Brain, Behavior, and Immunity 15, 371–387 (2001)

doi:10.1006/brbi.2001.0643, available online at http://www.idealibrary.com on

Behavioral Effects of Cytokines

Susan J. Larson* and Adrian J. Dunn†

*Department of Psychology, Concordia College, Moorhead, Minnesota 56562; and †Department
of Pharmacology and Therapeutics, Louisiana State University Health Sciences Center,
Shreveport, Louisiana 71130

INTRODUCTION
In a 1988 paper titled ‘‘Biological basis of the behavior of sick animals’’ Benjamin
Hart reviewed the changes in behavior observed in organisms experiencing immune
system activation caused by infection or other pathologies. Such changes include
decreased activity, decreased food intake, increased sleep, and reduced grooming.
Prior to this, these changes had been considered to reflect a nonspecific malaise.
However, Hart argued that ‘‘the behavior of a sick individual is not a maladaptive
and undesirable effect of illness but rather a highly organized strategy that is at times
critical to the survival of the individual if it were living in the wild state’’ (Hart,
1988). There has been a long-standing debate on the beneficial effects of fever, which
can impair the replication of many pathogens (e.g., influenza virus) while simulta-
neously enhancing immune activity. But Hart’s concept extended biological signifi-
cance to the behavior, because the behavioral response seemingly protected the sick
animal. This insight became a turning point. Subsequently, there have been substan-
tial efforts by many researchers to characterize the effects of illness and inflammation
on behavior and to understand how the immune system signals the central nervous
system to induce these behavioral changes. Kent, Bluthé, Kelley, and Dantzer (1992)
speculated on the generality of the responses to infection and injury and named it
‘‘sickness behavior.’’ The behaviors that researchers have focused on include mobil-
ity, feeding, exploration, social interaction, sexual behavior, cognitive function, and
sleep. In addition to these behaviors, anhedonia, or lack of interest in pleasurable
stimuli, has also been studied. Such changes are frequently associated with infection
or injury and related inflammation. They are considered nonspecific in the sense that
similar symptoms occur in association with immune activation, resulting from a vari-
ety of different causes observed across species.
Much recent research has attempted to understand how the immune system signals
the central nervous system to produce these behavioral changes. Currently the pre-
dominant hypothesis is that cytokines are mediators of these effects. Cytokines were
discovered as messengers among the various components of the immune system, but
with the revelation of the molecular identity of cytokines, it soon became apparent
that they were essentially hormones secreted by immune cells and that they had physi-
ological effects on nonimmune tissues. It has been known for some considerable time
that endotoxin (also known as lipopolysaccharide (LPS), the active component of
the cell walls of gram-negative bacteria) decreases feeding (McCarthy, Kluger, &
Vander, 1984). When it was learned that endotoxin was a potent stimulator of the
synthesis and release of cytokines, such as interleukin-1 (IL-1), interleukin-6 (IL-6),
and tumor necrosis factor α (TNF), it was natural to test their effects on behavior.
McCarthy, Kluger, and Vander (1985) subsequently showed that rats injected periph-
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All rights reserved.
372 LARSON AND DUNN

erally with IL-1 exhibited responses in fever and food intake similar to those follow-
ing LPS and suggested that IL-1 might be responsible for the anorexia associated
with infections. Numerous subsequent studies showed that IL-1 administration had
potent behavioral effects, inducing most if not all of the classic sickness behaviors.
Thus, it has been speculated that many of the behavioral changes associated with
infection and inflammation are induced by IL-1 and possibly the other proinflamma-
tory cytokines, such as IL-6 and TNF. The hypothesis that cytokines are the major
mediators of sickness behavior is a very attractive one and IL-1 has proven to be the
most potent agent tested. Administration of IL-6 or TNF has rarely been shown to
produce striking behavioral responses (e.g., Swiergiel, Smagin, Johnson, & Dunn,
1997b), although there is indirect evidence of their involvement in sickness behaviors
(e.g., Bluthé, Pawlowski, Suarez, Parnet, Pittman, Kelley, & Dantzer, 1994; Bluthé,
Michaud, Poli, Bernay, Parnet, & Dantzer, 1998; Bluthé, Michaud, Poli, & Dantzer,
2000). The present literature does not support the hypothesis that IL-1 can account
for all sickness behavior and there is speculation regarding roles for other as yet
undiscovered cytokines or other mediators.
An important recent literature is concerned with the mechanism by which IL-1 and
potentially other cytokines effect their behavioral responses. Direct administration of
IL-1 into the brain induces some sickness behaviors, and central administration typi-
cally requires smaller doses than peripheral administration to produce behavioral ef-
fects (e.g., Bluthé, Dantzer, & Kelley, 1997). This suggests the possibility that cyto-
kines penetrate the blood–brain barrier, which does not normally permit the transport
of such large molecules. Indeed, specific transporters capable of taking up a number
of different cytokines have been identified (Banks, Kastin, & Broadwell, 1995),
but it is not clear whether these transporters have the capacity to accumulate suffi-
cient cytokines in the appropriate locations to account for the behavioral responses.
Cytokines may exert some of their actions by entering the circumventricular organs
(CVOs) which lack a blood–brain barrier and inducing secondary mediators that can
diffuse through the rest of the brain (Katsuura, Arimura, Koves, & Gottschall, 1990).
Alternatively, cytokines may act on brain endothelial cells activating cyclooxygenase,
enabling the synthesis of prostaglandins, which could readily cross the endothelial
barrier to penetrate the brain parenchyma (Cao, Matsumura, Yamagata, & Watanabe,
1996; 1997) and be responsible for the behavioral effects induced. A substantial liter-
ature has implicated a vagally mediated pathway, in which peripheral IL-1 may acti-
vate vagal afferents to bypass the blood–brain barrier. An extension of this proposes
that the vagal activation ultimately results in IL-1 production in the brain, which in
turn elicits the behavioral responses (reviewed in Dantzer, Bluthé, Aubert, Goodall,
Bret-Dibat, Kent, Goujon, Layé, Parnet, & Kelley, 1996; Dantzer, 2001). Many of
these possible mechanisms were recently reviewed and discussed in an article by
Dantzer (2001) and thus will not be discussed further here. The remainder of this
paper will instead summarize the effects of infection and inflammation, as well as
cytokines, on the following behaviors: ingestive behavior, exploratory behavior, sex-
ual behavior, learning and cognitive functioning, sleep, and anhedonia.
INGESTIVE BEHAVIOR
In general, infection and inflammation decrease food intake. For instance, in an
animal model of colitis, inflammation of the bowel significantly decreased food intake
(McHugh, Weingarten, Keenan, Wallace, & Collins, 1993). Certainly, it could be
 CYTOKINES AND BEHAVIOR 373

