Although it is well recognized that infection is commonly associated with somnolence and fatigue, the mechanism of such behaviors has only been investigated within the last 10 years. For instance, it is now believed that muramyl peptide, a common microbial product, and bacterial endotoxin (LPS) stimulate the release of proinflammatory cytokines that interact with specific neurohormones and neurotransmitters in the brain to produce somnogenic activity (Krueger and Majde 1994).
Some human studies suggest that plasma levels of IL-1 peak at the onset of slow-wave sleep in healthy human volunteers and levels of IL-1 in cerebrospinal fluid increase during sleep (Moldofsky, Lue, Eisen, Keystone, and Gorczynski 1986; Lue, Bail, Jephthah-Ochola, Carayanniotis, Gorczynski, and Moldofsky 1988). Specific cytokines therefore seem to play a role in sleep regulation, particularly during an infection.
Although most research in this area have focused on IL-1, there is a growing evidence that TNF-a and interferons may also have somnogenic activities while IL-2 and IL-6 probably have not (Kronfol and Remick 2000).
Sleep regulation is a complex phenomenon and involves interactions between neuropeptides, biogenic amines, and other neurotransmitters. The exact role played by specific cytokines remains to be determined.
Sleep disturbances are an integral part of depressive disorder. Insomnia is a particularly frequent complaint, and it is reported by more than 90% of depressed patients (Thase 1999). Depressive disorders have multiple etiologies and might be well characterized as conditions of immune activation, especially hyperactivity of innate immune inflammatory responses. Increasing amounts of data suggest that inflammatory responses play an important role in the pathophysiology of depression. Depressed patients have been found to have higher levels of proinflammatory cytokines, acute phase proteins, chemokines and cellular adhesion molecules (Maes et al. 1991, 1995; Wichers and Maes 2002).
In addition, therapeutic administration of the cytokine interferon-a, leads to depression in up to 50% of patients. Moreover, proinflammatory cytokines have been proven to interact with many of the pathophysiological domains that characterize depression, including neurotransmitter metabolism, neuroendocrine function, synaptic plasticity, and behavior. Stress, which can precipitate depression, is also able to promote inflammatory responses through effects on sympathetic and parasympathetic nervous system pathways (Pavlov and Tracey 2005).
Major depression and the stress response share a number of similar phenomena, mediators and circuitries. Psychological stress is a common risk factor for the development of major depression in every culture examined, and most initial episodes of major depression are preceded by an identifiable stressor (Kendler, Thornton, and Gardner 2000). Consistent with the notion that stress might provide a link between depression and inflammation, more and more data indicate that psychological stress activates proinflammatory cytokines and their signaling pathways both in the periphery and in the CNS.
Major depression, however, is a complex disorder that can be divided into two major subtypes: melancholic and atypical. The features of melancholic depression include insomnia (most often early morning awakening), loss of appetite, weight loss, accompanied with negative behavioral changes, while the second major subtype is major depression with mostly opposite, atypical features characterized partly by hypersomnia, hyperphagia, lethargy, and fatigue.
It was supposed that melancholic depression represents activation of the principal effectors of the stress resulting in higher NE and CRH levels. Centrally, NE acts as a major alarm-producing neurotransmitter in the brain that inhibits sleeping. It was shown, that depressed patients had significantly higher NE as well as plasma and cerebrospinal fluid (CSF) cortisol levels, while despite their hypercortisolism, depressed patients had normal levels of plasma ACTH and that of CRH in their CSF (Wong et al. 2000; Leonard 2001b). Symptoms of depression can often be observed after treatment of patients with high doses of IFN-a or IL-2 (e.g., in chronic hepatitis or in malignant melanoma) (Capuron and Miller 2004). However, great differences exist in the prevalence of the development of depressive symptoms across studies. These symptoms include abnormal sleep patterns, irritability, anxiety, cognitive impairments, lethargy, and anorexia (Kronfol and Remick 2000; Corcos, Guilbaud, Hjalmarsson, Chambry, and Jeammet 2002; Wichers and Maes 2002). In major depression, increased serum levels of somnogenic cytokines, such as IL-1, IL-6 were demonstrated. Increases in the plasma concentration and in vitro production of IL-1, IL-6, soluble IL-2 receptors, soluble IL-6 receptors, and acute phase proteins were reported in patients with major depression (Maes, Bosmans, Meltzer, Scharpe, and Suy 1993; Maes et al. 1995). It was concluded from these data that the increase in proinflammatory cytokines in patients with major depression seemed to correlate with the severity of the illness and measures of HPA hyperactivity.
