Neuroscience and Biobehavioral Reviews 29 (2005) 891–909 www.elsevier.com/locate/neubiorev

Review Cytokines as mediators of : What can we learn from animal studies?

Adrian J. Dunna,*, Artur H. Swiergiela,b, Renaud de Beaurepairec

aDepartment of Pharmacology, Louisiana State University Health Sciences Center, P.O. Box 33932, Shreveport, LA 71130-3932, USA bInstitute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec, Poland cHoˆpital Paul Guiraud, Villejuif, and INSERM 513 Cre´teil, France

Abstract

It has recently been postulated that cytokines may cause depressive illness in man. This hypothesis is based on the following observations: 1. Treatment of patients with cytokines can produce symptoms of depression; 2. Activation of the immune system is observed in many depressed patients; 3. Depression occurs more frequently in those with medical disorders associated with immune dysfunction; 4. Activation of the immune system, and administration of endotoxin (LPS) or interleukin-1 (IL-1) to animals induces sickness behavior, which resembles depression, and chronic treatment with has been shown to inhibit sickness behavior induced by LPS; 5. Several cytokines can activate the hypothalamo–pituitary–adrenocortical axis (HPAA), which is commonly activated in depressed patients; 6. Some cytokines activate cerebral noradrenergic systems, also commonly observed in depressed patients; 7. Some cytokines activate brain serotonergic systems, which have been implicated in major depressive illness and its treatment. The evidence for each of these tenets is reviewed and evaluated along with the effects of cytokines in classical animal tests of depression. Although certain sickness behaviors resemble the symptoms of depression, they are not identical and each has distinct features. Thus the value of sickness behavior as an animal model of major depressive disorder is limited, so that care should be taken in extrapolating results from the model to the human disorder. Nevertheless, the model may provide insight into the etiology and the mechanisms underlying some symptoms of major depressive disorder. It is concluded that immune activation and cytokines may be involved in depressive symptoms in some patients. However, cytokines do not appear to be essential mediators of depressive illness. q 2005 Elsevier Ltd. All rights reserved.

Keywords: Cytokines; Depression; Interleukin-1; Interferon; ; ; HPA Axis; Sickness behavior; Animal models

Contents

1. Introduction ...... 892 1.1. Origins of the cytokine hypothesis ...... 892 2. Experimental evidence for the cytokine hypothesis of depression ...... 892 2.1. Responses to cytokine treatment in man ...... 892 2.2. Immune activation in depressed patients ...... 893 2.3. Depression in immune-related medical conditions ...... 894 2.4. Sickness behavior and depression ...... 894 2.4.1. Effects of treatments on sickness behavior ...... 898 2.5. HPAA activation by cytokines: the relationship to depression ...... 898 2.6. Brain catecholaminergic activation induced by cytokines: relationship to depression ...... 899 2.7. Cytokines, depression and serotonin ...... 900 3. Effects of immune activation and cytokines in classical tests of depression ...... 901

* Corresponding author. Tel.: C1 318 675 7850; fax: C1 318 675 7857. E-mail address: [email protected] (A.J. Dunn).

0149-7634/$ - see front matter q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.neubiorev.2005.03.023 892 A.J. Dunn et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 891–909

3.1. The Porsolt or forced swim test ...... 901 3.2. Tail suspension test (TST) ...... 902 3.3. Involvement of cytokines in other models of depression ...... 902 3.4. Usefulness of the cytokine induced sickness behavior model for the study of depression ...... 902 4. Conclusions ...... 903 Acknowledgements ...... 904 References ...... 904

1. Introduction depressed patients, but the results were inconsistent and highly variable (see Weisse, 1992). Subsequent studies In recent years, it has been postulated that depression may indicated that depressed patients often exhibited immune be caused by cytokine secretion associated with activation of activation, and that depression was more frequent in the immune system. This hypothesis was proposed initially patients with diseases having an immunological component because the incidence of immune abnormalities is higher in (Kronfol, 2002). However, the results were quite varied; depressed patients than in the general population, and immune function in depressed patients was decreased in because depression is a common side effect of cytokine some aspects, but activated in others. therapy. The hypothesis gained momentum when it was The interest in an immune system involvement in shown that immune activation and administration to animals depression intensified around 15 years ago with the of endotoxin (lipopolysaccharide, LPS) or the cytokine, juxtaposition of the above observations on immune interleukin-1 (IL-1), could induce a behavioral pattern abnormalities in depressed patients with the effects of resembling that commonly observed in sick animals, immune challenges in animals. In the animal studies, it was including man. This behavioral pattern has become known shown that administration of LPS or IL-1 induced a as sickness behavior. There are many similarities between behavioral syndrome that became known as ‘sickness sickness behavior and the symptoms of depression. Thus it behavior’ (Kent et al., 1992). Smith first suggested that was suggested that cytokines could induce depression, or depression was associated with increased secretion of indeed were the cause of depression. The hypothesis has cytokines (especially IL-1) by macrophages (Smith, come to be called the cytokine hypothesis of depression, 1991). He noted that administration of IL-1 mimicked not although proponents differ on whether cytokines are a cause only some of the behavioral characteristics of depression, of major depressive disorder, or the cause. but also activated the hypothalamo–pituitary–adrenocorti- cal axis (HPAA). This macrophage theory of depression attracted immediate attention, because it was compatible 1.1. Origins of the cytokine hypothesis with a number of earlier findings in depressed patients. The cytokine hypothesis of depression posits that depression is caused by the actions of cytokines. Cytokines are proteins and glycoproteins secreted by immune cells that 2. Experimental evidence for the cytokine hypothesis function as signals among and between immune cells. They of depression are the hormones of the immune system. It is now known that cytokines have effects on cells outside the immune The experimental evidence for the cytokine hypothesis of system, and that non-immune cells can synthesize and depression is summarized in Table 1. Each of these points secrete cytokines. Thus cytokines can be regarded as will be reviewed in turn, focusing on the evidence from classical hormones that can function locally or systemically animal models. to orchestrate immune responses, and can also coordinate immune responses with those of other physiological systems 2.1. Responses to cytokine treatment in man in the body, including the nervous system. The cytokine hypothesis of depression derives from both Cytokines have been shown to be effective in the clinical and experimental observations. The clinical obser- treatment of medical conditions, such as hepatitis C, vations were made on patients treated with interferons multiple sclerosis, some infections, leukemia, Kaposi’s (IFN’s) and interleukin-2 (IL-2). Such patients often sarcoma, melanoma, myeloma, renal carcinoma and other displayed influenza-like symptoms and nonspecific neuro- forms of cancer. The cytokines most commonly used are psychiatric symptoms, some of which are characteristics of IFNa, IFNb, IFNg and IL-2. Each of these cytokines has depression. However, the initial interest was not focused on been reported to produce side effects such as asthenia, depression, although depression is a relatively common myalgia, confusion and influenza-like symptoms. side-effect. Immune abnormalities in depressed patients Depression is most commonly associated with treatment have been widely reported for more than 30 years. The with IFNa and IL-2, and occasionally with IFNb but earliest studies suggested deficient immune function in not with IFNg (Valentine et al., 1998; Gohier et al., 2003). A.J. Dunn et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 891–909 893

Table 1 Experimental evidence cited for a cytokine hypothesis of depression

Evidence Principal cytokines implicated Treatment of patients with cytokines induces symptoms of major depressive disorder IL-2, IFNa Activation of the immune system is observed in many depressed patients. This may be reflected in elevated IL-6 circulating concentrations of cytokines Depressive disorders occur more often in medical disorders involving immune dysfunction than those that do not Activation of the immune system, and administration of LPS or cytokines to animals induces sickness behavior, IL-1 which resembles major depressive disorder. Chronic treatment with antidepressants inhibits LPS-induced sickness behavior Cytokines can activate the HPA axis. Elevated plasma cortisol is commonly observed in depressed patients IL-1, IL-6, TNFa, IFNa Cytokines activate brain noradrenergic systems. Elevated NE and its catabolites are commonly observed in the IL-1, TNFa CSF of depressed patients Cytokines activate brain serotonergic systems. Abnormalities of brain serotonin have been implicated in major IL-1, IL-6, TNFa depressive disorder and its treatment

