Sperner-Unterweger B, Fleischhacker WW, Kaschka WP (eds): Psychoneuroimmunology. Hypotheses and Current Research. Adv Biol Psychiatry.

Basel, Karger, 2001, vol 20, pp 4152

Changes in the Immune System in Some Animal Models of Depression

B.E. Leonard
Pharmacology Department, National University of Ireland, Galway, Ireland

The concept of an inter-relationship between the psychological state and the immune status can be traced back to antiquity. For example, Galen suggested in about 200 AD that melancholic women are more susceptible to breast cancer than those of sanguine temperament [see 1] and anecdotal reports appeared during the subsequent centuries linking depression with a predisposition to viral and bacterial infection. For example, Day cited unhappiness as a cause of lowered resistance in patients with active tuberculosis [2]. It is often overlooked that the only Nobel Prize ever awarded to a psychiatrist was granted to Julius Wagner-Jauregg of the University of Vienna in 1927 for his research demonstrating that the course of various mental illnesses could be influenced by activating the immune system with infectious agents [3]. However, even though it has been widely recognised for over 70 years that mediators of the immune system have profound effects on the course of psychiatric illness, the pathways and mechanisms whereby such mediators affect key brain functions are only now beginning to be elucidated. It is now generally accepted that psychological stress and psychiatric illness can compromise immune function [4]. In addition, it is well established that the cytokines and other soluble mediators of the immune system can cause changes in behaviour. Besides the changes in the immune system it is also apparent that the endocrine system also contributes to the biological changes which characterise major depression. Thus the well-established finding that a hypersecretion of cortisol is a frequent occurrence in depressed patients has led to the assumption that the immune system is suppressed. In support of this view is the finding that neutrophil phagocytosis, mitogen-stimulated lymphocyte proliferation and natural killer cell activity are suppressed in these patients [5]. However, other aspects of cellular and humoral immunity, such as

the secretion of pro-inflammatory cytokines from activated macrophages and an increase in the synthesis of acute phase proteins, are increased in patients with major depression [6]. Indeed, it has been hypothesised that the activation of the macrophages, both in the blood and also in the brain, plays a key role in the onset of the symptoms of depression [7]. This raises the possibility that depression, which has traditionally been considered to be a disorder of central monoamine function, may now be considered as a disorder that results from a dysregulation of the immune-endocrine axes. In recent years, several studies have examined changes in immune function in various rodent models of depression. These models include the forced swim test [8], chronic mild stress-induced anhedonia [9] and the olfactory bulbectomised rat (OB) model of depression [10]. The OB model is particularly suitable for studying immune and endocrine changes because it has been shown to exhibit many of the neurotransmitter, endocrine and immune changes seen in depressed patients [11]. Furthermore, the changes observed in the OB model are largely attenuated by the chronic administration of most classes of antidepressants [12]. This review will examine the evidence from both experimental and clinical studies that implicate the hypersecretion of the pro-inflammatory cytokines in the onset of depression and consider how antidepressants may bring about their therapeutic effects antagonising the effects of these cytokines.

Effects of Cytokines on Brain Function Cytokines are a heterogenous group of polypeptides that were first identified as soluble mediators within the immune system. Different types of cytokines are associated with the activation of the immune system and are closely involved in the inflammatory responses. Within the immune system, the cytokines are known to be pleiotropic molecules in that they act on a variety of different target cells where they often produce quite different biological effects. The role of this complex cytokine network has been extensively described elsewhere [13, 14]. In addition to the immune system, cytokines and their receptors have been identified in both the peripheral and central nervous systems. For example, receptors for the pro-inflammatory cytokines [interleukin-1 (IL-1), IL-6 and tumour necrosis factor- (TNF- )] and several other immune factors have been shown to be localised in the rodent brain with high densities being detected in the hippocampus and hypothalamus [15]. In addition, cytokines are synthesised in the brain, the microglia and astrocytes having macrophage-like properties and are known to release pro-inflammatory cytokines. In addition to the de novo synthesis of cytokines within the brain, cytokines secreted in the

