Fluoxetine inhibits the reuptake of serotonin, and dextroamphetamine enhances presynaptic release of monoamines. Although the excitatory effect of both noradrenaline and dopamine on motor behavior generally is accepted, the role of serotonin on motor output is under debate. In the current investigation, the authors evidenced a putative role of monoamines and, more specifically, of serotonin in the regulation of cerebral motor activity in healthy subjects. The effects on cerebral motor activity of a single dose of fluoxetine (20 mg), an inhibitor of serotonin reuptake, and fenozolone (20 mg/50 kg), an amphetamine-like drug, were assessed by functional magnetic resonance imaging. Subjects performed sensorimotor tasks with the right hand. Functional magnetic resonance imaging studies were performed in two sessions on two different days. The first session, with two scan experiments separated by 5 hours without any drug administration, served as time-effect control. A second, similar session but with drug administration after the first scan assessed drug effects. A large increase in evoked signal intensity occurred in the ipsilateral cerebellum, and a parallel, large reduction occurred in primary and secondary motor cortices (P < 10(-3)). These results are consistent with the known effects of habituation. Both drugs elicited comparable effects, that is, a more focused activation in the contralateral sensorimotor area, a greater involvement of posterior supplementary motor area, and a widespread decrease of bilateral cerebellar activation (P < 10(-3)). The authors demonstrated for the first time that cerebral motor activity can be modulated by a single dose of fluoxetine or fenozolone in healthy subjects. Drug effects demonstrated a direct or indirect involvement of monoamines and serotonin in the facilitation of cerebral motor activity.