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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
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ABSTRACT |
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
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INTRODUCTION |
Multidirectional communication
exists among the immune, autonomic, hormonal, and central nervous
systems (Blalock, 1994 ; Hopkins and Rothwell, 1995; Maier and Watkins,
1998). It has been suggested, in this respect, that the proinflammatory
cytokines interleukin-1 (IL-1), IL-6, and tumor necrosis
factor- (TNF-) may serve in a signaling capacity between the
immune system and the CNS (Dunn, 1992; Hopkins and Rothwell, 1995).
These cytokines could affect central processes directly, or they may do
so indirectly through stimulation of vagal afferents (Bluthe et al.,
1996; Maier and Watkins, 1998). Moreover, it has been suggested that
variations of peripheral cytokine activity may be interpreted by the
brain as a stressor (Dunn et al., 1989; Dunn, 1990; Anisman and Merali, 1999).
In addition to hormonal changes (e.g., plasma corticosterone or ACTH),
cytokines may provoke variations of central neurotransmitter activity
(Dunn and Welch, 1991; Linthorst et al., 1995), thus eliciting
behavioral alterations (Linthorst et al., 1995; Lacosta et al., 1998).
Interestingly, cytokines may not only have immediate effects but may
also result in the sensitization of neuroendocrine and neurotransmitter
processes, such that the subsequent response to cytokine or stressor
challenge is enhanced. For instance, IL-1 provoked increased
colocalization of arginine vasopressin (AVP) and
corticotropin-releasing hormone (CRH) in CRH terminals within the
external zone of the median eminence (Schmidt et al., 1995, 1996;
Tilders and Schmidt, 1998). Because AVP and CRH synergistically provoke
pituitary ACTH release, such a process may account for some of the
protracted effects of cytokine exposure (Tilders and Schmidt, 1998) and
may contribute to pathological states associated with stressor or
cytokine challenges (Ravindran et al., 1997).
In addition to the hypothalamic-pituitary-adrenal (HPA) alterations,
IL-1 influenced monoamine activity at several extrahypothalamic sites (Linthorst et al., 1995; Merali et al., 1997; Lacosta et al.,
1998; Song et al., 1999). As well, IL-1 and stressors
synergistically influenced central monoamine activity (Song et al.,
1999). In contrast to the attention devoted to the effects of IL-1,
a relative paucity of information exists concerning the immediate and
proactive central effects of TNF-. This is surprising because this
cytokine has been implicated in various CNS processes and pathologies
(e.g., neurodegenerative disorders, sepsis, head trauma, and cerebral ischemia) (Giulian and Robertson, 1990; Buttini et al., 1994; Sato et
al., 1997).
It was of interest to establish the immediate and proactive effects of
systemic TNF- treatment. In this respect, the present investigation
determined (1) the immediate effects of TNF- administration on an
index of sickness behavior (reduced locomotion and social interaction and consumption of a highly palatable food source), plasma
corticosterone, as well as central monoamine levels and turnover at
hypothalamic and extrahypothalamic sites, (2) whether administration of
this cytokine proactively influenced neurochemical and behavioral
processes after subsequent reexposure to subeffective cytokine doses,
and (3) whether such a sensitization was dependent on the time between
the initial TNF- treatment and subsequent reexposure.
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MATERIALS AND METHODS |
Male CD-1 mice, 8-10 weeks of age, were obtained from Charles
River (Laprairie, Quebec, Canada). Mice were housed in groups of four
in standard propylene cages and given at least 2 weeks to acclimate to
the laboratory. Animals were maintained on a 12 hr light/dark cycle
with lights on at 8 A.M., room temperature was kept at 21°C, and mice
were permitted an ad libitum diet of Ralston Purina (St.
Louis, MO) mouse chow. All experimental procedures were approved by the
Carleton University Committee for Animal Care and met the guidelines
set out by the Canadian Council on Animal Care.
Procedure. To minimize the contribution of diurnal
variations associated with neurotransmitter or neuroendocrine
processes, all experimental procedures were conducted between 8 A.M.
and 12 P.M. CD-1 mice were used in this experiment because central amine and neuroendocrine effects of stressors have been characterized in this outbred strain, as have the immediate behavioral and
neurochemical responses to IL-1 and TNF- (Shanks et al., 1991;
Brebner et al., 1998; Lacosta et al., 1998).
Mice (n = 20 per group) received an initial
intraperitoneal injection with either sterile nonpyrogenic saline
(0.9%) or 4.0 µg of TNF- in a volume of 0.4 ml of sterile saline,
followed by a second injection of 1.0 µg of the cytokine. The latter
treatment was administered 1, 7, 14, or 28 d after the initial
TNF- treatment. Three additional groups of mice were included; one
group received saline on two occasions 14 d apart; a second
received saline followed 14 d later by the low dose of TNF-
(1.0 µg); and the third group received TNF- (4.0 µg) followed
14 d later by saline. Human recombinant TNF- (specific
activity, 1.1 × 105 U/µg) was obtained from
R & D Systems (Minneapolis, MN) in lyophilized form, subsequently
dissolved in sterile PBS, and stored in 20 µl aliquots at  80°C.
