-p-tyrosine decreased binding of [3H]mazindol and dopamine release by d-amphetamine. The down-regulation of the DAT by alpha-methyl-p-tyrosine was not altered by co-treatment with a D2 receptor agonist or antagonist. However, chronic treatment with a D2 agonist, quinpirole, also decreased mazindol binding and amphetamine-induced release of dopamine. The results indicate that chronic inhibition of dopamine synthesis and stimulation of D2 receptors have similar, but independent, effects on DAT binding and function.