Daily administration of psychomotor stimulants in a distinctive environment can impart on the environment stimulantlike properties. Rats injected with amphetamine (0.75 mg/kg, sc) daily for 5 days exhibited a robust unconditioned locomotor response, measured in photocell cages, and showed a conditioned locomotor response when treated with saline on the 6th day. This conditioned locomotor response was found to be significantly attenuated by 6-hydroxydopamine (6-OHDA) lesions of the nucleus accumbens when the lesion was made either pre- or postconditioning. Similarly, although rats with 6-OHDA lesions of the nucleus accumbens exhibited a robust supersensitive unconditioned locomotor hyperactivity in response to apomorphine (0.1 mg/kg, sc), they did not show a conditioned response on the test day. These results suggest that the mesolimbic dopamine system may be responsible for both the unconditioned and conditioned locomotor responses to psychomotor stimulant drugs. Further, conditioned locomotion depends on a critical interaction between the physiological release of presynaptic dopamine and occupation of postsynaptic receptors.