The evidence has been reviewed recently by de Beaurepaire 1983) and complement (Kronfol and House, 1989). Maes et al. (2005) and will only be summarized here. The suggested that the chronic inflammatory state he believes incidence of depression associated with cytokine therapy is underlies depression can be explained by increased highly variable, ranging from 0 to 45% in different studies. production of cytokines by circulating monocytes and The reasons for this are multifold. They are in part related to macrophages (Maes, 1995). In his review, Kronfol cites the disease under treatment and the cytokines and doses reports of increased circulating leukocytes (Kronfol and used, but are also related to the assessment measures, the House, 1989) (see below), activated T-cells (Maes et al., patient’s psychiatric history, and the choice of comparison 1992), and elevated plasma concentrations of cytokines (control) subjects (de Beaurepaire et al., 2005). (Kronfol, 2002). Other studies have focused on the ability of In most cases, the depressive symptoms can be treated immune cells obtained from patients to produce cytokines in effectively with antidepressants. Interestingly, however, vitro (Maes, 1999; Anisman et al., 1999). Such assays antidepressants are sometimes more effective on the mood have been argued to provide functional measures of immune symptoms, and not on the neurovegetative symptoms, like activity, but the biological significance of such ex vivo anorexia, psychomotor retardation and sleep disorders measures is not at all clear. Also, neopterin, considered to (Miyaoka et al., 1999; Musselman et al., 2001a; Capuron be a marker of activation of cell-mediated immunity, et al., 2002), whereas it is the latter that are the focus of most was increased in the plasma and urine of depressed of the animal studies. patients (Duch et al., 1984; Dunbar et al., 1992). However, other authors have failed to find evidence for immune 2.2. Immune activation in depressed patients activation in depressed patients (Landmann et al., 1997; Natelson et al., 1999). Immune function in depressed patients has been the Several studies have focused on the possible elevation of subject of study for around half a century. Interestingly, the cytokines in depressed patients. IL-1b, interleukin-6 (IL-6) early studies indicated a tendency to decreased immune and the IFN’s have been reported to be increased in the function in depressed patients (Weisse, 1992), whereas the plasma of depressed patients (Maes et al., 1993a,b, 1994). more recent studies have emphasized immune activation Increases of plasma IL-1b reported in some studies (see review de Beaurepaire et al., 2005). According to the (Griffiths et al., 1997; Owen et al., 2001) were not replicated reviews of Maes (1995) and Kronfol (2002) major in others (Brambilla and Maggioni, 1998). Some have depression appears to be associated with increased plasma reported higher IL-6 concentrations in cancer patients with concentrations of positive acute-phase proteins (hapto- depression (Musselman et al., 2001b), but others found only globin, ceruloplasmin, C-reactive protein, hemopexine, normal concentrations of circulating cytokines in psychia- a1-antitrypsin, and a1-acid glycoprotein), and with lower tric patients, including those diagnosed with depression plasma concentrations of negative acute-phase proteins (Haack et al., 1999). One recent study indicated increases in (transferrin, albumin, and retinol-binding protein). Increases IL-1b and decreases in IL-6 in the cerebrospinal fluid (CSF) of acute-phase proteins associated with decreases in of depressed patients (Levine et al., 1999). In this study, the negative acute-phase proteins are considered to be indica- increase in IL-1b correlated with the severity of the tive of an inflammatory state. Thus, it has been postulated depression. that chronic depression is associated with chronic inflam- A recent meta-analysis of the clinical data on immune mation (Maes, 1995). Consistent with this are the reports abnormalities in depressed patients by Zorrilla et al. (2001) that depressed patients display elevated concentrations of found that patients with major depression exhibited: an inflammatory markers, such as prostaglandins (Lieb et al., overall leukocytosis, manifested as a relative neutrophilia 894 A.J. Dunn et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 891–909 and lymphopenia; increased CD4/CD8 ratios; increased and Schiffer, 1990), allergy (Marshall, 1993), rheumatoid circulating haptoglobin, prostaglandin E2,(PGE2) and IL-6 arthritis (Dickens et al., 2002), and stroke (Schwartz et al., concentrations; reduced natural killer (NK)-cell cytotox- 1993). In these diseases, the immune abnormalities precede icity; and reduced lymphocyte proliferative responses to the development of depression (Foley et al., 1992). Never- mitogens. Interestingly, plasma concentrations of IL-1, the theless, data on the correlations between depression only cytokine that clearly induces depression-like symp- and immune activation or plasma concentrations of toms in animals, were not consistently altered. The authors cytokines in patients with autoimmune diseases or chronic commented that ‘the degree of heterogeneity of the studies’ infections or inflammation are few and conflicting (see results raises questions about their robustness’. They also Pollmacher et al., 2002). noted that among these biological markers, only three were A complicating factor is that depression may also have a associated with chronic stress: increased CD4/CD8 ratios, higher prevalence in diseases characterized by a loss of reduced mitogen-induced proliferative responses, and immune function, although the loss of some immune reduced NK cell cytotoxicity (Zorrilla et al., 2001). mechanisms in these diseases is often accompanied by Pollmacher et al. noted that certain cytokines (most notably increases in others, for example in asthma or in stroke. If IL-1b) are undetectable in human plasma under normal depression were accompanied by the loss of immune physiological conditions as well as during experimental mechanisms of defense, diseases that develop because of a endotoxemia (Pollmacher et al., 2002). They also pointed loss of these mechanisms should have a higher incidence in out that the physiological fluctuations of the detectable depressed patients. Thus, for example, a higher prevalence cytokines (IL-6 and tumor necrosis factor a, TNFa) are very of infections and cancers should occur in depressed poorly characterized in normal and pathological states, and patients. Some epidemiological evidence indicates that the alterations of circulating cytokines observed in the this may be true, but there are major methodological depressed (as well as in immune-related medical conditions) problems, and the biological mechanisms are very uncertain are extremely modest compared with the concentrations of (see Kronfol, 2002). circulating cytokines that occur during cytokine treatments. These observations pose important issues for proponents of 2.4. Sickness behavior and depression a simple cytokine hypothesis of depression. It is also clear that the immune activations observed in depressed patients The concept of sickness behavior was defined by Ben Hart are not of the magnitude observed when sickness behavior is in a classic review (Hart, 1988). Sick animals, including induced by IL-1, LPS or infections with pathogen (see humans, exhibit decreases in a number of activities, most below). Another important caveat is that depression may notably feeding, exploration and sexual activity. They also occur in response to an undetected medical condition that exhibit increased body temperature (i.e. fever) and increased itself results in immune activation. sleep. Contrary to the prevailing opinion that the behavior of Overall the evidence for an activation of immune sick animals was a nonspecific malaise, Hart argued that it responses in patients with major depressive disorder is not was ‘not a maladaptive and undesirable effect of illness but very consistent (de Beaurepaire et al., 2005; Zorrilla et al., rather a highly organized strategy that is at times critical to 2001), although there are trends to leukocytosis, increased the survival of the individual if it were living in the wild CD4/CD8 ratios, elevated plasma concentrations of hapto- state’. The behavioral responses were important in facilitat- globulin, IL-6 and PGE2 and decreased NK cell activity and ing recovery from the illness, and defending the animal lymphocyte proliferative responses. It is clear that immune against pathogens and predators. The fever was thought to activation does not occur in all depressed patients. increase the efficacy of the host’s immune system, and in some cases to decrease the proliferation of pathogens. The 2.3. Depression in immune-related medical conditions behavioral responses were considered to drive the animal to hide, and remain safe, while the immune system cleared As indicated above, there is some evidence for a higher invading pathogens and aided the repair of damaged tissue. incidence of immune activation in depressed patients. If This revolutionary hypothesis immediately gained wide- immune activation were a direct cause of depression, it spread support. Hart also recognized that endotoxin and IL-1 should be possible to obtain evidence for this by assessing induced behavioral patterns that resembled very closely symptoms of depression and immune states in different those present in sick animals. Most authors have supported medical conditions. Depression should be more prevalent in and applauded his insight. patients that suffer from medical conditions associated with The term ‘sickness behavior’ was coined in a subsequent immune activation, and it should be possible to correlate the review (Kent et al., 1992), in which it was argued that the symptoms of depression with evidence of immune acti- relationships between sickness behavior and LPS and IL-1 vation (such as circulating cytokines) in those conditions. suggested that the symptoms of sickness might be treated Depression has been reported to be more common in with antagonists of the immune activation, such as cytokine non-infectious diseases associated with a chronic activation antagonists. The link to depression was made in Smith’s of the immune system, such as multiple sclerosis (Minden ‘macrophage theory of depression’ (Smith, 1991)in A.J. Dunn et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 891–909 895

