The effects of systemically administered interleukin-1beta (1.0 microg), interleukin-6 (1.0 microg) and interleukin-2 (1.0 microg) on in vivo variations of monoamines were assessed in the nucleus accumbens. Administration of interleukin-1beta did not affect extracellular accumbal dopamine, provoked a modest rise of homovanillic acid, and prevented the decline of dihydroxyphenylacetic acid ordinarily seen in saline treated rats. Also, interleukin-1 provoked a modest increase of extracellular 5-hydroxyindoleacetic acid from the nucleus accumbens. Following exposure to the stress of a series of air-puffs, a still greater increase of accumbal 5-hydroxyindoleacetic acid was evident. In contrast to interleukin-1, systemic administration of interleukin-6 and interleukin-2 both induced marked reductions of interstitial dopamine levels. The air-puff exposure further enhanced these effects in rats that had received the cytokine treatment. As well, interleukin-6 and interleukin-2 were both found to reduce the homovanillic acid response associated with the stress, and interleukin-2 promoted a decline of homovanillic acid levels. Treatment with interleukin-6, like that of interleukin-1, prevented the decline of dihydroxyphenylacetic acid ordinarily observed over time, while interleukin-2 was without effect in this respect. Finally, interleukin-6 provoked a modest rise of 5-hydroxyindoleacetic acid, which was most apparent following air-puff exposure, while administration of interleukin-2 did not affect accumbal 5-hydroxyindoleacetic acid. It is suggested that the cytokines may influence the release of biogenic amines in the nucleus accumbens, but the profile of changes were cytokine-specific. As well, it appeared that the cytokines, particularly interleukin-1 and interleukin-6, may act synergistically with the stressor in promoting the amine variations. Systemic administration of cytokines clearly influenced monoamine activity at the nucleus accumbens, a region associated with both rewarding and aversive events. Thus, it may be expected that cytokine treatments may affect behavior. Moreover, it seems that the effects of interleukin-1 and interleukin-6 may be influenced by the presence of stressful stimuli. It ought to be underscored that although cytokines share features with the effects of stressors, most notably the variations of hypothalamic-pituitary-adrenal hormones, the pattern of central neurochemical changes elicited by the cytokines could be distinguished from the amine variations ordinarily associated with stressors.