At 1.0 hr after the second injection mice were decapitated, and brains
collected, frozen in isopentane, and then stored at 80°C until
later sectioning and removal of nuclei for analysis of central biogenic
amines and metabolites. Trunk blood was centrifuged, and the
supernatant was stored at 80°C in tubes containing 10 µl of EDTA
for the determination of plasma corticosterone levels. The 1.0 hr
interval between TNF- administration and subsequent decapitation was
chosen on the basis of an earlier study showing that behavioral and
glucocorticoid variations were marked at this time (Brebner et al.,
1998).
In addition to the neurochemical alterations, this experiment also
assessed whether behavioral outputs would be associated with reexposure
to cytokine treatment and whether such behavioral effects would appear
sooner in mice that received the reexposure treatment. Behavioral
measures were recorded from half of the mice (i.e., in one of two
replications of the study) during the reexposure phase of the study
(n = 10 per group). After intraperitoneal injection
mice were returned to their home cages, and their behavior, including
social interaction with noninjected cage mates, was recorded up to the
time at which the brain and blood were collected. Commencing 15 min
after the intraperitoneal injection and at the three successive 15 min
intervals, the following behaviors were rated, for a 10 sec period, on
four-point scales: locomotor activity (1 = no movement; 2 = slow, lethargic movements; 3 = normal locomotion; and 4 = hyperactive, continuous movement); social interaction (1 = animal
huddling with cage mates; 2 = occasional interaction with cage
mates; 3 = predominately staying away from cage mates; and 4 = isolated from cage mates, typically in corner); overall sickness
(1 = normal looking; 2 = slightly lethargic, slow movement, slightly ruffled fur, and eyes slightly drooping; 3 = lethargic, fur ragged, eyes drooping, and breathing altered; and 4 = very sick appearance, ptosis, ragged fur, curled body posture, difficulty breathing, and general nonresponsiveness). This procedure was found to
provide >90% agreement between raters blind to the treatment mice received.
To obtain a further index of sickness behavior, an additional
experiment, involving naïve CD-1 mice, assessed the effects of
TNF- on consumption of a palatable solution. Mice that received ad libitum food were offered free access to chocolate milk
(Sealtest; Ault Foods, Etobicoke, Ontario, Canada; 1% partly skimmed)
for 1 hr each day during the light phase (commencing at 10 A.M.). Bottles were weighed at the beginning and end of the hour to determine total consumption (weights were converted to volume). After the establishment of a steady rate of drinking (3 consecutive days during
which consumption varied by <10%), mice received an acute intraperitoneal injection of either TNF- (1.0, 2.0, or 4.0 µg) or
saline and were then returned to their home cages. Two weeks later,
mice of each group (n = 10 per group) were subdivided
and treated with either saline or the lowest dose (1.0 µg) of
TNF-. Commencing 1 hr later, corresponding to the time of the
neurochemical determinations in the preceding study, chocolate milk was
presented to the mice individually, and consumption was recorded over a 1 hr period.
Brain dissection. Frozen brains were placed on a stainless
steel dissecting block with slots (spaced ~100 µm apart) that
served as guides for razor blades, which were used to provide a series of coronal brain sections. The dissection of the brain was conducted in
a cold chamber, with the brain resting on a stage containing dry ice.
Brain sections were mounted on glass slides and placed on a Petri dish
filled with powdered dry ice, which served as a cold stage. Using the
mouse brain atlas of Franklin and Paxinos (1997), brain nuclei were
removed by micropunch using hollow 16 or 20 gauge needles with a
beveled tip. Tissue was taken bilaterally from the paraventricular
nucleus of the hypothalamus (PVN), locus coeruleus, dorsal hippocampus,
central amygdala, and medial prefrontal cortex and then stored at
80°C until processed using HPLC.
HPLC procedure for analysis of brain amine and metabolite
levels. Levels of dopamine (DA), NE, and 5-HT and their respective metabolites 3-methoxy-4-hydroxyphenylglycol (MHPG),
3,4-dihydroxyphenylacetic acid (DOPAC), and 5-hydroxyindole acetic acid
(5-HIAA) were determined by HPLC using a modification of the
method of Seegal et al. (1986). Tissue punches were sonicated in a
homogenizing solution, which comprised 14.17 gm of monochloroacetic
acid, 0.0186 gm of EDTA, 5.0 ml of methanol and 500 ml of
H2O. After centrifugation, the supernatants were used for
the HPLC analysis. Using a Waters Associates (Milford, MA) M-6000 pump,
guard column, radial compression column (5m, C18 reverse phase, 8 mm × 10 cm), and three cell coulometric electrochemical detector
(ESA model 5100A), 20 µl of the supernatant was passed through the
system at a flow rate of 1.5 ml/min (1400-1600 psi). The mobile phase
used for the separation was a modification of that used by Chiueh et
al. (1983); each liter consisted of 1.3 gm of heptane sulfonic acid,
0.1 gm of disodium EDTA, 6.5 ml of triethylamine, and 35 ml of
acetonitrile. The mobile phase was then filtered (0.22 mm filter paper)
and degassed, after which the pH was adjusted to 2.5 with phosphoric
acid. The area and height of the peaks was determined using a
Hewlett-Packard (Palo Alto, CA) integrator. The protein content of
each sample was determined using bicinchoninic acid with a protein
analysis kit (Pierce Scientific, Brockville, Ontario, Canada) and a
spectrophotometer (PC800 colorimeter; Brinkmann Instruments, Westbury,
NY). The lower limit of detection for the monoamines and metabolites
was ~5.0 pg.
