Cocaine was administered daily (15 mg/kg, i.p. x 1 d followed by 30 mg/kg, i.p. x 5 d) to produce behavioral sensitization. Using microdialysis in the ventral tegmental area and medial substantia nigra, the effect of repeated cocaine was examined on the extracellular levels of dopamine. One day after discontinuing repeated cocaine injections, an acute challenge with cocaine (15 mg/kg, i.p.) produced a significant elevation in extracellular dopamine compared to rats pretreated with daily saline (x6 d). The augmentation in extracellular dopamine persisted longer than the sensitized behavioral response. In contrast, 14 d after discontinuing daily cocaine, the increase in extracellular dopamine produced by an acute cocaine challenge was not augmented, although behavioral sensitization was present. In separate animals, the basal concentration of dopamine in the ventral tegmental area/medial substantia nigra was measured by determining the concentration of dopamine at which no net flux occurred across the dialysis membrane in vivo. One day after discontinuing daily treatments, the basal level of extracellular dopamine in the cocaine pretreated rats was significantly elevated over the level in saline- pretreated animals (1.3 nM vs. 0.8 nM). By 14 d after the last daily injection, the basal levels of dopamine were equivalent in cocaine- and saline-pretreated animals. It is concluded that daily cocaine injections produce a transient alteration in the regulation of somatodendritic dopamine release. While such changes are not responsible for the long-term behavioral sensitization produced by repeated cocaine administration, they may be involved in the initiation of behavioral sensitization.