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Cytokines As Mediators of Depression: What Can We Learn from Animal Studies?

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Cytokines As Mediators of Depression: What Can We Learn from Animal Studies? Neuroscience and Biobehavioral Reviews 29 (2005) 891–909 www.elsevier.com/locate/neubiorev Review Cytokines as mediators of depression: 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 antidepressants 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; Norepinephrine; Serotonin; 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 antidepressant 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
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