The effects of the dopamine (DA) uptake blocking agents, benztropine, cocaine, nomifensine and mazindol, were studied on the amphetamine-induced circling behavior in mice that received a unilateral nigro-striatal lesion with 6-hydroxydopamine. When administered intrastriatally to these animals, none of the DA uptake inhibitors elicited net circling. However, they inhibited circling induced by amphetamine. In contrast, these agents had no effect on the circling produced by apomorphine in mice that received an electrolytic lesion destroying one striatum. In biochemical studies in vitro, all of the DA uptake blocking agents inhibited the stimulatory effects of amphetamine on [3H]DA synthesis and release in mouse striatal slices. In contrast to the DA uptake blocking agents, ethylene glycol bis(beta-aminoethyl ether)N,N'-tetraacetic acid (EGTA), which also inhibited amphetamine-induced circling, only inhibited the amphetamine-stimulated [3H]DA synthesis. EGTA did not inhibit the amphetamine-induced increase in the percentage of newly synthesized DA released into the medium. However, EGTA and the uptake blocking agents reduced the amount of [3H]DA found in the medium in the presence of amphetamine. If the amount of [3H]DA released into the medium in vitro reflects the amount of DA released from nerve terminals in the striatum in vivo then the inhibitory effect of the uptake blocking agents and EGTA on [3H]DA synthesis and/or release induced by amphetamine could account for their inhibitory effects on amphetamine-induced circling.