Table 2 sickness behavior is considered to be a coping strategy that Sickness behaviors bestows benefits on the individual, and has evolutionary Hypomotility (Lethargy) advantages (Kent et al., 1992; Hart, 1988; Larson and Dunn, in Hyperthermia (Fever) press). Although it has been argued that psychiatric states have Hypophagia (Anorexia) adaptive value (Nesse, 2000), this view has been disputed, Hyperalgesia Decreased interest in exploration and the issue is very controversial (Dubrovsky, 2002; Decreased sexual activity in females McLoughlin, 2002). Whether or not there are any benefits of Increased time spent sleeping depression for the suffering patient is questionable. With regard to the specific symptoms associated with which he noted the similarities between sickness behavior sickness behavior and with depression, fever is almost and depression, and proposed specifically that IL-1 secreted universally observed with pathogen infection and other by macrophages was responsible for the depression. This pathologies, but hyperthermia is not characteristic of exciting series of proposals caught the imagination of many depression (although there is a trend to a nocturnal researchers, and has achieved folklore status. However, the hyperthermia in depressed patients (Dietzel et al., 1986). simplest form of this hypothesis requires careful Hypomotility is characteristic of sickness behavior in assessment. animals, which is consistent with the psychomotor retar- Sickness behaviors induced by IL-1 and LPS dation observed in depressed patients, although depressed include: hyperthermia, hypomotility, hypophagia, hyperal- patients are sometimes agitated. gesia, decreased interest in exploring the environment, LPS and IL-1 induce a hypersensitivity to pain (Watkins decreased libido, and increased time spent sleeping et al., 1994), but depressed patients are not hypersensitive to (Kent et al., 1992; Dantzer et al., 2001; Larson and Dunn, pain and are more likely to suffer hypo-algesia (Adler et al., 2001)(Table 2). There are also indications that motivation 1993). and some cognitive functions may be affected (see Dantzer IL-1, LPS and infections decrease feeding (frequently et al., 2001; Larson and Dunn, 2001). referred to as anorexia or aphagia, but truly it is The administration of interferons in animals does not hypophagia), and consequent loss of body weight (Swiergiel induce classical sickness behavior. In humans, depression is et al., 1997a). Depressed patients may exhibit either hypo- often observed following treatment with IFNa, but many or hyperphagia; the hypophagia is characteristic of typical other neurobehavioral symptoms are observed, the most depression, whereas the hyperphagia is a defining charac- common of which is fatigue (Valentine et al., 1998; Meyers, teristic of atypical depression. 1999; Cleeland et al., 2003). IFNa administration to rodents IL-1 and LPS administration to rodents increases sleep does produce some behavioral symptoms (reviewed below), time, specifically an increase in the duration of slow-wave but they are generally less marked than those observed in sleep (Krueger et al., 2003). However, hypersomnia is not humans. Most notably, IFNa does not typically induce fever typical of depression; depressed patients are most often or HPA axis activation in mice as it does in humans insomniacs, although increased sleep occurs in atypical (Valentine et al., 1998, see below). depression. The analogies between sickness behavior and depression Depressed mood is difficult, if not impossible, to assess in are far from perfect. From a general biological perspective, animals, but may be common to sickness behavior and

Table 3 Psychobehavioral symptoms or concomitants of major depressive disorder and animal models of depression

Humans Animals DSM IV symptoms of depression Cytokine LPS or IL-1 administration Chronic mild stress (CMS) therapy Depressed mood C Indeterminate Indeterminate CC C(Willner, 1997) Significant loss of weight or appetite (Weight Gain in Anorexia Hypophagia Hypophagia (Forbes et al., 1996) Atypical) Insomnia (Hypersomnia in atypical) C Slow-wave sleep [ Disturbed sleep (Cheeta et al., 1997) Psychomotor agitation or retardation C Locomotor activity Y Locomotor activity ? (Gorka et al., 1996) Fatigue or loss of energy C Locomotor activity Y Locomotor activity ? (Gorka et al., 1996) ,,,,,,,,,,Y Feelings of worthlessness 0 Indeterminate Indeterminate Diminished ability to think or concentrate, or indeci- C Indeterminate Indeterminate siveness Recurrent thoughts of death or suicidal ideation G Indeterminate Indeterminate

A diagnosis of depressive disorder requires symptoms 1 or 2, plus four of 3–9 for a period of two weeks or more. References are included only when they are not cited in the text. 896 A.J. Dunn et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 891–909

Table 4 Comparison of physiological parameters in human depression, sickness behavior, and animal models

Physiological parameter Humans Animals Depression Cytokine therapy LPS or IL-1 injection Chronic mild stress HPAA (Plasma corticosteroids) CC C Ca Plasma catecholamines CCC(Dobrakovova et al., 1982)b Plasma KKc Brain NE activity C ?d C 0(Azpiroz et al., 1999) Brain 5-HT activity C Brain tryptophan C Brain CRF GGCBNST (Stout et al., 2000) Plasma IL-1b 00 CK(Morme`de et al., 2003) Plasma IL-6 CC C C(Morme`de et al., 2003) DST C C (Froger et al., 2004) CRF test C

