The ability of environmental cues associated with cocaine availability to cause relapse may result from conditioned activation of dopamine (DA) release. We examined this hypothesis in macaque monkeys by conducting microdialysis studies in animals during exposure to a cocaine predictive compound cue. In addition to studying DA release in mesolimbic and sensorimotor striatum, both DA and serotonin levels were determined in the prefrontal cortex (medial orbitofrontal and anterior cingulate). The compound cue employed visual, auditory, and olfactory components, and was salient to the animals as demonstrated by anticipatory lever pressing in the absence of cocaine. During a 10-min period of exposure prior to cocaine availability, there was no significant increase in striatal or cortical DA. The addition of a DA uptake inhibitor to the striatal perfusate to reduce the potential interference of neuronal uptake did not alter the results. In contrast to the lack of any change in striatal DA, a significant decrease in extracellular serotonin in the prefrontal cortex during the 10 min of cue exposure was observed.