Cognitive activation in conjunction with pharmacological challenge was used to demonstrate neuromodulation in man. Using positron emission tomography (PET), measurements of regional cerebral blood flow were made during the performance of memory tasks, before and after the administration of apomorphine (dopamine agonist), buspirone (5-HT1A partial agonist) or placebo. Drug effects on memory-induced increases in regional cerebral blood flow were assessed, on a voxel-by-voxel basis, using statistical parametric mapping. Increases of regional cerebral blood flow in response to the memory challenge were attenuated by apomorphine in the dorsolateral prefrontal cortex and augmented in the retrosplenial region of the posterior cingulate. Conversely, buspirone attenuated blood flow increases in the retrosplenial region. These interactions between drugs and a cognitive challenge can best be interpreted as neuromodulatory effects.