Amphetamine (AMPH)-induced psychosis is most frequently associated with a chronic high-dose "binge" or "run" pattern of stimulant abuse, generally preceded by a period of gradually escalating doses of the drug. We showed previously that animals subjected to such a regimen of AMPH administration developed, over multiple daily binges, a unique pattern of behavioral response that included a decrease in stereotypy and a pronounced increase in locomotion. Because of the involvement of mesolimbic and mesostriatal dopamine (DA) pathways in locomotion and stereotypy, respectively, we hypothesized that a persistent shift in the relative magnitude of caudate-putamen (CP) and nucleus accumbens (NAC) DA transmission may contribute to this altered behavioral profile. To test this hypothesis, we examined CP and NAC extracellular DA in response to multiple high-dose AMPH binges. Our results revealed that with multiple binges the CP DA response but not the NAC response developed a profound tolerance/tachyphylaxis to the drug-induced increase in extracellular transmitter. These differential regional response alterations seem to correspond to the shift in the relative expression of stereotypy and locomotion. We hypothesize that changes in DA synthesis, perhaps mediated by regionally specific adaptations in DA autoreceptor function, contribute to the differential extracellular transmitter response profiles, and suggest that these neurochemical changes may have important implications for the mechanisms underlying the addictive and psychotogenic properties of AMPH.