Chronic administration of cocaine to rats has been shown to produce a persistent decrease in dopamine (DA) and its metabolites in the brain and periphery. To further explore the alterations in the DA system following repeated administration of cocaine, we studied the regional differences in DA transporter binding as a function of time after the last injection of cocaine. Two groups of rats were treated with cocaine (10 mg/kg twice a day) or saline for 7 days. Rats were sacrificed 1, 2, 3, 6, and 12 weeks after the last injection. The corpus striatum and the frontal cortex were dissected and assayed with [3H]GBR 12935 for DA transporter binding. Time-related differences were observed in the frontal cortex but not in the striatum of the saline-treated control rats. Cocaine treatment prevented the time-dependent increase in Bmax over the course of 6 weeks, but not over the course of 12 weeks following withdrawal. Although there was no difference between the cocaine- and saline-treated group in the striatum at any of the time points, cocaine in the frontal cortex produced a 33% reduction in Bmax during weeks 2 and 3 and a 57% reduction in Bmax at week 6 of withdrawal; the reduction persisted for > or = 12 weeks. The KD was not affected by cocaine or time in either brain region. These findings may be functionally related to cocaine craving because the DA transporter has been identified as the neuronal structure and the medial prefrontal cortex as the anatomical site mediating cocaine reinforcement.