Sensitization to the effects of tumor necrosis factor-alpha: Neuroendocrine, central monoamine, and behavioral variations

Consistent with the proposition that cytokines act as immunotransmitters be tween the immune system and the brain, systemic administration of the proin flammatory cytokine tumor necrosis factor-alpha (TNF-alpha; 1.0-4.0 mu g) i nduced mild illness in CD-1 mice, increased plasma corticosterone concentra tions, and altered central norepinephrine, dopamine, and serotonin turnover . The actions of TNF-alpha were subject to a time-dependent sensitization e ffect. After reexposure to a subeffective dose of the cytokine (1.0 mu g) 1 4-28 d after initial treatment, marked illness was evident (reduced consump tion of a palatable substance and diminished activity and social exploratio n), 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 I d interval the corticosterone response to the cytokine was red uced. The increase of norepinephrine release within the paraventricular nuc leus of the hypothalamus, as reflected by elevated accumulation of 3-methox y-4-hydroxyphenylglycol, was augmented at the longer reexposure intervals. In contrast, within the central amygdala and the prefrontal cortex TNF-alph a reexposure at the 1 d interval was associated with a pronounced sensitiza tion-like effect, which was not apparent at longer intervals. Evidently, sy stemic TNF-alpha proactively influences the response to subsequent treatmen t; however, the nature of the effects (i.e., the behavioral, neuroendocrine , and central transmitter alterations) vary over time after initial cytokin e treatment. It is suggested that the sensitization may have important repe rcussions with respect to cognitive effects of TNF-alpha and may also be re levant to analyses of the neuroprotective or neurodestructive actions of cy tokines.