DST: dexamethasone suppression test; BNST: bed nucleus of stria terminalis. References are included only when they are not cited in the text. a Bielajew et al. (2002) and Ayensu et al. (1995) observed increases; Azpiroz et al. (1999) did not. b Chronic immobilization. c Decreased by IL-1, but not IFNa. d Depending on the brain region. depression. Table 3 lists the Diagnostic and Statistical of DA in hedonia, the effect of IL-2 would be consistent Manual (DSM-IV) criteria for a major depressive episode. with the reduction in apparent DA release, although the One or more such episodes in the absence of manic symptoms latter has only been reported after acute injection of IL-2 are necessary for a diagnosis of major depressive disorder. (Anisman et al., 1996). Similar effects of IL-2 were These symptoms are compared with those observed in observed in mice stimulated in the . patients treated with IFNa or IL-2, and with sickness In this case icv application of IL-2 (5 ng) elevated behavior, and chronic stress in rodents. Table 4 compares the frequency required to elicit self-stimulation from the the various physiological parameters in the same way. dorsal, but not the ventral A10 region (Hebb et al., 1998). A key symptom of depression is anhedonia, the inability Taken together these results suggest that IL-2, but not IL-1 to experience . Needless to say, one cannot and IL-6, can have long-lasting anhedonic effects in rats directly assess anhedonia in animals. It has been argued and mice. that the consumption of palatable foods, such as solutions of There has been less research on cognitive behavior. sucrose or saccharin, or sweetened milk may reflect hedonia, Certainly, sick animals may show cognitive deficits, for so that reductions in these reflects anhedonia, although it is example, in learning and memory tasks (see examples in difficult experimentally to distinguish the hedonic from the Dantzer et al., 2001; Larson and Dunn, 2001), but several of appetitive effects (see Merali et al., 2003). This is confounded the above characteristics of sickness behavior, could explain even more when studies are performed in food-deprived the apparent cognitive deficits. Major cognitive deficits are animals. The most popular models use saccharin, which it is not often observed in depressed patients, and when they are, argued appeals to the taste buds, but because it lacks caloric they are generally mild, normally restricted to some value, is not considered to reflect feeding (Yirmiya, 1996; cognitive bias (McKenna et al., 2000). Clinical research Yirmiya et al., 1999; De La Garza, 2005). has shown that cytokine administration (IFNa and IL-2) in Hedonia has also been assessed using intracranial self- cancer patients can affect cognitive functions, with effects stimulation (ICSS) paradigms. It is well established that rats reminiscent of the dysfunctions observed in neurodegen- will press a bar to stimulate themselves via electrodes erative diseases (Meyers, 1999). placed in various parts of the brain, especially in the medial Several observations are not compatible with a simple forebrain bundle (MFB). In a series of studies, Anisman’s model of cytokine-induced depression. For example, IL-1 group has shown that peripheral (ip) injection of IL-2 antagonists, such as the IL-1- antagonist (IL-1ra) altered self-stimulation via electrodes in the MFB (Anisman can effectively prevent the effects of IL-1, but the effects of et al., 1996, 1998). Curiously, there was relatively little LPS are only partially prevented, and those of influenza effect immediately after the IL-2, only a modest increase in virus are only slightly attenuated (Swiergiel et al., 1997b). the threshold at intermediate currents. But over the next Also, LPS induces hypophagia in IL-1-knockout mice several days, more substantial increases in the ICSS (Fantuzzi and Dinarello, 1996) and in IL-6-knockout mice threshold were observed. These effects were interpreted to (Swiergiel and Dunn, 2003). It must be concluded that, indicate that IL-2 induced a long-lasting anhedonia. No such whereas IL-1 is sufficient to induce sickness behaviors, it is effects were observed following administration of IL-1b or not necessary, and that other factors must contribute to the IL-6 (Anisman et al., 1998). Given the widely accepted role behavioral responses. Therefore, the mechanisms involved A.J. Dunn et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 891–909 897 in the expression of sickness behavior are complex and must for IL-1 in microglia in rat brain and sparsely in astroglia involve multiple mechanisms. It is certainly possible that after peripheral administration of a high dose of LPS these mechanisms involve cytokines other than IL-1, but no (2.5 mg/kg ip or intravenously (iv)). This result is consistent cytokine that induces sickness behavior as effectively as with those of Quan et al. (1994) using an immunoassay for IL-1 has yet been identified. IL-1 after a similar dose of LPS. A popular version of the cytokine hypothesis of A more recent study on the brains of multiple sclerosis depression proposes a role for cytokines within the brain. patients and controls also found IL-1b-like immunoreactiv- According to this model, immune activation in the periphery ity primarily im microglia, especially in the sclerotic plaques can induce the synthesis or appearance of cytokines and (Huitinga et al., 2000). However, IL-1b-like immunoreac- their receptors in the brain parenchyma. This could be tivity was also found in neuronal cell bodies in the regarded as a local inflammation within the brain. The major particularly in the paraventricular nucleus, route by which this is believed to occur involves stimulation but also in several other hypothalamic nuclei and in certain of afferents of the vagus nerve (Watkins et al., 1995; Bluthe´ neuronal fibers. The neuronal IL-1b immunoreactivity was et al., 1996) affecting cells in the brain stem, which in turn dramatically reduced in the brains of multiple sclerosis project to the forebrain. The hypothesis states that it is the patients. Curiously, all of the IL-1b-positive also cytokines induced within the brain that are responsible for contained oxytocin, although only about one-third of the the depressive symptoms (Licinio and Wong, 1999). The oxytocin neurons contained IL-1b. None of the cortico- major cytokine implicated has been IL-1. tropin-releasing factor (CRF)- or vasopressin-positive This is a novel and an intriguing idea, but more neurons contained IL-1b immunoreactivity. Huitinga et al. substantial evidence will be necessary to establish such a (2000) considered whether the association of IL-1b with mechanism. The experimental data cited to support this oxytocin neurons could be artifactual refecting another hypothesis are the induction of the appearance of IL-1 in protein with similar antigenic properties, although it various regions of the brain, and the ability of intracere- occurred with three different antibodies to IL-1b. Any brally administered IL-1 antagonists to prevent the effect of association of IL-1b in oxytocin-containing neurons with the peripheral treatments. Most of the studies indicating sickness behaviour requires explanation. induction of IL-1 in the brain have involved peripheral Several studies from Maier’s group have used ELISA’s administration of very high doses of LPS. Many of them to demonstrate the presence of IL-1 in the brain, especially have reported only the presence in the brain of mRNA for in the , following a variety of treatments IL-1 and/or the IL-1 Type I receptor (Laye´ et al., 1994; including LPS and various stressors (see Watkins et al., Wong and Licinio, 1994; Wong et al., 1997), and many of 1995). However, in none of these studies was the purported those have used non-quantitative techniques. Demonstration IL-1 purified, even partially, prior to the assay, so we cannot of the presence of the mRNA only indicates the propensity be certain that the apparent immunoreactivity truly reflected for the synthesis of the proteins, and in the case of IL-1, only IL-1, especially because the amounts of IL-1 reported were the synthesis of its precursor, pro-IL-1b which must be around the limits of the sensitivity of the assays. However, cleaved by interleukin-1 converting enzyme (caspase 1) to in one study, Quan et al., 1996) employed a bioassay to produce active IL-1b. Quan et al. (1998) showed that demonstrate the activity of partially purified IL-1 in the administration of LPS (2.5 mg/kg ip) to rats induced the brains of untreated rats. Classical criteria for the identifi- mRNA for IL-1 in the pituitary and the circumventricular cation of hormones and require more organs (CVO’s), i.e. outside the blood-brain barrier. Small rigorous techniques, involving extensive purification of the amounts of mRNA for IL-1b were found in the brain, but candidate molecule, and demonstration of its identity using most was present in microglia, thought to be derived from both immunological and bioassays. However to date, not macrophages that penetrated the endothelia and/or accessed even a Western blot has been published to demonstrate the the brain via the CVO’s (Quan et al., 1998). existence of IL-1 in the brain. Moreover, it cannot be Whether or not active IL-1 occurs in the normal brain is excluded that the presence of the limited amounts of IL-1 in controversial. As indicated above, most of the evidence these reports reflects local pathologies. The IL-1 may well indicates that IL-1b appears in the brain after high doses of have been present in microglia involved in the phagocytosis LPS and is largely localized in glia. An early immunohis- of dead cells or cellular components. tochemical study indicated the presence of IL-1 in post There are similar problems with the studies purporting to mortem (Breder et al., 1988), and immuno- demonstrate the presence of IL-1 receptors in the brain. An histochemical findings have subsequently been reported early study claimed widespread binding of [125I]IL-1 from the rat (Lechan et al., 1990) and the pig (Molenaar (mouse) to slices of rat brain (Farrar et al., 1987). Careful et al., 1993). The anatomical distributions of the IL-1 studies by Haour et al. (1992) and Takao et al. (1992) found expression differed somewhat among the individual human that the majority of IL-1 binding in the rat and the mouse brains in the human study, and there was little concordance brain was associated with the cells in the endothelia, which among the anatomical distributions observed in human, rat may explain the earlier results of Farrar et al. (1987). and pig. Van Dam et al. (1995) observed immunoreactivity Neither group found any evidence for binding of IL-1 in 898 A.J. Dunn et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 891–909 the brain parenchyma of the rat, although both observed inhibitory effect on LPS on the drinking of sweetened milk limited binding in the hippocampus of the mouse. It is in mice (Dunn and Swiergiel, 2001). Yirmiya has also possible that there are so few IL-1 receptors in the rat and indicated a failure to observe an effect of antidepressants on mouse brain that they could not be detected by these binding LPS-induced saccharin-drinking in mice (Yirmiya et al., techniques. It is thought that the presence of a very small 1999). From the above cited studies, it appears that the number of IL-1 receptors on a cell may be sufficient to effect of chronic antidepressant treatment is observed most induce biologic responses (Krakauer and Oppenheimer, often