The effects of repeated reserpine on the in vivo regional brain distribution of [18F]GBR 13119 (1-[(4-[18F]fluorophenyl)(phenyl)methoxy)ethyl]-4-(3-phenylpropyl) piperazine), a dopamine uptake inhibitor, have been examined. Repeated parenteral administration of reserpine (2 mg/kg i.p., once daily for three days) causes a decrease of the in vivo specific binding of [18F]GBR 13119 in mouse striatum, consistent with a down-regulation of available uptake sites in response to dopamine depletion. These results indicate that modification of endogenous dopamine concentrations, either due to pathological disturbance or pharmacological interventions, may affect in vivo studies of the dopamine uptake system using radioligands of the 1,4-dialk(en)ylpiperazine class, and complicate the interpretation of in vivo human studies of these radioligands using positron emission tomography.