argued that this effect was dependent upon aggravation of the bowel and gastrointesti-
nal discomfort. However, anorexia is a common symptom of infection and inflamma-
tion when induced in numerous other ways. Much studied, for example, is the de-
crease in food intake associated with tumor growth (e.g., Bernstein, Treneer, &
Goehler, 1985; Opara, Laviano, Meguid, & Yang, 1995). Additionally, short-term
illnesses, such as those induced by an injection of LPS, decrease food intake in vari-
ous species, including rats and mice (e.g., McCarthy et al., 1984; Swiergiel,
Smagin, & Dunn, 1997a; and many others). This effect is dose dependent and lasts
for a few hours before animals return to regular levels of food intake. Similar effects
are also seen after infection of mice with influenza virus (Swiergiel et al., 1997a). The
effect of LPS on food intake can be dissociated from its effect on body temperature in
that LPS-induced anorexia precedes LPS-induced changes in body temperature (Lar-
son, Collins, & Weingarten, 1996). Importantly, this demonstrated that anorexia asso-
ciated with sickness is not simply a byproduct of increased body temperature.
Most of the work investigating mediators of sickness-induced anorexia has focused
on proinflammatory cytokines, specifically IL-1β, TNF, and IL-6. Research has com-
pellingly demonstrated that IL-1β decreases food intake in a dose-dependent manner
(e.g., Kent, Rodriguez, Kelley, & Dantzer, 1994; Swiergiel et al., 1997a; and many
others). This effect is seen when this cytokine is administered both centrally and
peripherally. IL-1β predominantly affects meal size and not meal frequency (Plata-
Salamán, 1994), a finding similar to that seen with LPS (Larson et al., 1996). There
is some, albeit more limited, evidence suggesting a role for TNF in inducing anorexia
(Plata-Salamán, Oomura, & Kai, 1988) and a synergistic effect of TNF and IL-1 has
been suggested (van der Meer, Sweep, Pesman, Borm, & Hermus, 1995; Yang, Ko-
seki, Meguid, Gleason, & Debonis, 1994). Clear-cut findings of IL-6 effects on food
intake have been elusive (Plata-Salamán et al., 1988; Swiergiel et al., 1997b).
The effects of cytokines and illness-inducing agents on food-maintained behavior
have also been studied. Using an operant paradigm, animals are required to engage
in some response (e.g., lever pressing) in order to obtain food. After baseline behavior
has been established animals are administered an illness-inducing agent (e.g., LPS:
Bret-Dibat, Bluthé, Kent, Kelley, & Dantzer, 1995) or cytokine (e.g., IL-1β: Larson,
Romanoff, Dunn, & Glowa, 2001) and it has been shown that these agents decrease
the operant response maintained by food. Again, this effect has been shown to be
dose dependent (Larson et al., 2001) and lasts a few hours before behavior returns
to baseline levels (Bret-Dibat et al., 1995).
In addition to decreasing overall food intake, infection and cytokines decrease
water intake (Chance & Fischer, 1991), although this effect is less consistent than
effects on food intake. Indeed, in some circumstances, illness-inducing agents and
cytokines affect food intake without affecting fluid intake (e.g., Plata-Salamán et al.,
1988). This is important because it demonstrates that the anorectic effect of illness-
inducing agents is not a byproduct of decreased fluid intake. Additionally, the dissoci-
ation of food and water intake demonstrates that animals are capable of performing
some consummatory behavior during testing.
Proinflammatory cytokines and sickness also decrease the intake of other caloric
substances, such as sweetened condensed milk (Swiergiel et al., 1997a,b) and choco-
late milk (Anisman & Merali, 1999). When a solution is flavored but noncaloric
(e.g., saccharin), LPS also decreases its consumption (Yirmiya, 1996). Because these
substances (sweetened milk, chocolate milk, saccharin) vary in calorie content,
374 LARSON AND DUNN