Plasma corticosterone assay. Plasma corticosterone levels
were determined (in duplicate) using a commercially available
radioimmunoassay (RIA) kit (ICN Biomedicals, Costa Mesa, CA). To avoid
interassay variability, all samples within an experiment were assayed
within a single run. The intra-assay variability was <6%.
Statistical analyses. Consumption of chocolate milk was
analyzed in two stages. Specifically, the initial response to TNF-, as a function of the dosage (saline, 1.0, 2.0, or 4.0 µg) was evaluated as a repeated measures ANOVA comparing baseline consumption (the data from the 3 d before reexposure were averaged to provide the baseline score) and that observed 1 hr after TNF-. The second phase assessed the effect of reexposure to TNF-. To this end, the
consumption before, at reexposure, and 24 hr after reexposure was
analyzed as a repeated measures ANOVA as a function of the initial and
reexposure TNF- treatment that mice received.
The sickness behaviors animals displayed (overall appearance,
locomotion, and social interaction) and the plasma corticosterone concentrations were analyzed by single-factor ANOVAs, followed by
Newman-Keuls multiple comparisons ( = 0.05) of the significant main effects. Owing to the multiplicity of analyses required for the
neurochemical alterations across brain regions, multivariate ANOVA
(MANOVA) was called for. However, given the number of brain regions and
transmitters and metabolites, relative to the number of mice tested, a
single MANOVA was not possible. Accordingly, independent MANOVAs were
conducted for those regions in which NE, DA, 5-HT, and their
metabolites were assessed. Where significant effects were detected,
univariate analyses were conducted, followed by Newman-Keuls multiple
comparisons of the means of significant effects. Because only NE and
MHPG were analyzed within the locus coeruleus, these data were analyzed
by ANOVA, followed by multiple comparisons of the treatment means. It
might be noted, as well, that separate analyses were also performed
where (1) the data of the four groups that received TNF- on two
occasions (at different reexposure intervals) were compared by
single-factor ANOVAs and (2) the groups that received either saline on
two occasions or only a single TNF- injection (either on the initial
injection day or the reexposure day) were compared by ANOVA. Dunnett's
tests were used to compare the data for animals reexposed to TNF-
with those that received saline or that received only a single TNF- treatment. Because these analyses yielded the same effects as did the
simpler univariate analyses that included all of the groups, only the
results of the latter analyses are presented.
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RESULTS |
Behavioral changes associated with TNF- exposure
Consumption of chocolate milk varied as a function of the
interaction between TNF- treatment and the time of testing
(F(3,76) = 17.96; p < 0.01). As seen in Table 1 and confirmed
by Newman-Keuls multiple comparisons, at baseline the groups displayed
comparable levels of chocolate milk consumption. However, a
dose-dependent reduction of consumption was evident 1 hr after TNF-
administration, such that the 2.0 and 4.0 µg groups displayed lower
levels of consumption than did saline-treated animals, as well as
consumption levels below that observed at baseline.
As seen in Figure 1, relative to mice
that received only a single administration of TNF- (1.0 µg),
reexposure to the cytokine induced much greater variations with respect
to the consumption of chocolate milk. The ANOVA indeed revealed a
significant initial TNF- × reexposure TNF- treatment
interaction (F(3,72) = 2.97; p < 0.05). The multiple comparisons indicated that in
the absence of previous TNF- exposure, the 1.0 µg treatment
provoked a nonsignificant decline of chocolate milk consumption
(0.10 < p < 0.05). However, among mice that had
received TNF- treatment 2 weeks earlier, irrespective of the dosage,
reexposure to TNF- (1.0 µg) markedly reduced chocolate milk
consumption. Clearly, TNF- exerted a sensitization effect, such that
the behavioral consequences of the cytokine were greatly increased with
reexposure 2 weeks after initial treatment. Within 24 hr of TNF-
administration, consumption scores had returned to baseline values
irrespective of the treatment mice received.
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Figure 1.
Mean ± SEM consumption of chocolate milk
among mice that received either saline or TNF- (1.0, 2.0, or 4.0 µg) followed 2 weeks later by reexposure to either saline or the 1.0 µg dose of the cytokine. The consumption of chocolate milk after
first exposure to TNF- in these same animals is shown in Table 1.
*p < 0.05 relative to saline-treated mice;
§p < 0.05 relative to mice that
received acute TNF- injection.
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The general sickness profile of the mice was also altered after
reexposure to the cytokine, and this effect was also dependent on the
time between the initial and reexposure treatments (Table 2). In particular, the overall
appearance, locomotor activity, and social interaction varied as a
function of the time between TNF- treatments
(F(6,38) = 21.64, 10.57, and 6.76, respectively; p < 0.01). The Newman-Keuls multiple
comparisons confirmed that a single administration of the cytokine did
not influence the three indices of illness. Likewise, a second
injection of the cytokine 1 or 7 d after initial administration of
TNF- had little effect on these behavioral indices. However, those
animals that received the second injection of the cytokine 14 or
28 d after the initial treatment displayed greater illness,
reduced motor activity, and diminished social exploration relative to
mice that received only a single TNF- treatment.