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periphery can also act in the brain through one or more of the following mechanisms: by disruption of the blood-brain barrier, by penetration of the brain through the circumventricular organs sites in the brain in which the capillaries have open junctions and abundant fenestrations and by acting on peripheral nerves which then signal the brain. It is still unknown which of these mechanisms are involved in specific pathophysiological processes [16]. IL-1 administration by the intracerebroventricular route to rats has been shown to produce changes that simulate those occurring in depression and following chronic stress [17]. These changes include anorexia, anhedonia, cognitive and memory dysfunction, a loss of libido, disturbed sleep pattern, changes which are concurrently associated with an activation of the hypothalamicpituitary-adrenal (HPA) axis and in aspects of cellular and humoral immunity [18]. IL-1 is a potent stimulus to corticotrophic releasing factor (CRF) synthesis which, as a consequence, results in the activation of the HPA axis. As CRF hypersecretion is known to commonly occur in depression, it may be hypothesised that the dysfunction of the HPA axis is at least partly a consequence of the increased release of the pro-inflammatory cytokines within the brain. In addition to the behavioural and endocrine changes which are associated with the increase in the pro-inflammatory cytokines in depression and following their central administration to rats, changes are also known to occur in brain biogenic amine function which may be associated with the symptoms of depression [19]. Possible explanations for the changes in brain amine dysfunction involve the regulation by IL-1 of the serotonin transporter gene [20] together with the observation that the pro-inflammatory cytokines stimulate the activity of cyclooxygenase (COX) and thereby increase the synthesis of prostaglandin E2 (PGE2) [21]. An increase in the plasma and cerebrospinal fluid concentrations of PGE2 has been reported to occur in depressed patients and may contribute to the defect in brain biogenic amine function by impeding the release of the amines [22]. Besides their actions on the brain, it would also appear that cytokines cause changes which commonly affect the physical health of the depressed patient. For example, cytokines (possibly by causing hypercortisolaemia) are known to decrease bone density, increase inflammatory processes associated with arthritis and related diseases and possibly contribute to the increased incidence of cardiovascular disease by increasing platelet aggregation [23]. Thus it is possible that while the pro-inflammatory cytokines in the brain are involved in the pathophysiology of depression, the increase in these cytokines from peripherally activated macrophages could lead to osteoporosis, heart disease and autoimmune changes which are frequently associated with major depression.

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Changes in the Immune System in Some Animal Models of Depression Several approaches have been used to investigate the effect of stress and brain lesions on the immune system of rodents and of these approaches the use of bacterial cell wall lipopolysaccharide (LPS), sheep erythrocytes (SRBCs) and various pro-inflammatory cytokines have yielded valuable information regarding the interrelationship between the immune, endocrine and central amine neurotransmitters with the behaviour of the animal. With regard to the effects of LPS, SRBCs and cytokines in intact animals, it would appear that the changes are similar to those occurring following a severe stress [24, 25]. Thus a common feature of such treatments is a reduction in the activity of reward motivated behaviour [26], a situation which is common to those patients with major depression. In addition to the anhedonia experienced by rodents following the immune challenges, other behavioural symptoms which simulate those occurring in depression include anorexia, anxiety, reduced social exploration and memory impairment [see 27, 28]. It is possible that the changes observed in these studies reflect sickness behaviour in the animals and that the anhedonia observed, usually reflected in a reduction in the consumption of saccharineor sweetened milk-flavoured water, is an expression of the lack of reward. However anhedonia may not inevitably be a consequence of sickness behaviour. For example, Anisman and Merali [29] have shown that IL-1 administration causes sickness behaviour in rats without affecting the response of the animal to brain reward stimulation. This emphasises the need for caution in extrapolating from the results of animal studies with regard to the effects of immune challenges to the interpretation of the changes in depressed patients. It has been assumed that the effects observed in rodents following an LPS challenge are primarily the result of an increase in pro-inflammatory cytokines, in particular IL-1. However the impact of an acute rise in the concentration of corticosterone which commonly occurs following most stressful challenges is seldom considered. To investigate the possible interaction between stress, the rise in the brain IL-1 concentration and plasma glucocorticoids, Nguyen et al. [30] compared the effects of inescapable electroshock stress with LPS-induced stress. It was found that whereas LPS produced a widespread increase in the concentration of IL-1 in the brain, electroshock stress did not. It was subsequently shown that, following adrenalectomy, electroshock stress did cause an increase in brain IL-1 thereby demonstrating that the central expression of pro-inflammatory cytokines depends upon the degree of activation of the HPA axis. This was also demonstrated in a study by Johnson et al. [31] who explored the effects of corticosterone on the LPS response in rats. It was shown that a low dose of LPS (10 g/kg) caused an increase in the plasma corticosterone