protein/fat/carbohydrate ratios, and palatability, and they differ from traditional ro-
dent chow on these dimensions, there may be qualitative differences between de-
creased food intake and decreased intake of these other solutions. Regardless of these
possibilities, the data demonstrate general changes in ingestive behavior in organisms
experiencing infection and inflammation, as well as after administration of IL-1.
A common and related effect of infection and cytokines is a decrease in body
weight (e.g., McCarthy et al., 1986; Swiergiel et al., 1997a). Many studies that have
not directly measured food intake have demonstrated decreased body weight associ-
ated with illness and cytokine treatment (e.g., Bluthé, Dantzer, & Kelley, 1992) and
it is thought that these weight changes reflect decreased food intake. However,
changes in body weight due to infection and inflammation may also reflect altered
metabolic activity.
EXPLORATORY BEHAVIOR
One aspect of the behavior of sick organisms often noted is decreased activity.
Frequently, this is measured in an open field in which animals are placed in an open
chamber, divided into sections by grid lines on the floor. Behaviors such as rearing
and crossing from one section to another are recorded. Infections and inflammation
have been shown to decrease open field activity and this effect is mediated by proin-
flammatory cytokines such as IL-1β (Yirmiya, Avitsur, Donchin, & Cohen, 1995;
Swiergiel, Burunda, Patterson, & Dunn, 1999). Changes in open field activity may
be due to a general reduction in motor activity or to a specific effect on exploratory
behavior. Because the open field test does not explicitly assess exploratory behavior,
various other procedures have been employed to evaluate the effects of illness on
exploration. Two often studied paradigms include social exploration and the explora-
tion of novel environments. With both paradigms, it has been reliably demonstrated
that illness-inducing agents and cytokines disrupt exploratory behavior.
Exploration of a Novel Environment
Several investigations of exploration of a novel environment have been conducted
by Dunn and colleagues using a multicompartment chamber (MCC). The chamber
is divided into nine compartments, each of which has a round hole in the floor. A
loosely coiled ball of steel wire is fixed as a stimulus in each hole below floor level.
As a dependent measure, activity in the MCC is recorded by counting passage be-
tween the compartments and investigations of the holes and novel stimuli (Arnsten &
Segal, 1979). Using this paradigm, it has been shown that LPS, IL-1α, and IL-1β
decreased exploration of the novel environment whether administered icv (Spadaro &
Dunn, 1990) or peripherally (Dunn, Antoon, & Chapman, 1991; Dunn, Chapman, &
Antoon, 1992). However, the effects noted were dependent upon specific measures
of exploration. For instance, IL-1α or IL-1β decreased investigation of the novel
stimuli, as shown by decreased stimulus contact time. The same doses of IL-1 did
not decrease compartment entries, demonstrating that not all aspects of exploration
are affected similarly by cytokines (Spadaro & Dunn, 1990).
Social Exploration
The social exploration paradigm has been most extensively used by Dantzer and
colleagues. In these investigations an adult male, typically a rat or mouse, is exposed
to a juvenile conspecific for a brief period of time, during which social exploration
 CYTOKINES AND BEHAVIOR 375

such as anogenital sniffing, close following, and head and neck grooming are re-
corded. These investigators find that social exploration is disrupted by both sickness-
inducing agents, such as LPS (e.g., Bluthé et al., 1992), and IL-1β (e.g., Bluthé,
Michaud, Poli, Bernay, Parnet, & Dantzer, 1998). The effects are both time and dose
dependent. In general, the effects last 4 to 6 h, and social exploration is more pro-
foundly affected when larger doses of the cytokine or illness-inducing agent are used
(for a review, see Dantzer et al., 1996). Similar effects have been seen with TNF
(Bluthé, Dantzer, & Kelley, 1991; Bluthé et al., 1994) but not IL-6 (Lenczowski,
Bluthé, Roth, Rees, Rushforth, Van Dam, Tilders, Rothwell, & Luheshi, 1999). Be-
cause of the robustness of the findings with IL-1, Dantzer and colleagues have used
this paradigm to investigate other aspects of sickness behavior. For instance, using
social exploration as a dependent measure, they have investigated the role of the
vagus nerve in signaling the brain to produce sickness behaviors (for more informa-
tion on these studies, see Dantzer et al., 1996).
As can be seen from the studies outlined above, infection and inflammation de-
crease activity as measured by the open field and also decrease exploratory behavior.
While the two exploratory behavior paradigms described assess different aspects of
behavior (social exploration versus exploration of novel stimuli), the data provide
converging evidence that exploration is reduced by infection and cytokines. It is
important to note, however, that not all cytokines produce decreased activity, and
there is evidence that IL-2 and IL-6 may increase locomotor activity in mice tested
in the open field paradigm (Zalcman, Murray, Dyck, Greenberg, & Nance, 1998).
LEARNING AND COGNITIVE FUNCTION
Impairments in cognitive functioning due to illness have been noted in human
populations. Subsequent to these reports, it has been shown that infection and in-
flammation impair learning and cognitive functioning, in particular spatial and con-
textual learning, in nonhuman animals.
To assess the effects of illness on spatial learning, a Morris water maze forced
swim task has been used. In this task, animals are placed in a pool of opaque water
that requires them to swim until they reach a buried platform, at which point they
can obtain relief from swimming. Over repeated trials, animals improve their ability
to find the buried platform and do so by making use of spatial cues. It has been
demonstrated that infection and proinflammatory cytokines impair the expression of
spatial learning in the Morris water maze without affecting initial discovery of the
platform. For instance, Legionella pneumophila, which has no immediate effects on
spatial navigation, impairs the ability of mice to navigate the Morris water maze on
tests following L. pneumophila exposure (Gibertini, Newton, Friedman, & Klein,
1995). Similar findings have been observed in animals administered IL-1β (Gibertini,
1996; Oitzl, van Oers, Schöbitz, & de Kloet, 1993), but not IL-6 (Oitzl et al., 1993).
Clearly, illness and cytokines impaired spatial learning, perhaps by disrupting mem-
ory formation. It has been argued further that this disruption of spatial learning occurs
only when memory formation is hippocampus dependent (Gibertini, 1996).
Maier, Watkins, and colleagues have also demonstrated that infection and cyto-
kines impair hippocampus-dependent learning using a contextual fear paradigm in
which an animal is exposed to a novel environment paired with an aversive stimulus,
typically foot shock. Subsequent to initial exposure, animals are given the opportunity
to enter the shock-associated environment. With successful contextual fear condition-
376 LARSON AND DUNN