Corticosterone
Levels of plasma corticosterone, shown in Figure
2, were significantly influenced by
TNF- (F(6,118) = 22.60;
p < 0.01). The multiple comparisons indicated that
acute administration of 1.0 µg of the cytokine increased plasma
corticosterone levels appreciably, whereas a 4.0 µg dose administered
2 weeks earlier was without effect. As in the case of the behavioral
changes, the effects of the reexposure treatment varied as a function
of the interval between initial TNF- administration and subsequent
reexposure to the cytokine. Specifically, when the second
administration occurred 1 d after the initial treatment, levels of
corticosterone were significantly reduced relative to that seen after
acute TNF- treatment. As the interval between the treatments was
lengthened, the effects of the reexposure became progressively greater;
at 7 and 14 d after initial treatment, reexposure to the cytokine yielded corticosterone levels comparable with that of acutely treated
mice, whereas at 28 d TNF- reexposure provoked corticosterone levels significantly greater than those seen after a single TNF- injection.
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Figure 2.
Plasma corticosterone levels (mean ± SEM)
among mice exposed to various TNF- regimens. All mice received two
intraperitoneal injections; the three groups to the left
(solid bars) received saline only, saline followed 2 weeks later by the low dose of TNF- (1.0 µg), or a high dose of
TNF- (4.0 µg) followed 2 weeks later by saline treatment. The four
groups on the right (hatched bars)
received two injections of TNF-: an initial 4.0 µg dose followed
by a second 1.0 µg dose 1, 7, 14, or 28 d later.
*p < 0.05 relative to saline treated mice;
§p < 0.05 relative to mice that
received acute TNF- injection.
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Monoamine variations
In general, TNF- influenced central monoamine activity in a
region-specific manner. It appeared, as well, that at least some of the
effects of the cytokine were subject to a sensitization effect, which
was dependent on the time between the two TNF- treatments. The
MANOVAs indicated that neurochemical and metabolite levels within the
PVN, hippocampus, prefrontal cortex (PFC), and central amygdala varied
as a function of the interaction between the neurochemical substrate
and the treatment mice received: Pillais = 0.55, F(30,515) = 1.75; p < 0.01; Pillais = 0.31, F(18,306) = 1.91; p = 0.014; Pillais = 0.60, F(30,515) = 2.35; p < 0.01; Pillais = 0.67, F(30,515) = 2.36; p < 0.01, respectively.
Univariate analyses revealed that within the PVN, MHPG levels varied as
a function of the treatment mice received
(F(6,126) = 2.87; p = 0.01). Relative to saline-treated animals, a single injection of
TNF- (1.0 µg) increased the accumulation of MHPG. Among mice
reexposed to TNF- 1 or 7 d after the initial treatment the
increase was less marked, whereas at the 14 and 28 d intervals the
MHPG increase was somewhat greater, significantly exceeding that of
saline-treated mice. However, in neither case did the MHPG level exceed
that of mice that received only a single TNF- treatment. Unlike the
MHPG accumulation, the levels of NE did not differ dramatically across
groups, and none of the TNF- treatments yielded NE levels that
differed from those of saline-treated mice (Fig.
3). A separate ANOVA was conducted of the
MHPG/NE ratio within the PVN to ascertain whether the reexposure
treatment influenced NE turnover using this particular index. This
analysis yielded a significant effect of the treatment
(F(6,123) = 3.16; p < 0.01), and multiple comparisons confirmed that relative to
saline-treated mice (MHPG/NE ratio, 0.17 ± 0.01) acute
administration of TNF- significantly enhanced NE turnover (MHPG/NE
ratio, 0.30 ± 0.04). Interestingly, among mice reexposed to the
cytokine after a 1 d interval the NE turnover was reduced relative
to that seen after acute TNF- treatment (MHPG/NE ratio, 0.21 ± 0.02), whereas reexposure to the cytokine after 28 d resulted in
an elevation of the amine turnover (MHPG/NE ratio, 0.38 ± 0.06)
relative to saline-treated mice or mice that were reexposed to the
cytokine after a 1 d interval. At the 28 d reexposure period
the increase relative to acutely treated mice approached, but did not
quite reach statistical significance (p < 0.07), whereas at the 7 and 14 d reexposure intervals the turnover
of NE was at an intermediate level. In contrast to the variations of NE
turnover, within the PVN neither DOPAC, DA, 5-HIAA, nor 5-HT varied
among the treatment groups.
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Figure 3.
Mean ± SEM concentrations of NE
(top) and MHPG (bottom) within the PVN as
a function of TNF- treatment. The three groups on the
left (solid bars) received saline on two
occasions, saline followed 2 weeks later by the low dose of TNF-
(1.0 µg), or a high dose of TNF- (4.0 µg) followed 2 weeks later
by saline. The four groups on the right (hatched
bars) received an initial 4.0 µg dose of TNF- followed by
a second 1.0 µg dose 1, 7, 14, or 28 d later. The protein
(mean ± SEM) concentrations of the PVN equaled 7.65 ± 0.24 µg. *p < 0.05 relative to saline-treated
mice.
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Within the locus coeruleus the accumulation of MHPG varied as a
function of the treatment condition
(F(6,114) = 3.35; p < 0.01). The multiple comparisons indicated that a single injection of
TNF- (1.0 µg) increased MHPG accumulation relative to
saline-treated mice. Reexposure to TNF- was likewise associated with
an elevation of the metabolite concentration, particularly at the 1 and
28 d intervals. In no instance, however, was the rise greater than that observed in mice that received only a single injection of the
cytokine (Fig. 4). Indeed, this
conclusion was confirmed by a separate analysis of the MHPG/NE ratio.