with LPS, is less evident with IL-1, and the effects on 1999). Nevertheless, it is clear that the existence of IL-1 LPS are evident in rats and not in mice. Other evidence receptors in the brain parenchyma is limited at best. Other suggests that antidepressants may affect the induction of studies have identified mRNA for the IL-1 Type 1 receptor IL-1 production by LPS (Yirmiya et al., 1999; Castanon in the brain (Wong and Licinio, 1994; Yabuuchi et al., 1994; et al., 2003; Connor et al., 2000), and reflect a peripheral Ericsson et al., 1995). However, the presence of mRNA is rather than a central mechanism. A peripheral mechanism of insufficient to prove the existence of functional receptors, action for antidepressants is highly unlikely, so that for which other proteins, such as the IL-1 receptor accessory Yirmiya’s exciting initial observation has failed to provide protein, are required. strong support for an IL-1 hypothesis of depression. The major evidence cited to indicate a role for cytokines Another important aspect of sickness behavior is that it in the brain is based on the use of intracerebral injections of does not appear to be stereotyped but is adaptive. This IL-1ra (Dantzer et al., 1999; Pugh et al., 1999; Borsody and means that the specific expression of sickness behaviors can Weiss, 2004). Such data are useful and suggestive of a role vary according to the needs of the organism (see Larson and for IL-1, but much more evidence will be needed to define Dunn, in press) For example, although hypophagia is a and establish a physiological role for IL-1 in the brain, not typical symptom of sickness behavior, it may not be the least in depression. expressed if the food supply is limited, or the animals are food-deprived (McCarthy et al., 1986; Kent et al., 1994; 2.4.1. Effects of antidepressant treatments on sickness Larson et al., 2002). It may also be diminished if there is behavior only one source of food (Aubert et al., 1997a). Priorities for Depression in humans responds reasonably well to food and warmth may also be altered (Aubert et al., 1997b). antidepressant drugs. Antidepressants also have useful Another example is sexual activity, which is inhibited by anti-stress effects (Strohle and Holsboer, 2003), but they IL-1 and LPS in females, but not in males (Avitsur et al., are not particularly effective in alleviating the feeling of 1998). This presumably reflects the obvious danger for the being sick. In a creative series of studies, Yirmiya used sick gravid female and her offspring, but is not a threat for ingestion of a saccharin solution by rats as a measure of the male. hedonia (Yirmiya, 1996). He showed that treatment of rats In sum, although there are many similarities between with LPS, which is a potent stimulator of the production and sickness behavior and the behavior of patients suffering secretion of the pro-inflammatory cytokines, IL-1, IL-6, from major depressive disorder, there are many aspects in TNFa and IFNg, decreased the frequency with which rats which the sickness behavior model does not resemble the pressed a bar to obtain the saccharin solution. This response human syndrome. Furthermore, it has been shown that in was considered to reflect anhedonia, a cardinal symptom of experimental endotoxemia, the fever and corticosterone depression. This hypothesis was tested by treating the rats responses occur at a time when there are no detectable chronically (for 3–5 weeks) with the classic tricyclic increases in circulating endotoxin or cytokines (Campisi antidepressant, imipramine, which inhibits the reuptake of et al., 2003). These discrepancies suggest that cytokines both norepinephrine (NE) and serotonin (5-hydroxytrypta- may not be necessary for the activation of the endocrine and mine, 5-HT). This treatment prevented the induction by LPS sickness responses, nor for major depressive disorders. of the ‘anhedonia’ in the rats. Similar results were obtained by Shen et al. using the NE-selective reuptake inhibitor, 2.5. HPAA activation by cytokines: the relationship desmethylimipramine (Shen et al., 1999), and by Yirmiya to depression using the 5-HT-selective reuptake inhibitor (SSRI), fluox- etine, although in the latter case, the prevention was less The potent activation of the HPAA by IL-1 (Besedovsky complete (Yirmiya et al., 2001). However, Shen et al. et al., 1986) was a seminal discovery because it extended the observed no such effect of the SSRI, paroxetine, nor of the concept of stress to immune activation. In this sense, the 5-HT and NE reuptake inhibitor, venlafaxine (Shen et al., immune system acts a sensor of invading pathogens, 1999). Thus the effect of antidepressants appears to be less signalling the brain of a threatening environmental event evident with the SSRI’s than with the tricyclic antidepress- (Blalock, 1984). It is highly significant that the major ants (Yirmiya et al., 1999; Shen et al., 1999). However, the mechanism by which immune stimuli activate the HPAA is atypical antidepressant, was effective chronically the same as that involved in the responses to psychological but not acutely (Castanon et al., 2003). We failed to observe and physical stressors, namely activation of CRF-containing any effect of chronic imipramine or venlafaxine, on the neurons in the paraventricular nucleus of the hypothalamus, A.J. Dunn et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 891–909 899 and subsequent secretion of anterior pituitary ACTH Dunn and Swiergiel, 1999), while the hypophagic responses (although there is evidence that IL-1 may activate the to IL-1 and LPS are normal (Dunn and Swiergiel, 1999). HPAA by multiple mechanisms (see Silverman et al., 2003; The principal factors mitigating against a hypothesis of Dunn, 2005). Interestingly, there is little evidence for IL-1-induced HPAA activation in depression is the failure to habituation (desensitization) of the HPAA response to IL-1, observe consistent elevations of plasma concentrations of although there is rapid tolerance to the responses to LPS IL-1 in depressed patients, and the fact that one third or (Fan and Cook, 2004). more of depressed patients do not exhibit HPAA activation, The HPAA-activating effect of IL-1 is shared by other or other abnormalities of HPAA function. cytokines, most notably, IL-6 and TNFa, but the latter are markedly less potent than IL-1, and may have limited 2.6. Brain catecholaminergic activation induced physiological significance, except perhaps in the absence of by cytokines: relationship to depression IL-1 (Silverman et al., 2003; Dunn, 2005). Treatment with antibodies to IL-6 and studies in IL-6-knockout mice In mice and rats, central noradrenergic systems are indicate that IL-6 contributes only modestly to the elevation markedly activated by IL-1 as indicated by classical of plasma ACTH and corticosterone by LPS in mice (Wang neurochemical studies showing increases in the NE and Dunn, 1999; Swiergiel and Dunn, 2003) However, catabolite, 3-methoxy,4-hydroxyphenylethyleneglycol because plasma concentrations of IL-6 can be dramatically (MHPG) (Dunn, 1988; Dunn, 2001; Kabiersch et al., elevated by infections and other pathologies in which the 1988). The noradrenergic activation is not uniform, the HPAA is activated, IL-6 may contribute to this activation ventral system (ventral noradrenergic ascending bundle, (Silverman et al., 2004) Depending on the physiological VNAB) being activated substantially more than the dorsal conditions, IL-6 apparently has the ability to activate the system. Consistent with this, reductions in the hypothalamic HPAA via the hypothalamus, the pituitary and the adrenal content of NE have also been observed in rats (Fleshner cortex (Silverman et al., 2003; Silverman et al., 2004; Dunn, et al., 1995). Microdialysis studies in rats have indicated a 2004; Dunn, 2005). similar activation (Shintani et al., 1993; Smagin et al., 1996; Administration of IFNa and IFNg, but not IFNb causes Wieczorek and Dunn, 2003). There is no evidence for marked activation of the HPAA in man (e.g. Shimizu et al., noradrenergic activation associated with IL-6 (Wang and 1995; Capuron et al., 2003). However, curiously, IFNg Dunn, 1998), although TNFa has such an effect in mice at elevates cortisol, but has little effect on ACTH (Holsboer high doses (Ando and Dunn, 1999). The latter could be et al., 1988). There appear to be marked species differences, attributed to TNFa-induced IL-1 secretion. because administration of relatively high doses of IFNa In contrast to these robust effects of IL-1 on NE, this (human or mouse) to mice did not alter plasma corticoster- cytokine does not consistently affect (DA) one (Dunn, 1992, 2005). In rats, both peripheral (ip) and metabolism, although small increases are occasionally intracerebroventricular (icv) administration of hIFNa observed (Dunn, 2001). IL-6 and TNFa have not been induced decreases in plasma ACTH and corticosterone reported to affect DA. However, IL-2 (1 mg ip) induced a (Saphier, 1989; Saphier et al., 1993), although one study marked reduction in microdialysate concentrations of DA showed modest increases in ACTH and corticosterone from the of the rat (Anisman et al., following iv rat IFNa (Menzies et al., 1996). 1996). The latter result is consistent with the increase in Indepressed patients, activation ofthe HPAA is perhaps the thresholds for ICSS observed in rats following similar most consistent biological marker, yet it occurs in only treatments with IL-2, indicative of anhedonia (see above). 50–70% of patients. A similar proportion of depressed patients Reports of the effects of interferons on brain catechol- are abnormal in the dexamethasone suppression test and the amines have been quite varied (see also Schaefer et al., CRF challenge tests (Strohle and Holsboer, 2003). Smith cited 2003). Shuto et al. found that chronic (but not acute) the ability of IL-1 to activate the HPAA as support for a administration of hIFNa (15!106 Units ip) induced small cytokine hypothesis of depression (Smith, 1991). It is relevant decreases in whole brain (minus cerebellum) DA and its that the HPAA activation by IL-1 can be dissociated from its catabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), but behavioral effects. Inhibitors of the enzyme cyclooxygenase there were no changes in the DOPAC:DA ratio nor in NE (COX) more or less prevent several behavioral responses to (Shuto et al., 1997). They also reported a decrease in the IL-1 (Swiergiel et al., 1997a; Dunn and Swiergiel, 2000), but apparent turnover of DA, assessed by blocking its synthesis the HPAA activation is affected only after iv injection of IL-1, with a-methyl-p-. Kumai et al. reported that and in the early phase after ip injections (Dunn and Chuluyan, repeated subcutaneous treatment (7 days) with hIFNa 1992). The role of CRF also differs in the HPAA and the increased the DA and NE contents of the cortex, behavioral responses. It appears to be involved in the HPAA hypothalamus and medulla, but not of the hippocampus or responses to IL-1, because antibodies to CRF prevent IL-1- thalamus (Kumai et al., 2000). We observed no effects of a induced HPAA activation in rats and mice (Dunn, 1993; single ip injection of mouse IFNa (1000 or 10,000 U/ Turnbull and Rivier, 1999). Also, HPAA activation is mouse) on DA, NE or any of their metabolites (Dunn, 2001). minuscule in CRF-knockout mice (Muglia et al., 2000; On the other hand, a single icv injection of IFNa (200 or 900 A.J. Dunn et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 891–909

