The present study was designed to reveal the relationship between cocaine-induced dopamine uptake changes and patterns of cocaine self-administration observed under a fixed-ratio schedule. Cocaine was intravenously infused into anesthetized rats, according to inter-infusion intervals obtained from self-administering animals, and dopamine uptake changes (apparent K(m)) were assessed in the nucleus accumbens using voltammetry. The data demonstrate that cocaine-induced dopamine transporter (DAT) inhibition accounts for the accumbal dopamine fluctuations, which are associated with the cyclic regularity of cocaine intake observed during self-administration. Specifically, the inter-infusion intervals that are maintained during cocaine self-administration correlate with the maintenance of a rapidly changing level of dopamine uptake inhibition, which appears to be tightly regulated. Furthermore, this maintained level of dopamine uptake inhibition was found to shift upward using intervals from animals that had shown an escalation in the rate of cocaine self-administration. Although no significant change in the apparent K(m) was revealed in animals that exhibited an escalation in the rate of cocaine intake, an increased dopamine uptake rate was found suggesting an upregulation of DAT number in response to a history of high cocaine intake. This is the first demonstration of the tight correlation that exists between the level of dopamine uptake inhibition and rates of cocaine self-administration. Moreover, a new mathematical model was created that quantitatively describes the changes in cocaine-induced dopamine uptake and correctly predicts the level of dopamine uptake inhibition. This model permits a computational interpretation of cocaine-induced dopamine uptake changes during cocaine self-administration.