In addition to the altered turnover, concentrations of NE within the
locus coeruleus were altered by the TNF- treatments
(F(6,118) = 3.07; p < 0.01). The multiple comparisons indicated that levels of NE were
increased by acute administration of the cytokine. Likewise, after
reexposure to TNF- at 7 and 28 d after the initial treatment,
the levels of NE were elevated relative to that of saline-treated
animals, but a comparable rise was not evident at the 1 d
reexposure interval. In fact, at this time NE levels were lower than
among mice acutely treated with the cytokine. In effect, these data
suggest that after reexposure to TNF- 28 d after initial
treatment the increased use of NE was met with a compensatory increase
of synthesis, leading to elevated amine concentrations. However, at the
1 d reexposure interval a compensatory increase of synthesis was
not provoked, hence precluding elevated concentrations of NE.
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Figure 4.
Mean ± SEM concentrations of NE
(top) and MHPG (bottom) within the locus
coeruleus as a function of TNF- treatment. The three groups on the
left (solid bars) received saline on two
occasions, saline followed 2 weeks later by the low dose of TNF-
(1.0 µg), or a high dose of TNF- (4.0 µg) followed 2 weeks later
by saline. The four groups on the right (hatched
bars) received an initial 4.0 µg dose of TNF- followed by
a second 1.0 µg dose 1, 7, 14, or 28 d later. The protein
(mean ± SEM) concentrations of the locus coeruleus were
19.62 ± 0.77 µg. *p < 0.05 relative to
saline-treated mice; §p < 0.05 relative to
mice that received acute TNF injection.
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Within the hippocampus the levels of NE and 5-HT were unaffected by
treatment with TNF-, whereas concentrations of the metabolites MHPG
and 5-HIAA were significantly influenced by the cytokine (F(6,116) = 2.51 and 2.18;
p < 0.05, respectively). Once again, MHPG was
increased by the acute administration of TNF-, as well as by
reexposure to the cytokine, at least at the 1 and 28 d intervals between injections. However, there was no indication of a sensitization effect, because the extent of the increase was comparable with that
observed after a single administration of TNF- (Table
3). Likewise, in the case of 5-HIAA it
was found that acute treatment as well as reexposure to TNF-
enhanced the metabolite accumulation; once again, however, there was no
indication of a sensitization effect being apparent.
The amine variations within the PFC could be dissociated from those
seen in the PVN, hippocampus, and locus coeruleus. Within the PFC, the
levels of MHPG varied as a function of the TNF- treatment
(F(6,127) = 10.60; p < 0.01). The multiple comparisons confirmed that relative to
saline-treated mice, MHPG levels were elevated after acute
administration of TNF-. In mice that were reexposed to the cytokine
1 d after the initial treatment, a further elevation of MHPG
accumulation was evident, such that the metabolite concentrations were
double that of mice that had received the acute treatment.
Interestingly, if the TNF- was administered 7, 14, or 28 d
after the initial treatment, then metabolite levels exceeded those of
saline-treated mice but were comparable to those seen after acute
cytokine treatment (Fig. 5). The levels
of NE were likewise found to vary as a function of the cytokine
administration (F(6,127) = 3.84;
p < 0.01). Acute TNF- did not affect the levels of
the transmitter; however, in mice reexposed to the cytokine at the
1 d interval the levels of NE exceeded those of saline animals or
those of mice that had received acute TNF- treatment. At longer
reexposure intervals the NE concentrations were indistinguishable from
those of acutely treated mice (data not shown). Unlike NE and MHPG, the
levels of DA and DOPAC were not significantly influenced by the
cytokine treatments. However, it is noteworthy that, although not
significantly elevated, DOPAC accumulation was increased by 65% in
animals reexposed to the cytokine 1 d after the initial treatment,
whereas at longer intervals the increase was less pronounced (20-40%).
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Figure 5.
Mean ± SEM concentrations of MHPG
(top) and 5-HIAA (bottom) within the PFC
as a function of the TNF- treatment mice received. The three groups
on the left (solid bars) received saline
on two occasions, saline followed 2 weeks later by the low dose of
TNF- (1.0 µg), or a high dose of TNF- (4.0 µg) followed 2 weeks later by saline. The four groups on the right
(hatched bars) received an initial 4.0 µg dose of
TNF- followed by a second 1.0 µg dose 1, 7, 14, or 28 d
later. The protein (mean ± SEM) concentration of the PFC equaled
286.70 ± 8.72 µg. *p < 0.05 relative to
saline-treated mice; §p < 0.05 relative to mice that received acute TNF- injection.
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Although TNF- administration affected 5-HT activity within the PFC,
the profile apparent at the various reexposure intervals was clearly
distinguishable from that observed with respect to NE activity.
Specifically, although the levels of 5-HT were not affected by the
cytokine, the accumulation of 5-HIAA varied significantly as a function
of the treatment mice received (F(6,126) = 5.41; p < 0.01). The multiple comparisons confirmed
that a single administration of the low dose of TNF- provoked a
marked elevation of 5-HIAA, whereas the 4.0 µg dose administered 2 weeks earlier was without effect. If mice were reexposed to TNF-
1 d after the initial treatment, then the levels of 5-HIAA were
not significantly different from those of saline-treated animals and
were lower than those of acutely treated mice. In contrast, with
TNF- reexposure 7, 14, or 28 d after the initial treatment,
levels of 5-HIAA within the PFC were significantly increased relative
to saline-treated mice and were comparable with those of mice that
received acute TNF- administration (Fig. 5). In effect, it appeared
that the initial cytokine treatment provoked a desensitization in
response to later TNF- administration, but this effect was only
apparent at the earliest retest period.
