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The Journal of Neuroscience, July 1, 1999, 19(13):5654-5665
Sensitization to the Effects of Tumor Necrosis Factor- :
Neuroendocrine, Central Monoamine, and Behavioral Variations
Shawn
Hayley1,
Karen
Brebner1,
Susan
Lacosta1,
Zul
Merali2, and
Hymie
Anisman1
1 Institute of Neuroscience, Carleton
University, Ottawa, Ontario K1S 5B6, Canada, and 2 School
of Psychology and Department of Cellular and Molecular Medicine,
University of Ottawa, Ottawa, Ontario K1N 6N5, Canada
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- (TNF-; 1.0-4.0 µg) induced mild illness in CD-1 mice, increased plasma corticosterone concentrations, and altered central norepinephrine, dopamine, and serotonin turnover. The actions of
TNF- were subject to a time-dependent sensitization effect. After
reexposure to a subeffective dose of the cytokine (1.0 µg) 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- reexposure at the 1 d interval was
associated with a pronounced sensitization-like effect, which was not
apparent at longer intervals. Evidently, systemic TNF- 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- and may also
be relevant to analyses of the neuroprotective or neurodestructive
actions of cytokines.
Key words:
tumor necrosis factor-; cytokine; sensitization; desensitization; corticosterone; norepinephrine; dopamine; serotonin; sickness behavior
Copyright © 1999 Society for Neuroscience 0270-6474/99/19135654-12$05.00/0
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