ing, animals are slower and less likely to enter the shock-associated environment
when compared to controls. Fear conditioning can also be achieved by using an audi-
tory stimulus to signal an oncoming shock. In this procedure, animals learn to freeze
at the sound of the tone, evidence that fear conditioning has occurred. It is well
established that contextual fear conditioning requires intact hippocampal function,
whereas auditory fear conditioning does not (Pugh, Fleshner, Watkins, Maier, &
Rudy, 2001). Maier, Watkins, and colleagues have extensively assessed the extent
to which sickness-inducing agents, such as LPS and gp120, and IL-1β disrupt fear
conditioning and have found that contextual fear conditioning, but not auditory fear
conditioning, is affected by the administration of these agents (Pugh, Kumagawa,
Fleshner, Watkins, Maier, & Rudy, 1998; Pugh, Johnson, Martin, Rudy, Maier, &
Watkins, 2000). Importantly, the cytokines or cytokine-inducing agents were admin-
istered after the initial exposure to the shock-associated context, eliminating the possi-
ble confound of attentional deficits produced by sickness. Subsequent studies from
this laboratory have suggested that stress may induce expression of IL-1β in the
brain and that the presence of the IL-1 can block contextual fear conditioning (Pugh,
Nguyen, Gonyea, Fleshner, Watkins, Maier, & Rudy, 1999). These findings have
been interpreted to indicate that cytokines and cytokine-inducing agents can impair
the consolidation of memories required for successful contextual fear conditioning
(Pugh et al., 2001).
As the above examples demonstrate, infection and cytokines disrupt learning that
requires the processing of information based on spatial cues. Others have found that
the disruptive effect of sickness on learning generalizes to nonspatial learning para-
digms. For instance, Aubert, Vega, Dantzer, and Goodall (1995) demonstrated that
sickness and cytokines block the acquisition of autoshaping. In this task, animals in
an operant chamber are exposed to presentations of food pellets on a regular, continu-
ing basis. Typically, animals will begin lever pressing prior to the delivery of food,
even though food is presented independently of behavior. Aubert and colleagues as-
sessed the effects of LPS, baker’s yeast, and IL-1β on the acquisition and expression
of autoshaping. They found that if these substances were administered during acquisi-
tion of the autoshaped response (i.e., lever pressing), acquisition was disrupted on
following test sessions. However, if these substances were administered after the
response had been acquired, responding was not affected (Aubert et al., 1995).
As can be seen from these examples, infection and cytokines impair cognitive
function by disrupting the acquisition of a learned response. It is postulated that this
is due to impaired memory formation. This is supported by evidence of IL-1-disrupted
long-term potentiation, considered an electrophysiological model of memory forma-
tion (Bellinger, Madamba, & Siggins, 1993; Katsuki, Nakai, Hirai, Akaji, Kiso, &
Satoh, 1990).
SEXUAL BEHAVIOR
The effect of illness on sexual behavior has received relatively little research atten-
tion compared to other sickness behaviors. Yirmiya and colleagues demonstrated that
both LPS and IL-1β produce changes in sexual behavior. However, these changes
were sex specific. For instance, they have shown that LPS and IL-1β decreased pro-
ceptive behavior and lordosis in females, therefore demonstrating decreased sexual
receptivity. LPS, IL-1β, and TNF also decreased preference for a viable sexual part-
 CYTOKINES AND BEHAVIOR 377