The NE variations associated with TNF- within the central amygdala
were, in several respects, reminiscent of the variations seen within
the PFC. Specifically, although the levels of NE did not vary
significantly, MHPG accumulation was markedly influenced by the
treatments (F(6,122) = 2.57;
p < 0.01). The multiple comparisons showed that acute
administration of the cytokine produced a relatively modest (40%),
nonsignificant elevation of MHPG (Fig.
6). However, a much greater rise (86%)
was seen in mice that received the 1.0 µg dose 1 d after the
initial TNF- treatment. In contrast, at longer reexposure intervals
the metabolite accumulation was not enhanced relative to that of
saline-treated mice. Thus, although TNF- provoked the sensitization
of amygdala NE activity in response to later challenge with the
cytokine, this effect was again restricted to the earliest time
point.
View larger version (39K):
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|
Figure 6.
Mean ± SEM concentrations of MHPG
(top) and 5-HIAA (bottom) within the
central amygdala as a function of the TNF- treatment. The three
groups on the left (solid bars) received
intraperitoneal administration of saline on two occasions, saline
followed 2 weeks later by the low dose of TNF- (1.0 µg), or a high
dose of TNF- (4.0 µg) followed 2 weeks later by saline. The four
groups on the right (hatched bars)
received an initial 4.0 µg dose of TNF- followed by a second 1.0 µg dose 1, 7, 14, or 28 d later. The protein (mean ± SEM)
concentrations of the central amygdala were 21.90 ± 0.51. *p < 0.05 relative to saline treated-mice;
§p < 0.05 relative to mice that received acute
TNF- injection.
|
|
In contrast to the variations of NE activity, the changes of 5-HT and
DA functioning within the central amygdala were markedly different from
those seen within the PFC. In the case of 5-HT levels, the TNF-
treatment was without effect, whereas 5-HIAA accumulation was
appreciably influenced by the cytokine
(F(6,122) = 3.46; p < 0.01). Among mice that were acutely treated with TNF- or mice that
received the cytokine 2 weeks earlier, the accumulation of 5-HIAA was
somewhat elevated, but in neither case was the increase a statistically
significant one. However, as seen in Figure 6, among mice that received
the cytokine on two occasions, the accumulation of 5-HIAA was
relatively marked at each of the reexposure intervals, with the
greatest accumulation being evident at the 7 d period.
Finally, DA levels within the central amygdala were unaffected by the
TNF- treatment, although there appeared to be somewhat of an
elevation, particularly at the 14 and 28 d reexposure periods. The
accumulation of DOPAC, however, varied significantly as a function of
the cytokine treatments (F(6,121) = 2.40;
p = 0.03). The multiple comparisons indicated that
acute TNF- did not significantly affect DOPAC accumulation, being
associated with only a 20% rise of the metabolite. However, in mice
that were reexposed to the cytokine the levels of DOPAC were reduced
relative to acutely treated mice (data not shown). This effect was
particularly pronounced at the longer reexposure intervals, and at the
14 d interval DOPAC accumulation was significantly lower than that
seen in saline-treated animals.
Behavioral effects of murine TNF-
Inasmuch as the preceding experiments involved human TNF-
(hTNF-), the possibility was considered that the outcomes observed reflected cross-species TNF- effects (e.g., time-dependent endotoxic reaction to hTNF-). Accordingly, an additional experiment was conducted to evaluate the effects of acute murine TNF- on sickness behaviors, as well as the effects of reexposure to this cytokine. Murine TNF- was obtained from R & D Systems and had a specific activity of 2.7 × 105 U/µg. Mice of five
groups (n = 10 per group) received two intraperitoneal injections 28 d apart; treatment comprised either two saline
injections, administration of saline followed 28 d later by murine
TNF- (mTNF-; 1.0 µg), or mTNF- (at doses of 0.5, 1.0, or 2.0 µg) followed 28 d later by the 1.0 µg dose of the cytokine.
Sickness behaviors (overall appearance, locomotion, and social
interaction) were determined and analyzed as described earlier.
The ANOVA confirmed that the mTNF- treatment markedly affected the
overall appearance of the mice (F(4,45) = 8.42; p < 0.01; locomotor activity,
F(4,45) = 5.68; p < 0.01;
and social interaction, F(4,45) = 7.72;
p < 0.01). As seen in Table
4 and confirmed by Newman-Keuls multiple
comparisons, the acute administration of mTNF- hardly influenced
behavior relative to saline-treated mice. However, this dosage of the
cytokine markedly influenced sickness behaviors among mice that had
previously received mTNF-. This was the case regardless of the
dosage mice previously received (i.e., even when mice had initially
received subthreshold doses of the cytokine). In each instance, the
reexposure treatment elicited marked illness profiles relative not only
to saline treated animals but also to those that had received acute
mTNF- administration. As well, the extent of the illness became
progressively more pronounced over the course of the 1 hr evaluation
session. In fact, by the end of the session ~50% of the animals
reexposed to mTNF- appeared moribund, whereas only 1 of 10 mice that
received acute mTNF- exhibited obvious illness.
