The neuromodulatory effect of manipulating monoaminergic receptor function was assessed by combining a psychological and a pharmacological activation during repeated positron emission tomographic (PET) scans. The effects of buspirone (a 5-HT1A receptor partial agonist) on changes in regional cerebral blood flow (rCBF) associated with free word recall were examined. A factorial design was used to demonstrate a significant interaction (changes in rCBF brought about by psychological activation which depend on drug administration) in the left parahippocampal region. This interaction was an attenuation of increases in local neuronal activity (rCBF) related to memory function. Buspirone-induced decreases in rCBF, independent of the memory effect, were seen in the left prefrontal and parietal cortices. We suggest that combined psychological and pharmacological activation is a way of measuring direct (main) drug effects and modulatory effects on neurotransmission associated with cognitive functions (interaction).