ner, interpreted as decreased sexual motivation (Avitsur, Cohen, & Yirmiya, 1997a;
Avitsur, Pollak, Weidenfeld, & Yirmiya, 1998).
Sexual behavior was not disrupted in males administered LPS and IL-1β (Yirmiya
et al., 1995). In particular, ejaculation latency, mount rate, and intromission were not
affected by these substances. In addition, there was no effect of LPS or IL-1β on
preference for a sexual partner. Importantly, the doses of these substances were be-
haviorally active as evidenced by decreased open field activity. While sickness in
males did not disrupt their sexual behavior toward a healthy partner, an infected
female impaired sexual functioning of the male. Male mating strategies were more
inefficient with females treated with IL-1β (e.g., longer time to ejaculation, more
mounts), likely due to decreased sexual receptivity in the females. In terms of sexual
preference, males preferred a control subject over an IL-1-injected female (Avitsur,
Pollak, & Yirmiya, 1997b), demonstrating sensitivity to the health of sexual partners.
SLEEP
Both infection and cytokines have been shown to produce changes in sleep patterns
in organisms of many species, including the much studied rats (Opp, Obal, &
Krueger, 1991) and rabbits (Kimura, Majde, Toth, Opp, & Krueger, 1994). Stated
generally, cytokines increase time spent in non-rapid eye movement (NREM) sleep
and increase the EEG amplitude (Kruger & Majde, 1995). While this is the general
finding, it has been demonstrated that the effect of cytokines on sleep is dose depen-
dent. For example, a low dose of IL-1β increased NREM sleep and EEG amplitude
in rats. At higher doses, however, IL-1β inhibited NREM sleep (Opp et al., 1991).
These effects may also depend upon the dark–light cycle. Slow-wave sleep has been
shown to be enhanced during the dark portion of the cycle but inhibited during the
light portion of the cycle (Opp et al., 1991). TNF (Kapas & Krueger, 1992) and
interferons α and β (Kimura et al., 1994) have similar effects on sleep; like IL-1 they
increase NREM sleep, often accompanied by decreased REM sleep. These findings—
increased NREM sleep, increased EEG amplitude, and in some cases suppressed
REM—are similar to what is seen when animals are exposed to many different infec-
tions, including LPS, influenza virus, and Staphylococcus aureus (as reviewed in
Krueger & Toth, 1994; Opp & Krueger, 1992).
ANHEDONIA
Immune system activation and cytokine administration also decrease behavior
maintained by pleasurable, or hedonic, stimuli, and this effect is often referred to as
anhedonia. The anhedonic effect of sickness has been assessed using various para-
digms. As stated previously, infection and cytokines decrease the consumption of
palatable solutions, including sweetened milk (Swiergiel et al., 1997a), chocolate
milk (Anisman & Merali, 1999), and saccharin solutions (Yirmiya, 1996), and these
findings can be interpreted as reflecting illness-induced anhedonia. More specifically,
it has been shown that LPS will decrease a preference for a palatable solution (e.g.,
saccharin) without decreasing water intake (Yirmiya, 1996). This finding importantly
demonstrates a disruption of behavior maintained by highly palatable solutions dis-
tinct from overall changes in ingestive behavior. The specificity of cytokines at dis-
rupting consumption of the more palatable solution suggests specific anhedonic ef-
fects of sickness-inducing agents.
378 LARSON AND DUNN

Other assessments of anhedonia have examined the effect of cytokines on behavior

maintained by intracranial electrical brain stimulation. In this paradigm, animals pro-
duce an operant response, such as a lever press, and this delivers a brief electrical
pulse to the brain, something which can be highly rewarding for the animal. Anisman
and colleagues have found that electrical brain stimulation is disrupted in animals
that have been treated with IL-2 (Anisman, Kokkinidis, & Merali, 1996) or an illness-
inducing agent, such as LPS (Borowski, Kokkinidis, Merali, & Anisman, 1998), but
not IL-1β (Anisman, Kokkinidis, Borowski, & Merali, 1998). Decreased intracranial
self-stimulation (ICSS) induced by LPS and IL-2 suggests that the rewarding value
of the ICSS is disrupted, an interpretation analogous to anhedonia.
Finally, it has been shown that cytokines can decrease breaking points on progres-
sive ratio (PR) schedules. On PR schedules animals are reinforced for a behavior
(such as a nose-poke response), and after each reinforcement is presented, the re-
sponse requirement necessary to earn the next reinforcer increases. The rewarding
value of the stimulus is determined by assessing how many responses the animal
will make for a single reward before they cease responding (called the breaking
point). This procedure is used to measure reward in animals, and it has been shown
that drugs that block reward decrease PR breaking points (Stafford, LeSage, &
Glowa, 1998). We have shown that IL-1β decreased PR breaking points, supporting
suggestions that IL-1 disrupts the rewarding value of the sweetened milk solution
(Larson et al., 2001).
In sum, there is much converging evidence supporting the suggestion that illness-
inducing agents and cytokines are capable of producing anhedonia, a finding espe-
cially relevant for relating sickness behavior to depression (Dantzer, 2001; Dantzer,
Wollman, & Yirmiya, 1999).
IS SICKNESS BEHAVIOR ADAPTIVE?
Although we have discussed changes in specific behaviors induced by illness, sev-
eral studies have investigated multiple aspects of sickness behavior, e.g., anhedonia
and activity levels (Yirmiya, 1996), body weight and social exploration (Bluthé et
al., 1992), and sexual behavior and open field activity (Yirmiya et al., 1995). This
concurrent expression of multiple aspects of sickness behavior suggests that the same
profile of sickness behavior may occur in any given animal, associated with any
malady. Moreover, it is apparent that most of the changes associated with illness and
cytokine administration involve decreases in behavior, e.g., decreased food intake,
decreased social exploration, or increased sleep, or impaired function, e.g., cognition.
Thus, it is tempting to speculate that all the behavioral changes observed in sick
organisms result from behavioral impairments and/or a general decrease in activity.
Counter to this, a few studies have shown that infections and cytokines decrease
behavior under some conditions but not others. Based on such findings, it is argued
that changes in behavior during illness do not simply result from depression or impair-
ment of all ongoing activity and do not necessarily occur in the same way each time
the organism is exposed to infection and cytokines.
The first report demonstrating a differential effect of endotoxin on behavior was
by Miller (1964). In his studies, endotoxin administration decreased bar pressing
when it resulted in an appetitive stimulus like food or water, but endotoxin did not
decrease responding when it resulted in the termination of an aversive event. Rats
given an endotoxin injection increased bar pressing to stop the rotation of a drum,
 CYTOKINES AND BEHAVIOR 379

