S. Hayley et al., Sensitization to the effects of tumor necrosis factor-alpha: Neuroendocrine, central monoamine, and behavioral variations, J NEUROSC, 19(13), 1999, pp. 5654-5665
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.