| |
DISCUSSION |
Behavioral effects of TNF-
Commensurate with earlier reports (Bluthe et al., 1994; Kent et
al., 1996), TNF- dose-dependently elicited sickness behaviors, which
were subject to a time-dependent sensitization, as observed with other
pharmacological and stressor treatments (Antelman, 1988). Reexposure to
the cytokine either 1 or 7 d after initial treatment provoked few
signs of sickness. However, at longer reexposure intervals palatable
food consumption was greatly reduced, and mice displayed ptosis,
ruffled fur, curled body posture, immobility, and reduced social
exploration. This effect was not exclusive to mice that received human
TNF-, because a behavioral sensitization was also elicited by the
recombinant murine form of the cytokine.
Effects of hTNF- on plasma corticosterone
Elevated HPA functioning can be elicited by lipopolysaccharide
(LPS) (Rivier, 1993; Ericsson et al., 1994), systemic IL-1 (Dunn,
1988, 1990; Zalcman et al., 1994; Van Der Meer et al., 1996), and
TNF- (Bernardini et al., 1990). Conversely, central administration
of antibodies directed against TNF- reduced the ACTH response to LPS
(Turnbull and Rivier, 1998). Coupled with the finding that TNF-
elicits an anxiogenic effect (Connor et al., 1998), the increased
plasma corticosterone supports the contention that TNF- is
interpreted centrally as if it were a stressor. This is not to say that
processive (psychological) and systemic (metabolic) stressors involve
identical mechanisms. The HPA alterations elicited by processive
stressors may involve activation of limbic forebrain regions, whereas
systemic stressors (e.g., cytokines) stimulate brainstem nuclei, which
directly innervate the PVN (Herman and Cullinan, 1997).
Paralleling the behavioral changes, corticosterone alterations
associated with TNF- reexposure varied over time since the initial
treatment. After reexposure to the cytokine after 28 d, plasma
corticosterone levels exceeded those of acutely treated mice but were
reduced at a 1 d reexposure interval. In effect, the cytokine may
have either a sensitizing or desensitizing effect, depending on the
time of its readministration. Although the p55 receptor may play a
primary role in subserving the actions of TNF- in mice (Benigni et
al., 1996; Sipe et al., 1996), the p75 receptor may also contribute in
this respect (Ericcson et al., 1994; Declercq et al., 1998). However,
it appears unlikely that the time-dependent sensitization was related
to alterations of receptor sensitivities, because murine TNF-, which
stimulates both receptor subtypes, also promoted a time-dependent
sensitization of sickness and corticosterone levels (Hayley et al.,
1999). The finding that TNF- biphasically influences the response to
later cytokine treatment is consistent with reports of critical periods during which TNF- pretreatment has either sensitizing or
desensitizing effects (Wallach et al., 1988; Matsuura and Galanos,
1990). The source for such time-dependent actions is unclear but may
reflect interactions involving other endogenous cytokines, including
interferon- (IFN-) and IL-12 (Cauwels et al., 1995, 1996),
IFN- and TNF- (Bundschuh et al., 1997; Nansen et al., 1997), and
IFN- and IL-1 (Chung and Benveniste, 1990). An alternative
explanation for the sensitization comes from studies that showed that
viruses may sensitize neurons to some of the cytotoxic effects of
TNF- by inhibiting the production of an as yet unidentified,
endogenous protective factor, thereby increasing susceptibility to
subsequent challenges (Sipe et al., 1996).
In the context of potential central mechanisms mediating cytokine- and
stressor-elicited sensitization, an exciting mechanistic model was
offered involving the synthesis of hypothalamic regulatory peptides
(Tilders et al., 1993; Schmidt et al., 1995, 1996; Tilders and Schmidt,
1998). It was demonstrated that with the passage of time after IL-1
administration or stressor exposure a phenotypic change occurred within
CRH terminals of the median eminence, such that AVP coexpression was
increased. Thus, the augmented pituitary ACTH secretion elicited by
subsequent IL-1 or stressor challenge may reflect the synergistic
actions of these secretagogues (Bartanusz et al., 1993; Tilders et al.,
1993; Schmidt et al., 1996). Inasmuch as TNF- stimulates CRH and
ACTH activity, it remains possible that this cytokine, like IL-1,
engenders upregulation of AVP expression, hence promoting a
time-dependent sensitization. In the case of the IL-1 effects, the
phenotypic AVP and CRH coexpression was relatively long-lasting
and influenced the response to later cytokine or stressor challenges
(Schmidt et al., 1995; Tilders and Schmidt, 1998). Although some
sensitization effects observed in the present investigation were
clearly transient, notably the extrahypothalamic amine variations,
other effects, including the corticoid and NE alterations in the PVN,
were clearly long-lasting. Whether these effects were permanent or were
modifiable by other treatments remains to be determined.