2000 U of hIFNaA/D) was reported to decrease frontal mechanism of action is thought to be inhibition of cortical NE (Kamata et al., 2000). However, in yet another NE uptake) (Delgado et al., 1999) or cognitive therapy study, 1000 U hIFNa injected icv increased apparent DA (O’Reardon et al., 2004). It appears that medicated patients turnover (DOPAC:DA ratio) in the hippocampus (primarily are more likely to experience relapse following tryptophan caused by a substantial decrease in DA), although no such depletion than unmedicated patients (Moore et al., 2000). effect was observed in the or Tryptophan depletion may also induce depression in (De La Garza and Asnis, 2003). susceptible individuals (Bell et al., 2001). There is also Many studies have indicated hypersecretion of brain NE evidence that individuals that exhibit mood changes in in depression, principally assessed by increased CSF or response to rapid tryptophan depletion may be at risk for urinary concentrations of the NE catabolite, MHPG depression (Moreno et al., 2000). (3-methoxy,4-hydroxyphenylethyleneglycol), but also by There is some limited support for this mechanism from direct measurement of CSF NE (Wong et al., 2000). Thus an animal studies. Repeated tryptophan depletion of rats IL-1-mediated elevation of cerebral NE activity could be increased anxiety-like behavior in the open field and taken as evidence for a role of IL-1 in depression, although immobility in the forced swim test (thought to reflect as in the case of the HPAA activation, the failure to observe depression-like behavior, see below), but did not alter consistent elevations of plasma IL-1 in depressed patients behavior in the Morris water-maze (Blokland et al., 2002). tempers this evidence. However, acute tryptophan depletion did not alter the behavior of rats in the open-field test, the home cage 2.7. Cytokines, depression and serotonin emergence test, and the forced swim test, but decrements were observed in an object recognition test (Lieben et al., Currently, the prevailing hypothesis is that depression is 2004). caused by some disorganization of brain serotonergic IL-1, IL-6 and TNFa have been shown to activate brain systems, perhaps a deficiency in serotonergic neurotrans- serotonergic systems, increasing brain tryptophan concen- mission. This hypothesis is based largely on the observation trations and the metabolism of 5-HT as indicated by that many effective antidepressants affect serotonergic increases in the brain concentrations of its catabolite, transmission. Also, serotonin receptor abnormalities are 5-hydroxyindoleacetic acid (5-HIAA) (Dunn, 2001; found in the brains of depressed patients (for reviews, see Zalcman et al., 1994; Clement et al., 1997). Apparent Bell et al., 2001; Coppen and Wood, 1978; Wichers and 5-HT release by peripherally administered IL-6 has also Maes, 2004). Antidepressants are presumed to work by been indicated by microdialysis and in vivo chronoampero- normalizing a defect in brain serotonergic transmission metry (Zhang et al., 2001). The acute effects of IL-1 and through plastic changes or neurotrophic effects (Manji et al., IL-6 appear to increase the available tryptophan in the brain, 2001). perhaps enhancing serotonergic activity, which could be An interesting mechanism by which infections might considered to have an antidepressant effect. The problem for induce depression, relates to the metabolism of tryptophan and 5-HT). Infections, especially viral ones, induce IFNg, a hypothesis that cytokines induce depression by activating which is a potent inducer of indoleamine 2,3-dioxygenase serotonin is that such an effect is apparently in the wrong (IDO) in macrophages and certain other cells. IL-2 and direction, because SSRI’s also induce increased extracellular IFNa have similar effects on IDO, but to a lesser extent. 5-HT. This could perhaps be explained if the chronic effects This enzyme degrades tryptophan, so that infections are of the cytokines differed from the acute ones. The effects of typically associated with decreases in plasma tryptophan. chronic administration of the cytokines on serotonin IDO enables the conversion of tryptophan to kynurenine, metabolism have not been studied extensively, but one and the production of neopterin, both of which are elevated report indicated that repeated TNFa administration increased in the plasma of infected subjects. The resulting catabolism its effects on 5-HT (Hayley et al., 2002). IL-1b has also been of tryptophan decreases its circulating concentrations. reported to activate the , which could Lower plasma concentrations of tryptophan have been decrease extracellular 5-HT (Morikawa et al., 1998). associated with depression (Coppen and Wood, 1978), but There are few data on the effects of IFN’s on brain 5-HT. low plasma tryptophan is not a particularly reliable biologic A single icv injection of 200 or 2000 U of hIFNa was marker for depressive illness (Bell et al., 2001). It has been reported to decrease the 5-HT content of the frontal cortex, postulated that such a decrease may limit the availability of and both 5-HT and 5-HIAA were decreased in the tryptophan to the brain, thus limiting serotonin synthesis, and the striatum of rats (Kamata et al., 2000). However, we and precipitating depression (Wichers and Maes, 2004). observed no effects of ip human or mouse IFNa on 5-HT or Such a mechanism for the induction of depression has not 5-HIAA in mice at doses (400–16,000 U/mouse) that been adequately demonstrated, but lowering plasma trypto- induced behavioral changes (Dunn, 2001). However, in phan can precipitate a relapse in depressed patients treated another study a single icv injection of IFNa (1000 U) with SSRI’s (Delgado et al., 1994, 1999), but not in those increased 5-HIAA:5-HT ratios in the prefrontal cortex, but treated with desmethylimipramine (whose primary not in the striatum or the hippocampus of rats (De La Garza A.J. Dunn et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 891–909 901 and Asnis, 2003). This latter effect appeared to be prevented pharmacologically, even though the drug treatments work by diclofenac pretreatment. after one, two or three treatments, rather than the chronic Therefore, there are several hypothetical mechanisms by treatments required in depressed patients. Porsolt also which cytokines could act on brain serotonergic systems and developed a test for use in mice, but in this test the mice thus contribute to the pathophysiology of depression. are forced to swim only once, usually with the antidepress- However, relationships between these potential mechanisms ant treatments applied shortly before the test. Immobiliz- and depression remain to be demonstrated in depressed ation is scored during the last 4 min of the 6-minute test patients. (Porsolt et al., 1977b). However some researchers have employed a 2-day test in mice like that in rats. Surprisingly, there are few data in the literature on the 3. Effects of immune activation and cytokines in classical effects of cytokines or immune stimulation using the FST. In tests of depression an early report, del Cerro and Borrell found that IL-1 (5 U) administered icv reduced floating in rats by more than two- The cytokine hypothesis of depression would be strength- fold (del Cerro and Borrell, 1990), an apparent antidepress- ened if immune stimulation or cytokine administration ant effect. In direct contradiction to these results, Huang and proved positive in classical models of depression. Generally, Minor reported (in abstract form only) that icv injection of these models are based on the assumption that a particular 2 ng of IL-1b significantly increased floating in rats in the behavioral pattern resembles a human depressive symptom, FST, and that this response was prevented by icv and/or it is selectively sensitive to clinically effective administration of 6 mg of IL-1ra or by ip caffeine, the latter antidepressant treatments. The most recent reviews indicate implicating adenosine receptors (Huang and Minor, 2000). that there are some half dozen rodent models of depression As discussed above, patients medicated with IFNa may (Cryan et al., 2002; Cryan and Mombereau, 2004; Porsolt, display depressive symptoms that can be successfully 2000). The two tests most commonly used are the forced treated with antidepressants (Musselman et al., 2001a). swim test (FST), and the tail suspension test (TST). Makino et al. reported that recombinant human IFNa (60,000 U/kg iv) increased floating in the FST in rats, 3.1. The Porsolt or forced swim test without altering locomotor activity (Makino et al., 2000a). Human IFNa-2, and IFNa-2b also increased floating in the The forced swim test introduced by Porsolt et al. (1977a) FST in mice (Makino et al., 1998). Curiously, this effect was is by far the most frequently used. The test involves placing observed only with human IFNa; hIFNb and hIFNg, and a rat or a mouse in a tall cylinder of water from which it mouse IFNa, IFNb and IFNg were all ineffective. Pretreat- cannot escape, so that it must swim or float to survive. In