These studies investigated whether endogenous activation of CCK(A) receptors mediates the expression of amphetamine (AMP)-induced locomotor activity. In Experiment 1, locomotor activity was assessed in rats pretreated with the CCK(A) antagonist devazepide (0.001, 0.01, and 0.1 mg/kg) and subsequently injected with AMP (1.5 mg/kg). In Experiment 2, rats were administered AMP (1.5 mg/kg) once daily for 7 days. Following a 10-day withdrawal, locomotor activity was assessed following treatment with devazepide (0.001, 0.01, and 0.1 mg/kg) and AMP (0.75 mg/kg). In both studies, rats were classified as low (LR) or high (HR) responders based upon a median split of their locomotor response to a novel environment. Results from Experiment 1 showed that AMP potentiated the expression of locomotor activity, and this effect was most pronounced in HR rats. However, devazepide did not affect AMP-induced locomotion. Results from Experiment 2 demonstrated that chronic AMP pretreatment augmented the locomotor response to subsequent AMP challenge, and this effect was most pronounced in the HR group. Further, this augmented response was blocked by devazepide in HR rats. These findings constitute the first demonstration that endogenous CCK(A) receptor activation is an important substrate mediating AMP-induced locomotor activity in animals with a previous history of AMP treatment.