a mildly aversive stimulus (Miller, 1964). Importantly, this demonstrated that activity
is not necessarily decreased following exposure to sickness-inducing agents. Instead,
the effect of the sickness-inducing agent may be influenced by the consequence of
the behavior. Based on Miller’s, as well as more recent findings, it has been hypothe-
sized that sickness behaviors reflect motivational changes and a reorganization of
behavioral priorities (Aubert, 1999; Dantzer, 2001). In many instances, this reorgani-
zation does lead to behavioral depression. However, in cases where behavioral de-
pression leads to an aversive consequence, infection and inflammation are less likely
to decrease behavior.
In support of this hypothesis, it has been shown that environmental conditions can
be determinants of the behavioral change induced by illness or cytokines. For in-
stance, LPS suppressed nest building in lactating mice tested at normal room tempera-
ture (22°C). However, nest building activity was not suppressed when the ambient
temperature was 6°C. The consequences of failing to build a nest in a 6°C environ-
ment are more severe than failing to build a nest in a 22°C environment and therefore,
motivation to nest build may be greater in the cooler environment (Aubert, Goodall,
Dantzer, & Gheusi, 1997a). Aubert and colleagues also demonstrated that food-
hoarding was less disrupted by LPS treatment when rats received all of their food
from hoarding, compared to rats that had supplemental food in their home cage (Au-
bert, Kelley, & Dantzer, 1997b). In a related finding, we have found that sweetened
milk intake in food-restricted mice is less affected by IL-1β than intake in free-feed-
ing animals (Larson et al., 2001). In both our study and Aubert’s, the failure to engage
in feeding or feeding-associated behaviors during testing might have adverse conse-
quences for the food-restricted organisms, and thus they may have been highly moti-
vated to eat when tested with IL-1β or LPS. Taken together these findings show that
when there are possible adverse effects of behavioral depression, behavior is less
likely to be disrupted by infection and cytokines.
Related analyses have assessed the influence of ongoing behavior on cytokine-
induced behavioral changes. As indicated previously, cytokines affect behavior main-
tained on an operant schedule of reinforcement, generally decreasing operant re-
sponding. Further analyses revealed that the extent to which cytokines depress
operant behavior depends upon the response cost (e.g., a high response requirement
is more readily affected by IL-1β than a low requirement) and response rate (e.g.,
high rates of responding are more readily affected by IL-1β than low rates of re-
sponding) (Larson et al., 2001). These findings demonstrate that IL-1β interacts with
the response requirement and ongoing rate of responding to produce behavioral ef-
fects, suggesting that the effects of cytokines on behavior are more complex than
previously described. Quite clearly, cytokines do not simply reduce behavior indepen-
dently of ongoing behavior.
Other work has shown a dissociation of behavioral changes induced by illness.
For instance, Dunn and colleagues observed that cytokines and cytokine-inducing
agents depress only some of the behaviors measured in the multicompartment cham-
ber (Spadaro & Dunn, 1990). Also, LPS and cytokines decrease saccharin intake
without affecting water intake in a two-bottle test (Yirmiya, 1996), demonstrating
that not all ingestive behaviors are depressed by these treatments. Zacharko, Zalcman,
MacNeil, Andrews, Mendella, and Anisman (1997) reported that administration of
sheep red blood cells (SRBC), which induce an immune response, suppressed ICSS
in mice when the electrode was placed in the nucleus accumbens, but not in the
380 LARSON AND DUNN

substantia nigra, indicating a selective effect of SRBC. These demonstrations indicate