the ment with naloxone, but not indomethacin prevented the original form of the test, rats were placed in the cylinder of FST response to hIFNa (Makino et al., 2000b). We have water on the first day for 15 min. It has been suggested that observed consistent increases in floating in the FST in rats this session may be necessary for the rats to learn that escape injected icv with 150 or 1500 U rat IFNa (Dunn and is impossible (Borsini and Meli, 1988). The rats are tested Swiergiel, unpublished observations). In preliminary results again 24 h after the first trial after potential antidepressant in mice, we have also observed increased floating times treatments. In its original form, drugs or other treatments following icv administration of mIFNa (500–5000 U) were administered immediately after the session on the first (Dunn and Swiergiel, unpublished observations). day, and then again five hours and one hour before the test Several other reports pertain indirectly to a role of on the second day (Porsolt et al., 1977a). However, Porsolt cytokines in behavior in the FST. Tannenbaum et al. showed subsequently showed that many antidepressant treatments that chronic stress increased sickness scores and the tested positively with only one or two of the three duration of floating in the FST, and although they reported treatments, although in many cases the three-treatment that chronic stress augmented the sickness behavior induced regimen was more effective (Porsolt et al., 1978). The key by ip IL-1b, they did not report the effects of IL-1b in the parameters affected by antidepressants are the time spent FST (Tannenbaum et al., 2002). Deak et al. showed that immobile (floating) and the latency to stop active swimming exposure to the FST did not alter the concentrations of IL-1 (struggling) or attempting to escape. Antidepressants measured in the brain or in peripheral tissues, and concluded increase the latency to float and decrease the floating that the production of IL-1 in the brain was unlikely to play time; whereas chronic stress and certain other treatments a role in the behavioral consequences of the forced swim considered depressogenic increase the time spent floating. (Deak et al., 2003). This test has been shown to work for most antidepressant A potential role for IL-6 was demonstrated by Sakic et al. treatments, including atypical antidepressants, such as the (2001) who observed that a spontaneous increase in serum monoamine oxidase inhibitors (MAOI’s) and electrocon- interleukin-6 (IL-6) concentrations in lupus-prone vulsive therapy (ECT) (Cryan and Mombereau, 2004; (MRL-lpr) mice coincided in time with increased immo- Porsolt, 2000), although the SSRI’s are less effective and bility in the FST. Also, sucrose intake was decreased when some are ineffective. Thus the test has been validated IL-6 was over-expressed systemically in healthy mice, 902 A.J. Dunn et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 891–909 suggesting that sustained elevation of plasma IL-6 might immobility and it was concluded that the IFNa induced affect other behaviors. High circulating concentrations of depression-like behavior by acting centrally (Yamano et al., IL-6, were achieved in mice by infecting them with 2000). Yamano et al. suggested that IFNa induced depression Ad5mIL6 adenovirus. This treatment reduced exploration via IL-1b release, which in turn was responsible for the CRF of a novel object, as well as food, water, and sucrose intake, secretion. In preliminary studies, we have also that is, resembling changes observed in sickness. Further- observed increases in the time spent immobile in the TST more, in lupus-prone mice the presence of CD45-positive after icv mIFNa (500–5000 U/mouse) (Dunn and Swiergiel, cells (leukocytes) in the choroid plexus and in the brain unpublished observations). parenchyma correlated positively with floating in the FST A summary of the biological effects observed in (Farrell et al., 1997). These results suggest that immune depression and in animal models is provided in Table 4. system alterations may affect the behavior in the FST. Even though the data are incomplete, the table clearly However, elevations of IL-6 are commonly associated with indicates the existence of common features between sickness, but whether or not the IL-6 is responsible for the depression and sickness behavior, as well as some aspects symptoms has not been established. It is significant that IL-6 of chronic stress in animals. administration has not been shown to induce any sickness behaviors (Bluthe´ et al., 1998; Swiergiel and Dunn, 1999). 3.3. Involvement of cytokines in other models Comparing results derived from sickness behavior studies of depression and the FST requires careful interpretation. If sickness behavior is considered adaptive, its functional adaptive There are very limited data on the involvement of behavioral equivalent in the FST may be an increased floating cytokines in other models of depression. In the chronic mild (usually interpreted as an increase in behavioral despair), as stress (CMS) model for depression, Kubera et al. showed opposed to active swimming that could be considered that 3 weeks of CMS increased the ability of splenocytes to maladaptive (Nishimura et al., 1986). An appropriate response produce IL-1 and IL-2, an effect that was partially prevented to LPS or IL-1 would be to increase flotation, not because it by chronic treatment with imipramine (Kubera et al., 1996; produces depression, but because it is an appropriate strategy Kubera et al., 1998). A decrease in NK cell activity was also for survival. Thus the biological significance of the effects of observed (Kubera et al., 1998). Morme`de et al. (2003) immune challenges, LPS or cytokines in behavioral patterns observed decreases in body weight after 21 days of CMS, observed in the FST remains unclear. but these were not accompanied by changes in the hematocrit or plasma concentrations of corticosterone. 3.2. Tail suspension test (TST) However, the consumption of sucrose was decreased, consistent with an anhedonic effect. Spleen cells did not The tail suspension test, the second most widely used test display any changes in the production of IFNg or IL-6. for depression, is conceptually similar to the FST. This test However, the mRNA’s for IL-1b and IL-6 were decreased is most commonly used in mice, because it is very difficult in the liver, while they were increased in the hypothalamus to implement in rats. The animal is suspended by its tail and (Morme`de et al., 2003). the latency to cease struggling and the duration of passive A number of immune abnormalities have been observed immobility are scored. The duration of immobility dis- in the rat olfactory bulbectomy model (see Leonard and played by the suspended animals is reduced by antidepress- Song, 2002). In the only published study involving ant treatments (Cryan et al., 2002; Cryan and Mombereau, cytokines, the serum concentrations of IL-1b and TNFa 2004). The TST has the advantage of eliminating con- were increased by LPS administration, but this response was founding effects of thermal effects of the swimming (Cryan decreased by bulbectomy (Connor et al., 2000). Treatment and Mombereau, 2004). Nevertheless, the FST and TST with desmethylimipramine decreased the responses in both may differ in the biological substrates underlying the bulbectomized and control rats. These changes paralleled observed behaviors (Cryan and Mombereau, 2004). Lines the increases in plasma corticosterone. of helpless mice responding to antidepressants, have been developed by selective breeding for responses in the TST 3.4. Usefulness of the cytokine-induced sickness behavior (Vaugeois et al., 1996). model for the study of depression Relatively few data are available on the effects of immune activation or cytokines on responses in the TST. Yamano et al. The value of animal models of human diseases is to reported that YM643 (2!108–2!109 U iv), a consensus provide insight into the mechanisms involved in the IFNa, and sumiferon (2–20!106 U), a natural IFNa, diseases, which may suggest potential therapies that can administered iv, increased immobility time in the TST in then be tested in the models. Because such models will mice (Yamano et al., 2000). Icv and repeated subcutaneous normally involve artificial interventions, it is important to injections were also effective. Peripheral pretreatment with use them intelligently. Thus if cytokine administration is imipramine or CP-154,526 (a CRFR1 receptor antagonist), but used to induce a model for depression, then the introduc- not with naloxone or indomethacin, reversed the IFN-induced tion of appropriate cytokine antagonists should prevent A.J. Dunn et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 891–909 903 the symptoms in the model. However, unless cytokines are no effect against more complex immune challenges, such as the cause (or a cause) of major depressive disorder, influenza virus infection or tumors (Swiergiel et al., 1997a; cytokine antagonists are unlikely to be