Consistent with the proposition that cytokines act as immunotransmitters between the immune system and the brain, systemic administration of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha; 1.0-4.0 microg) induced mild illness in CD-1 mice, increased plasma corticosterone concentrations, and altered central norepinephrine, dopamine, and serotonin turnover. The actions of TNF-alpha were subject to a time-dependent sensitization effect. After reexposure to a subeffective dose of the cytokine (1.0 microgram) 14-28 d after initial treatment, marked illness was evident (reduced consumption of a palatable substance and diminished activity and social exploration), coupled with an elevation of plasma corticosterone levels. In contrast, cytokine reexposure 1-7 d after initial treatment did not elicit illness, and at the 1 d interval the corticosterone response to the cytokine was reduced. The increase of norepinephrine release within the paraventricular nucleus of the hypothalamus, as reflected by elevated accumulation of 3-methoxy-4-hydroxyphenylglycol, was augmented at the longer reexposure intervals. In contrast, within the central amygdala and the prefrontal cortex TNF-alpha reexposure at the 1 d interval was associated with a pronounced sensitization-like effect, which was not apparent at longer intervals. Evidently, systemic TNF-alpha proactively influences the response to subsequent treatment; however, the nature of the effects (i.e., the behavioral, neuroendocrine, and central transmitter alterations) vary over time after initial cytokine treatment. It is suggested that the sensitization may have important repercussions with respect to cognitive effects of TNF-alpha and may also be relevant to analyses of the neuroprotective or neurodestructive actions of cytokines.

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Systemic administration of interleukin-1beta (IL-1beta) promoted behavioral changes in an open-field exploratory test. In particular, while the cytokine suppressed locomotor activities, these behaviors were not particularly sensitive to dosage differences. In contrast, dose-dependent biphasic variations that varied over time were evident with respect to the exploration of a novel container. Within this paradigm, the behavioral changes did not appear to be related to neophobia. In addition, despite the marked effects of IL-1beta on exploratory and locomotor behaviors, habituation/exploration in a free-running spontaneous alternation task was unaffected by the cytokine. In addition to the behavioral variations, IL-1beta dose-dependently increased plasma ACTH and corticosterone concentrations, and also induced several central monoamine alterations. In particular, IL-1beta increased the utilization of norepinephrine (NE) within the paraventricular nucleus, arcuate nucleus/median eminence, locus coeruleus, and prefrontal cortex, while the turnover of dopamine (DA) was evident in the arcuate nucleus/median eminence. It is suggested that although systemic IL-1beta treatment induces some stress-like effects, the profile of central neurochemical changes induced by the cytokine can be distinguished from psychological or processive types of stressors.

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