Central neurotransmitter variations
Within 1 hr of its systemic administration, marked central
neurochemical alterations were induced by TNF-. It is not clear whether these actions were mediated directly (i.e., penetration into
the brain via passive or active transport) (Gutierrez et al.,
1993) or indirectly, through stimulation of afferent neural circuits
(e.g., vagal and/or spinal projections) (Dantzer et al., 1998; Maier
and Watkins, 1998) or enzymatic alterations at peripheral target sites,
such as the liver (Libert et al., 1991). Receptors for IL-1 have
been demonstrated on the nodose vagal ganglia, which sends projections
to several brain regions, notably the nucleus of the solitary tract (Ek
et al., 1998). As well, LPS and IL-1 induce c-fos
expression in this vagal complex (Gaykema et al., 1998; Goehler et al.,
1998). Interestingly, as in the case of IL-1, subdiaphragmatic
vagotomy abrogated the effects of peripheral administration of TNF-
on conditioned taste aversion, fever, and circulating corticosterone
levels (Goehler et al., 1995; Fleshner et al., 1998; Maier and Watkins,
1998), suggesting that TNF- also influences central processes by
stimulating vagal afferents. Regardless of the mechanism, it is
apparent that acute TNF- administration increased the accumulation
of the NE metabolite MHPG within the PVN. Because monoamines stimulate
CRH release from the median eminence (Fuller, 1992; Pacak et al., 1992,
1995; Dinan, 1996), it is possible that corticosterone elevations
induced by TNF- were secondary to the amine alterations. In addition to the hypothalamic amine variations, TNF- also influenced amine activity at several extrahypothalamic sites. Commensurate with in
vitro observations (Ignatowski et al., 1997), acute TNF-
increased NE use within the locus coeruleus and the dorsal hippocampus
and enhanced 5-HT activity in the PFC and hippocampus. Yet, in
vivo dialysis studies indicated that central TNF-
administration did not affect hippocampal 5-HT release (Pauli et al.,
1998), raising the possibility that tissue level changes do not
necessarily translate into alterations of amine release.
The central circuitry associated with cytokine treatment may involve
several pathways and sites of entry into brain, culminating in diffuse
neuronal activation (Brady et al., 1994; Rivest, 1995). Interestingly,
after cytokine challenge, c-fos mRNA expression may follow a biphasic
temporal course across brain regions (Rivest, 1995), likely reflecting
different diffusion routes or actions of the cytokines (Brady et al.,
1994; Gaillard, 1995). Inasmuch as amine activity in the present
investigation was only determined at a single time (1 hr) after TNF-
treatment, the fine temporal resolution possible using in
vivo dialysis could not be discerned (Westerink, 1995), and it is
possible that biphasic, region-specific amine variations were
associated with the treatment.
As observed with respect to CRH and AVP after IL-1 challenge
(Schmidt et al., 1995, 1996; Tilders and Schmidt, 1998), time-dependent sensitization of central monoamine activity was associated with TNF-
administration. However, several distinct temporal patterns of regional
monoamine activity were apparent after TNF- reexposure. In
particular, the profile of NE use within the PVN (reflected by MHPG
accumulation and the MHPG/NE ratio) paralleled the time-dependent corticosterone changes, being greater with reexposure 28 d after initial treatment than at the 1 d interval. In contrast, within the PFC and central amygdala, increased NE use was evident with reexposure to TNF- 1 d after the initial treatment but entirely absent at longer intervals. The early sensitization of amine activity coincided with the desensitization of plasma corticosterone seen after
reexposure to TNF-. Because the PFC may exert inhibitory control
over neuroendocrine actions of the PVN (Herman and Cullinan, 1997), it
is possible that the sensitization of PFC amine activity may involve
such an inhibitory neural circuit.
The mechanisms responsible for the region- and time-dependent
sensitization patterns is not immediately evident. However, functionally, it might be expected that cytokine treatments, by virtue
of their effects on central neurotransmitter functioning, may affect
behavioral outputs. Although the progressive rise of PVN NE activity
may be related to illness symptoms, the early sensitization (i.e., the
enhanced PFC and amygdala amine increases), appeared independent of
illness factors, because mice did not display obvious malaise at this
time. However, it is possible that other effects engendered by TNF-
(e.g., vigilance, arousal, and anxiety) (Connor et al., 1998) may be
related to the aminergic alterations. In this respect, consideration of
the time-dependent central actions of TNF- and IL-1 may be
relevant, particularly given their potential therapeutic use.
Finally, one further issue warrants some consideration. Specifically, a
mild ischemic episode or electrical stimulation of the brain causing
seizure (kindling) may protect against the damaging consequences
elicited by a later, more pronounced insult (Glazier et al., 1994;
Kelly and McIntyre, 1994; Barone et al., 1998). Such effects
may, among other things, be dependent on the timing of the two
incidents (Barone et al., 1998). Although cytokines may underlie these
neuroprotective effects (Tasaki et al., 1997; Nawashiro et al., 1997),
cytokines could also act in a neurodestructive manner (Buttini et al.,
1994; Saito et al., 1996; Rothwell et al., 1997). Although several
factors could account for cytokines acting in both manners (e.g.,
cytokine dosage and cofactors released from glial cells), it might be
considered that time-dependent sensitization or desensitzation
associated with challenges may contribute to the specific actions provoked.
| |
FOOTNOTES |
Received Jan. 21, 1999; revised April 8, 1999; accepted April 20, 1999.
This research was supported by Grant MT-13124 from the Medical Research
Council of Canada. The assistance of Jerzy Kulczycki is greatly appreciated.
Correspondence should be addressed to Hymie Anisman, Life Science
Research Building, Carleton University, Ottawa, Ontario K1S 5B6, Canada.
| |
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