Following reserpine pretreatment to disrupt vesicular stores of dopamine and norepinephrine, in vivo microdialysis was used in behaving rats to evaluate the role of vesicles in the neurochemical and behavioral responses to amphetamine and cocaine. Reserpine (2.5 mg/kg, 24 hr) completely prevented the hippocampus norepinephrine responses to 20 mg/kg of cocaine and to 0.5, 1.25 and 5.0 mg/kg of amphetamine. Likewise, reserpine almost completely abolished the caudate putamen dopamine response to cocaine. In contrast, the effect of reserpine on the amphetamine-induced dopamine response varied as a function of amphetamine dose. Although the dopamine response to 1.25 mg/kg of amphetamine was unchanged by reserpine pretreatment, the dopamine responses to both the lowest (0.5 mg/kg) and highest (5.0 mg/kg) doses of amphetamine were significantly attenuated by about 65% and 50%, respectively. These results indicate that the norepinephrine response to amphetamine is dependent on vesicular stores of transmitter at all doses of the drug. However, although amphetamine can release dopamine from a reserpine-resistant (non-vesicular) pool, it also appears that this response partially depends on vesicular stores, especially at low and high doses of drug. Concomitant behavioral assessments revealed that the behavioral responses to cocaine and the lowest dose of amphetamine, like the dopamine responses, were significantly suppressed by reserpine pretreatment. In contrast, at the intermediate dose of amphetamine, stereotypies were significantly enhanced. These altered behavioral profiles are discussed in terms of a balance between increases in both dopamine and norepinephrine produced by amphetamine.