The effects of systemically administered interleukin-1beta (1.0 microg) on in vivo variations of monoamines was assessed in several brain regions. Administration of the cytokine provoked a modest increase of extracellular 5-HIAA and HVA from the nucleus accumbens, and 5-HIAA from the hippocampus. Following mild neurogenic stressor (application of a series of air puffs), a still greater increase of accumbal 5-HIAA and HVA was evident, a transient increase of hippocampal 5-HT was noted and the 5-HIAA increases were augmented. Additionally, while the air puff stress was without effect on DOPAC and HVA in the prefrontal cortex of saline treated rats, a significant rise of these metabolites was apparent in rats treated with the cytokine. It appears that interleukin-1 administration may have effects on forebrain monoamines, and also results in greater neuronal reactivity to mild neurogenic stressors. This study reveals that although effects of neurogenic stressors (air puffs) and cytokine (somatic stressor) may share some similarities (e.g., HPA activation), the pattern of central neurochemical changes elicited by the cytokine could be distinguished from that induced by a more neurogenic stressor (air puffs), and that these effects showed selective synergism. These data also lend support to the contention that neurogenic stressors may have a much greater impact on central neurotransmission under conditions of immune activation.