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hepatic vagus nerve. Afferent stimuli can thus reach the nucleus tractus solitarius, via
the dorsal nucleus of the vagus in the brainstem. The former projects to the hypothala-
mus and hippocampus, via ascending noradrenergic pathways.
Pro-inflammatory cytokines can also be synthesized by microglia, astrocytes, and
blood vessels within the brain, either constitutively or following an immune challenge
[3,4]
. Furthermore, various parts of the brain, including the hypothalamus and hip-
pocampus, express mRNAs for pro-inflammatory cytokines such as IL-1, IL-2, IL-6,
and TNF-
[5,6]
. Specific neuronal binding sites for cytokines are present in brain
regions such as the area postrema, hypothalamus, amygdala, hippocampus, and pre-
frontal cortex. Thus, cytokines can have a direct effect on neuronal function and are
ideally placed to play a role in modulating behavioral as well as autonomic and neu-
roendocrine responses
[7,8]
.
Specific neurochemical changes occur within the brain in response to an immu-
nological challenge or following the administration of pro-inflammatory cyto-
kines. Systemic or intracerebral administration of IL-1 can enhance the turnover of
noradrenaline in the hypothalamus and hippocampus, 5HT in the hippocampus and
prefrontal cortex, and dopamine (DA) in the prefrontal cortex
[9-12]
. Peripheral
administration of IL-2 produces an increase in noradrenaline metabolism in the
hypothalamus and hippocampus and of DA metabolism in the prefrontal cortex and
striatum. However, IL-2 does not affect 5HT function
[12]
, although it inhibits ace-
tylcholine release from the hippocampus and frontal cortex
[13]
. Furthermore, IL-2,
unlike IL-1, does not significantly increase plasma corticosterone concentrations.
Chronic IL-2 treatment also produces neuronal loss and degenerative changes in the
hippocampus and a reduction in memory
[14]
. IL-6 increases DA and 5HT turnover in
the hippocampus and prefrontal cortex, without affecting noradrenaline in the hypo-
thalamus
[12]
. However, noradrenaline itself can stimulate astrocytic IL-6 release,
raising the possibility that noradrenaline released during activation of the autonomic
nervous system will activate the cytokine cascade
[15]
. There are many similarities
between the neurochemical changes evoked by IL-1 and IL-6 in the brain. For exam-
ple, both cytokines enhance 5HT turnover in the hippocampus and prefrontal cortex,
and increase the 3,4-dihydroxy-phenyl acetic acid (DOPAC:DA) ratio in the latter
region. However, IL-6, unlike IL-1, does not affect hypothalamic noradrenaline (NA)
or plasma corticosterone concentrations
[9,12]
. The acute release of tumor necrosis
factor (TNF)- stimulates noradrenaline secretion, whereas chronic release inhibits it,
for example, in the median eminence
[16]
. Thus, pro-inflammatory cytokines can dif-
ferentially affect neurochemical function in brain regions that mediate neuroimmune
interactions and that are important in the regulation and integration of the behavioral
and neuroendocrine responses to physical and psychological stressors.
12.2 Cytokines and Sickness Behavior
Following exposure to an immune challenge, pro-inflammatory cytokines induce a
series of symptoms that are known collectively as
sickness behavior
. These are adap-
tive behaviors which, together with fever and the associated neuroendocrine changes,