that the profile of behavior change induced by infection and inflammation is not the
result of a general decrease in all behaviors. However, because the expression of any
individual component of sickness behavior is dose dependent, a high enough dose
of the sickness-inducing agent or proinflammatory cytokine might eliminate any se-
lective effects on behavior.
MEDIATORS OF SICKNESS BEHAVIOR
While we have emphasized the significance of environmental variables on the ex-
pression of sickness behavior, it is also important to note that multiple physiological
events interact with the effects of infection and inflammation to produce behavioral
changes. Fully understanding the behavioral effects of infection and cytokines re-
quires an appreciation of the role of the mediating factors. Although it is beyond the
scope of this paper to describe all of the possible mediators, we will mention a few
examples.
Glucocorticoids have been shown to decrease the anorectic effects of IL-1β (e.g.,
Pezeshki, Pohl, & Schöbitz, 1996; Uehara, Sekiya, Takasugi, Namiki, & Arimura,
1989). Corticosterone levels are also important determinants of the effect of LPS
and IL-1β on social exploration. For example, Goujon, Parnet, Aubert, Goodall, and
Dantzer (1995) showed that adrenalectomized mice experienced more pronounced
disruption of social exploration when exposed to LPS and IL-1β than adrenalecto-
mized animals receiving corticosterone replacement. Thus, corticosteroids can dimin-
ish multiple aspects of the behavioral changes induced by cytokines, revealing that
the behavioral effects of infection and inflammation may depend on stress.
Monoaminergic systems are potential mediators of the behavioral effects of infec-
tion and inflammation. Administration of IL-1β reliably promotes release of norepi-
nephrine and serotonin with little effect on dopamine, while LPS affects all three
amine neurotransmitters (Anisman & Merali, 1999; Dunn, 2001; Linthorst, Flachs-
kamm, Holsboer, & Reul, 1996). All three of these amines have been implicated in
feeding behavior. Nevertheless, acute treatment with antagonists of noradrenergic
and serotonergic receptors, as well as with dopaminergic, histaminergic, muscarinic,
cholinergic, and a variety of other antagonists failed to block the effects of IL-1β
and LPS on ingestion of sweetened milk (Swiergiel et al., 1999). Chronic, but not
acute, treatment with the antidepressants imipramine (Yirmiya, 1996) and tianeptine
(Castanon, Bluthé, & Dantzer, 2001) have been reported to attenuate the effects of
LPS on saccharin intake and social exploration, respectively. These latter results sug-
gest that the behavioral effects of infection and cytokines may be mediated by mono-
amine activity. However, Shen, Connor, Nolan, Kelly, and Leonard (1999) failed to
replicate the effect of imipramine and also found that fluoxetine and venlafaxine were
ineffective. In the mouse sweetened milk model, we have observed no effects of
chronic imipramine or venlafaxine on the reductions of milk intake in response to
IL-1β or LPS (Dunn & Swiergiel, 2001).
The pharmacological agents that have most commonly been shown to effectively
antagonize sickness behavior in the animal models are the nonsteroidal anti-inflam-
matory drugs (NSAIDs), such as aspirin, acetaminophen, and ibuprofen. Their activ-
ity is thought to reflect the ability of NSAIDs to inhibit the enzyme cyclooxygenase
(COX, also known as prostaglandin synthetase), which is essential for the synthesis
of prostaglandins. COX inhibitors have long been known to be effective inhibitors
 CYTOKINES AND BEHAVIOR 381

of IL-1- and LPS-induced behaviors (Crestani, Seguy, & Dantzer, 1991; Swiergiel
et al., 1997a; Dunn & Swiergiel, 2000). The role of COX has recently been reinforced
by observations in COX knockout mice (Swiergiel & Dunn, 2001). Interestingly,
however, the COX inhibitors are very effective antagonists of IL-1-induced behav-
iors, but the efficacy decreases with the complexity of the immune stimulus. Thus,
COX inhibitors are less effective antagonists of LPS-induced behavior (Dunn &
Swiergiel, 2000; Swiergiel et al., 1997a) and have very little efficacy against influenza
virus infection in mice (Swiergiel et al., 1997a) and in clinical practice.
These are only a few of the many possible mediators of the behavioral changes
associated with infection and cytokines. Elucidating the interactions of these and
other body states with infection and cytokines will be important in fully understand-
ing sickness behavior. Also, understanding these interactions may be relevant when
evaluating the applicability of models of sickness behavior to depression or other
neuropsychiatric illnesses. Abnormal functioning of any one of these systems, in
conjunction with infection and inflammation, may influence infection- and cytokine-
induced behavioral changes and be related to neuropsychiatric symptomatology. Fi-
nally, it is important to establish the detailed mechanisms by which cytokines exert
their behavioral effects. This may establish more clearly whether different cerebral
mechanisms are involved in the different sickness behaviors. If different mechanisms
are involved this would allow selective manipulation of the behavior and may even
have therapeutic significance. A good example is the anorexia associated with cancer,
which can be very deleterious to the health of human patients. This anorexia may
have been beneficial in primitive environments when food gathering was more time
consuming. However, in our present society, it may be more beneficial to the sick
person if these effects are treated.
CHANGES IN HUMAN BEHAVIOR AND RELEVANCE FOR
UNDERSTANDING NEUROPSYCHIATRIC CONDITIONS
Up to this point, we have mainly described work from nonhuman animals docu-
menting the effects of infection and cytokines on behavior. Anecdotal evidence re-
ports similar effects of infection and cytokines on human behavior and a small body
of research has directly assessed the effects of cytokines and endotoxin in humans.
Many of these findings parallel those reported in the animal literature. In fact, de-
creased ingestive behavior, impaired cognitive functioning, depressed activity, in-
creased sleep, and altered mood are all reported by individuals experiencing various
types of immune activation.
Humans self-report decreased appetite when sick and this is correlated with de-
creased ingestive behavior. This finding is confirmed in people experiencing various
disease states (e.g., HIV infection, cancer) (Plata-Salaman, 1997, 2000). Indeed, the
effects of some chronic illnesses on food intake can be so severe that malnutrition
may result (a classic example is cancer-related anorexia). Less noticeable to individu-
als experiencing acute bouts of immune system activation is a significant impairment
of cognitive function. However, people who are sick often report ‘‘fuzzy headiness’’
and this symptom has also been reported by people undergoing cytokine therapy.
For example, impaired memory and cognitive functioning is evident in leukemia
patients on interferon-α therapy (Pavol, Meyers, Rexer, Valentine, Mattis, & Talpaz,
1995). Recent findings by Reichenberg, Yirmiya, Schuld, Kraus, Haack, Morag, and
Pollmacher (2001) demonstrated that acute exposure to Salmonella endotoxin impairs
382 LARSON AND DUNN

