Two aryl 1,4-dialkylpiperazines (GBR 12909 and GBR 13098) and one aryl 1,4-dialkenylpiperazine (GBR 13069) were very potent inhibitors of [3H]dopamine uptake in vitro in tissue slices obtained from rat neostriatum (IC50 values between 40 and 51 nM). Each compound was considerably weaker as an inhibitor of [3H]norepinephrine uptake in tissue slices obtained from rat occipital cortex (IC50 values between 560 and 2600 nM). These compounds thus are relatively specific inhibitors of [3H]dopamine uptake in vitro. The three compounds caused ipsilateral circling in rats with unilateral lesions of the nigrostriatal pathway as well as increased locomotor activity in naive mice, both of which could be greatly attenuated by pretreatment of the rodents with the dopamine receptor antagonist haloperidol. It thus follows that the compounds have dopaminergic activity in vivo. Ex vivo experiments with GBR 13069 (drug administration in vivo, uptake in vitro) suggested that these compounds may have the same relative specificity as dopamine uptake blockers in vivo. These compounds should prove to be useful pharmacological agents.