Unfortunately, these observations have not been replicated consistently. Most investigators could confirm the increase in the plasma levels of acute phase proteins (Leonard 2001a), while others found a reduction in the secretion of IL-1P, IL-2, and in IL-3-like activity in depressed patients as compared to control subjects (Weizman, Laor, Podliszewski, Notti, Djaldetti, and Bessler 1994). This finding and other reports of mild leukocytosis, neutrophilia with elevated C-reactive protein and complement components (Kronfol and House 1989; Leonard 2001a) suggests a mild inflammatory response in depression, possibly initiated by cytokines since these elevated proinflammatory mediator levels induce hypercortisolemia and a hypernoradrenergic state (Wong et al. 2000; Gold and Chrousos 2002).
Growing evidence suggests that overactivation of innate immune responses following stress and during depression might come at the expense of decreased cellular and humoral acquired immune responses (Raison and Miller 2003). Activation of the stress system might promote cytokine production through several mechanisms (Fig. 18.2). Despite of suppression certain immune process, activation of the sympathetic nervous system (SNS) has been linked in several studies to proinflammatory activation in the periphery, which might, in turn, influence inflammatory processes in the CNS. It was demonstrated that stress-induced activation of NF-kB in peripheral blood mononuclear cells appeared to be dependent on norepinephrine and can be abrogated by a1-adrenoceptor blockade (Bierhaus et al. 2003). Chronic P-adrenoceptor blockade reduces plasma levels of IL-6 in concert with symptomatic improvement in patients with congestive heart failure (Murray, Prabhu, and Chandrasekar 2000; Mayer, Holmer, Hengstenberg, Lieb, Pfeifer, and Schunkert 2005). Decrease in vagal activity in response to stress might also promote inflammation, given the evidence that efferent vagal activity inhibits NF-kB activation (and the release of TNF-a from macrophages) via cholinergic signaling through the a-7 subunit of the nicotinic acetylcholine receptor (Pavlov and Tracey
2005). Finally, chronic stress promotes the development of glucocorticoid resistance, which is associated with increased cytokine production and might also release the sympathetic nervous system from inhibitory control, further promoting inflammatory activation (Leonard 2001b). The exact role of cytokines in the pathophysiology of mood disorder however, remains to be clarified (Raison, Capuron, and Miller 2006).
Figure 18.2. The inflammation-sleep-depression loop. An inadequate response to cognitive or noncognitive stimuli shifts the balance both between the release and uptake of monoamines and between the production of proinflammatory and anti-inflammatory cytokines. Norepinephrine (NE) release is negatively regulated by the presynaptic a2B-adrenoceptor, while for its uptake the norepinephrine transporter (NET) is responsible. Altered release, uptake, or metabolism of relevant neurotransmitters such as NE, are known to be involved in the development of depression. Uptake of NE is inhibited by monoamine-transporter blocking antidepressants. Activation of the innate immune system is linked to activation of nuclear-factor-kappa-B (NF-kB) through Toll-like receptors (TLR) during immune challenge (e.g., with LPS). This leads to an inflammatory response including the release of the proinflammatory cytokines TNF-a, IL-1, and IL-6. These cytokines are able to access the brain via various mechanisms and their signals participate in pathways known to be involved in sleep regulation and in the development of depression. Cytokine production might also be increased within the brain by stress. NE provides a dampening signal on LPS-induced inflammatory response via a2-adrenoceptors on macrophages by increasing intracellular cAMP levels. Drugs, inhibiting cAMP degradation (PDE inhibitors, e.g., rolipram) exhibit antidepressant effects. Corticosteroids alleviate the inflammatory response by regulating gene transcription via interfering with transcription factor binding to DNA response elements, such as NF-kB. High levels of inflammatory mediators and dysregulation of monoamine neurotransmitters play important roles both in physiological and pathological sleep regulation and in behavioral changes. Feedback mechanisms occur at several levels and participate in the common regulatory cascades forming the inflammation-sleep-depression loop.
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