verbal and nonverbal memory, and this effect was correlated with plasma concentra-
tions of TNF-α, IL-6, and IL-1 receptor antagonist. Reichenberg et al. (2001) also
demonstrated that endotoxin negatively affected mood variables by increasing anxi-
ety and depressing mood. Again, this parallels findings in patients undergoing cyto-
kine therapy, who often report that mood disturbances coincide with cytokine treat-
ment (Pavol et al., 1995). Finally, several studies have investigated the claim that
infection and inflammation produce sleepiness and increased sleep in humans. The
findings have been mixed, although, in general, it has been confirmed that endotoxin
infection can increase daytime sleepiness (Hermann, Mullington, Hinze-Selch,
Schreiber, Galanos, & Pollmacher, 1998) and may increase NREMS (Mullington,
Korth, Hermann, Orth, Galanos, Holsboer, & Pollmacher, 2000).
As can be seen, there are similarities between the effects of infection and cytokines
on both human and nonhuman animal behavior. Thus, the animal models outlined
in this paper are useful tools for further understanding the behavior changes people
experience during illness. In addition, there are similarities between the behavior
changes resulting from infection and inflammation and those observed in people ex-
periencing certain psychiatric disorders, most notably major depression. Thus, it has
been suggested that immune activation may play a role in the etiology of depression
(Charlton, 2000; Dantzer et al., 2001; Yirmiya, 1996, 1997). Sickness behaviors that
can be considered characteristic of depression include decreases in food intake, loss
of interest in pleasurable activities, and changes in sleep, although changes in sleep
patterns are quite different following infections from those typically observed in de-
pressed patients. Many people suffering with depression report symptoms, such as
extreme sadness and feelings of guilt/worthlessness, that are not part of the sickness
behavior profile and the DSM IV criteria require either sadness or the inability to
experience pleasure (anhedonia) for the diagnosis of major depression. Thus, there
are likely qualitative differences between the behaviors of sick and depressed persons.
Consideration must also be given to the fact that some key indicators of depression
(e.g., insomnia) are incompatible with sickness behavior. Additionally, even though
there may be similarities between the behavior changes induced by illness and in
depression, it is not necessarily the case that they have similar causes. There may
be different physiological antecedents so one must be cautious in interpreting the
behavioral symptomatology until a more complete understanding of the mechanisms
of cytokine effects on behavior is attained.
In this paper, we have considered the possibility that sickness behavior is an adap-
tive response, which can assist the organism in fighting a pathogen or infection. As
part of this analysis, it has been considered that behavior changes induced by illness
reflect a motivational change in organisms and the behavior changes that occur de-
pend upon their consequences. It has been demonstrated that when the illness-induced
behavior change is followed by aversive consequences, it is less likely to occur. Much
of the behavior change experienced in depressed persons is followed by aversive
consequences (e.g., loss of jobs, poor family relations, poor health, etc.) and despite
these consequences, the behavior persists. This suggests that the motivational aspects
of depression differ from those associated with infection and inflammation.
SUMMARY AND CONCLUSIONS
This review has made it clear that infection and inflammation produce changes in
various behaviors in both human and nonhuman animals. In particular, infection and
 CYTOKINES AND BEHAVIOR 383

cytokines decrease ingestive behavior, decrease exploration, impair cognitive func-

tion, inhibit female sexual behavior, increase NREM sleep, and may induce anhedo-
nia. Much of the research assessing the effects of infection and inflammation on
behavior has used LPS to induce immune system activity. However, there are many
reports of other illness-inducing agents producing behavior changes similar to those
seen with LPS. The literature points to IL-1β as being the most likely mediator of
behavioral changes associated with infection and inflammation, but there are limited
reports of behavioral effects of other cytokines, such as TNF, IL-6, and IL-2. Never-
theless, cytokines may not be the only mediators of such responses. Studies with
selective cytokine antagonists have at best shown only partial antagonism of the re-
sponses (Swiergiel & Dunn, 1997b, 1999). Although infections and cytokines tend
to produce decreases in most behaviors studied, the behavioral changes depend upon
the consequences for the animal. If negative consequences follow typical infection-
and cytokine-induced behavioral changes, they are minimized. In addition to being
influenced by its consequences, sickness behavior is influenced by the current behav-
ioral state of the infected organism. Changes in behavior produced by infections and
cytokines are also dependent on the existing physiological state of the infected organ-
ism. Knowing the mechanisms of sickness behavior and the way in which these mech-
anisms are influenced by ongoing behavior and the existing physiological state will
be important for a complete understanding of the behavior changes associated with
infections and inflammation.
There are substantial similarities between cytokines and infection and inflamma-
tion-induced behavior changes in humans and nonhuman animals. A resemblance
between behavior changes observed in sick organisms and in humans with major
depression has led some to suggest a role for immune activation in depression. Al-
though such an hypothesis is attractive it appears unlikely that immune activation is
the major cause of depression in humans.

ACKNOWLEDGMENT
The authors’ own research described in this review was supported by a grant from the National Institute
of Neurological Diseases and Stroke (NS35370).

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Received April 30, 2001