effective clinically. McCarthy and Daun, 1993; Jain et al., 2001). Moreover, provided they are safe and non-toxic, the cytokine antagonists could be tested directly in patients, negating the need for the model. The model could be used 4. Conclusions to assess the toxicity of the treatments or the efficacy of chronic treatment, but such tests would normally employ The above review indicates some associations between standard tests for toxicity and not use the disease model. If the appearance of cytokines and major depressive disorder. cytokine antagonists are not effective in the clinical However, no clear causal relationship has been established. situation, there would be no need to test them in the Administration of certain cytokines to humans (especially animal model, and the model would have little value. IFNa and IL-2) induces symptoms of depression in some Models are most useful if they are based on the etiology of patients, but such responses occur in only a minority of the human disease, or to test a proposed underlying patients, and many other neuropsychiatric symptoms may mechanism. also be induced. Immune activation appears more frequently It is unlikely that treatments effective in the model will in depressed patients than in the general population, but is work if the method used to induce the model is unrelated to not observed in all depressed patients. It is possible that the the basic mechanism(s) of the disease. A example of the immune activation may reflect other medical conditions, successful use of an animal model is the development of which may themselves induce depression. Alternatively, treatments for attention deficit hyperactivity disorder depression may ensue when a patient hears a diagnosis with (ADHD). When it was observed that methylphenidate (an a poor prognosis. Nevertheless, it is possible that excessive -like drug that stimulates DA release) para- production of cytokines may induce symptoms of doxically reversed the hyperactivity observed in 6-hydroxy- depression in some patients. dopamine-treated rats (Shaywitz et al., 1976), it was Although there is some evidence that depressed patients reasoned that it might counter the hyperactivity observed exhibit elevated plasma concentrations of cytokines, such in children with ADHD. Such treatment has proven very effects are not observed consistently. Elevations are not effective in humans (Shaywitz et al., 2001). In this case, the observed in all depressed patients, and when they do occur model was useful most probably because ADHD in children they are frequently quite small. IL-1 is the major cytokine involves an abnormality in brain catecholamine systems. known to induce depression-like symptoms, but the But not all models have proven so useful. For example, the evidence for elevations of this cytokine in depressed olfactory bulbectomy model mimics depression in several patients is sparse. The only cytokine consistently elevated tests, and the effects respond appropriately to very many in the plasma of depressed patients is IL-6. Plasma treatments effective in depressed patients (see Cryan et al., concentrations of IL-6 are frequently elevated during 2002; Cryan and Mombereau, 2004; Kelly et al., 1997). infections and other pathological conditions (and following Nevertheless, although the model is of considerable some forms of stress), Thus there is unlikely to be any scientific interest, it has failed to provide insight into the specific relationship between plasma IL-6 and depression. mechanism of depression and has so far failed to inspire Moreover, in most studies in which IL-6 was administered useful clinical therapies. to rats and mice, it failed to induce sickness behavior. Needless to say, we do not yet know the value of the Sickness behavior induced by immune stimulation or IL-1 cytokine-induced sickness behavior model of depression, has many similarities with the behavior of depressed patients. but we do have some insight into what will probably not However, there are important differences, for example, in the work. For example, there is general agreement that many effects on body temperature, in the sensitivity to pain, and in behavioral responses to IL-1 are largely prevented by the specific changes in sleep patterns. Therefore, it may be inhibition of COX, a key enzyme for the production of premature to consider experimentally induced sickness prostaglandins and other eicosanoids (Swiergiel et al., behavior as a true model for depressive illness. Nevertheless, 1997a; Uehara et al., 1989; Bluthe´ et al., 1992). This certain aspects of depression may be studied in this way, if observation led Charlton (2000) (and subsequently others) the results are interpreted conservatively. Nevertheless, to propose that COX inhibitors (the non-steroidal anti- experiments in which animals were treated chronically inflammatory drugs (NSAID’s), such as aspirin, indometha- with antidepressant drugs have failed to provide strong cin and ibuprofen) should have antidepressant activity. support for the idea that such treatments work by antagoniz- However, depressed patients have frequently taken ing the actions of cytokines. NSAID’s, but there is no good evidence for any anti- The cytokine hypothesis is not in conflict with earlier depressant activity. Reference to the animal data indicates hypotheses of depression, such as those involving hyper- something of the problem. Whereas COX inhibitors more or activity of the HPAA, of CRF, or of noradrenergic systems, less prevent several sickness behaviors induced by IL-1, because IL-1 activates the HPAA and brain noradrenergic they are much less effective against LPS, and have virtually systems. Also, CRF appears to be involved in the HPAA 904 A.J. Dunn et al. / Neuroscience and Biobehavioral Reviews 29 (2005) 891–909 responses to IL-1, because antibodies to CRF prevent IL-1- Anisman, H., Kokkinidis, L., Borowski, T., Merali, Z., 1998. Differential induced HPAA activation in rats and mice, and HPA effects of interleukin (IL)-1b, IL-2 and IL-6 on responding for responses to IL-1 are minuscule in CRF knockout mice. A rewarding lateral hypothalamic stimulation. Brain Res. 779, 177–187. Anisman, H., Ravindran, A.V., Griffiths, J., Merali, Z., 1999. Endocrine and cytokine hypothesis could also be consistent with a cytokine correlates of major depression and dysthymia with typical or serotonin hypothesis of depression, because IL-1, IL-6 and atypical features. Mol. Psychiatr. 4, 182–188. TNFa have each been shown to affect brain serotonergic Aubert, A., Kelley, K.W., Dantzer, R., 1997a. Differential effects of transmission. However, IL-1, IL-6 and TNFa administered lipopolysaccharide on food hoarding behavior and food consumption in acutely appear to increase 5-HT release, which would rats. Brain Behav. Immun. 11, 229–238. achieve an effect similar to that induced by the many Aubert, A., Goodall, G., Dantzer, R., Gheusi, G., 1997b. Differential effects of lipopolysaccharide on pup retrieving and nest building in lactating commonly used antidepressants that inhibit 5-HT re-uptake, mice. Brain Behav. Immun. 11, 107–118. so that these cytokines ought to have antidepressant effects. Avitsur, R., Pollak, Y., Weidenfeld, J., Yirmiya, R., 1998. Gender Although drugs that inhibit serotonin reuptake are the differences in the behavioral response to interleukin-1: neurochemical most useful currently available for the treatment of mechanisms. Neuroimmunomodulation 5, 63. depression, there is no strong direct evidence that Ayensu, W.K., Pucilowski, O., Mason, G.A., Overstreet, D.H., abnormalities in 5-HT cause depression. More research on Rezvani, A.H., Janowsky, D.S., 1995. Effects of chronic mild stress on serum complement activity, saccharin preference, and corticosterone the effects of antidepressants on the immune system would levels in Flinders lines of rats. Physiol. Behav. 57, 165–169. be useful. In particular, the associations of abnormalities in Azpiroz, A., Fano, E., Garmendia, L., Arregi, A., Cacho, R., Beitia, G., tryptophan and serotonin with pathogen infection, with Brain, P.F., 1999. Effects of chronic mild stress (CMS) and imipramine immune activation, and with depression, are potentially administration, on spleen mononuclear cell proliferative response, very significant, and require further investigation. serum corticosterone level and brain norepinephrine content in male These observations do not exclude a role for cytokines in mice. Psychoneuroendocrinology 24, 345–361. Bell, C., Abrams, J., Nutt, D., 2001. Tryptophan depletion and its inducing depression. It is certainly possible that increased implications for psychiatry. Br. J. Psychiatr. 178, 399–405. cytokine production may induce depression in some patients, Besedovsky, H.O., del Rey, A., Sorkin, E., Dinarello, C.A., 1986. and certain cytokines may contribute to a variety of Immunoregulatory feedback between interleukin-1 and glucocorticoid neuropsychiatric symptoms in patients with a variety of hormones. Science 233, 652–654. diseases. 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