Investigation of residual behavioral states produced by withdrawal from different routes of cocaine administration indicates that depending on the mode of intake, chronic cocaine produces either tolerance or sensitization to subsequent challenge doses of cocaine. We studied the effect of routes of cocaine administration on the dopamine transporter receptors (DATR), the presumed neuronal mediator of cocaine reward, using the diphenyl substituted piperazine derivative, [3H]GBR 12935 and the cocaine analogue [3H]WIN 35,428. Alzet osmotic mini-pumps filled with either cocaine (100 mg/ml) or saline were surgically implanted on rats into a subcutaneous pocket at the dorsal midline, continuously infusing cocaine at the rate of 40 mg/kg/day. The pumps were removed 14 days later, and the rats were killed 7 days after the removal of pumps. For the intermittent administration, two groups of rats were injected daily either with 40 mg/kg of cocaine or saline for 14 days. Rats were killed 7 days following the last injection. Continuous infusion of cocaine did not alter the [3H]GBR 12935 dopamine transporter (DAT) binding either in the caudate nucleus or in the prefrontal cortex, but it enhanced the density of [3H]WIN 35,428-labeled DAT receptor sites in the caudate putamen. In contrast, intermittent administration of cocaine resulted in a selective alteration of [3H]GBR 12935 binding in the prefrontal cortex but not in the caudate; the cocaine-injected rats had a 48% decrease in [3H]GBR 12935, Bmax (p < .05), without changing the KD. The contrast between the lack of effect of cocaine on [3H]GBR 12935-DATR and the increased binding of [3H]WIN 35,428-DATR highlights the differential sensitivities of the two binding sites to the continuous presence of cocaine.