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concentration without inducing sickness behaviour whereas adrenalectomised animals exhibited the sickness behaviour; corticosterone completely reversed the sickness behaviour experienced by the adrenalectomised rats. The results of this study clearly indicate that corticosterone modulates the behavioural and metabolic effects of LPS, which suggests that the HPA axis plays an important role in preventing the profound behavioural disturbances to low grade immune stimulation by infectious agents or stress. It is noteworthy that most of the experimental studies used high doses of LPS as an immune challenge and it is difficult to compare the interrelationship between the elevation in the plasma corticosterone concentration and the changes in the behaviour and immune responses across the various studies. This is essential if any firm conclusions are to be drawn regarding the relationship between sickness behaviour in animals and depression. The effects of antidepressant treatments on the behavioural and immune responses to an LPS challenge may throw some insight into the interrelationship between the sickness behaviour and the immune system. Thus it has been shown that the chronic administration of desipramine attenuated the LPSinduced anorexia, weight loss, reduction in the consumption of saccharine water and exploratory activity in a novel environment [28]. These data are consistent with the study of Yirmiya [32] who also showed that imipramine attenuated the LPS-induced behavioural effects. The possible mechanisms whereby antidepressants modify the effects of LPS will be discussed later. With regard to an SRBC challenge, it has been shown that the timedependent changes in responding for a brain stimulation reward from the nucleus accumbens in rats was qualitatively similar to that seen following exposure to a stressor, the interference with the brain stimulation reward response coinciding with the peak time of the immune response and with the maximal dopamine efflux from the accumbens [32, 33]. It is of interest to note that both IL-1 and IL-2 also caused a disruption of the brain reward system [33]. Exposure of rodents to chronic mild stress causes a reduction in sucrose consumption, an effect which persists for several weeks following the removal of the stress [34]. This stress-induced anhedonia can be reversed by chronic treatment with imipramine, maprotiline and fluoxetine in addition to dopamine receptor agonists [30]. Unfortunately to date no information is available regarding the changes in the immune system that occur as a result of the chronic mild stress. However, there is a possible connection between the changes in dopamine, anhedonia and the central action of some pro-inflammatory cytokines. Thus IL-1 has been shown to increase the release of dopamine, noradrenaline and serotonin [35], effects that are shared to a lesser extent by IL-6 and TNF- . In addition to their individual effects, there is also evidence that IL-1, IL-6 and TNF- may act synergistically in the brain and thus have an enhanced impact

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on the behaviours associated with the activity of central monoamine neurotransmitters. Thus studies in mice have shown that the co-administration of IL-1 and TNF synergistically increases the plasma corticosterone concentration while IL-1 and IL-6 synergistically increase both the ACTH and corticosterone concentrations [36]. The OB rat model of depression is particularly suitable for immunological studies because it has been shown to exhibit many neurochemical, endocrine and immune changes that are also found in depressed patients [12]. These changes are largely attenuated by chronic antidepressant treatments. For example, both fluvoxamine and sertraline were found to reverse the suppression of lymphocyte proliferation that followed olfactory bulbectomy at a time which coincided with the normalisation of the noradrenaline and serotonin concentrations in several limbic regions of the brain [37]. The behavioural changes of the OB rats in the open field apparatus and in the elevated plus maze were also largely corrected by the chronic administration of these selective serotonin reuptake inhibitors. Leucocyte adhesiveness and aggregation has been used as a marker of stress [38]. Studies in the OB rat showed that the percentage of neutrophils was increased, and the lymphocytes decreased, following bulbectomy [39]. Leucocyte adhesiveness was significantly increased in the OB rats, an effect which was not reduced by the chronic administration of desipramine but was reduced by thymopeptides. Thymopeptides play an important role in immune regulation and have been shown to reverse many of the immune deficits caused by bulbectomy [40]. This is one of the functions ascribed to the thymopeptides in the regulation of immune function in stressful situations [41]. However, even though the thymopeptides are effective in reversing impaired immune function in OB rats, and stimulate lymphocytes to produce cytokines which modulate both immune and neurotransmitter function [42] they do not normalise the behavioural deficits. By contrast, desipramine largely normalises the behavioural deficits without appreciably improving the defect in leucocyte adhesiveness. Studies on changes in the immune system of OB rats have mainly concentrated on ex vivo measures of immune function. While such determinations are valuable in gaining an insight into the relationship between changes in behaviour and the immune system, it is possible that the ex vivo changes may not accurately reflect the immunocompetence in vivo. For this reason the immune status of OB rats has been studied following a challenge with LPS, and the consequent rise in the plasma concentrations of IL-1, IL-6 and TNF- determined. Using such an approach, it has been shown that desipramine attenuates the hyperactive response of OB rats in the open field apparatus [43]. The rise in the plasma concentrations of IL-1 and TNF- was also significantly lower in

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the OB rats following a LPS challenge than it was in the sham-operated animals. Chronic treatment with desipramine further depressed the plasma concentrations of these cytokines; the hypersecretion of corticosterone following the LPS challenge was also significantly reduced by the desipramine treatment. The mechanism whereby the proinflammatory cytokines are suppressed in the OB rats following the LPS challenge is unclear. There is no evidence that the number of circulating monocytes is decreased in these animals even though there is evidence that the nocturnal secretion of corticosterone is increased following bulbectomy. This may be a factor in reducing the response of the OB rats to the LPS challenge but is unlikely to account for the effect of desipramine which has been shown to suppress corticosterone secretion in OB rats [43]. This suggests that desipramine has a direct effect on activated macrophages and suppresses the release of pre-inflammatory cytokines. This action is possibly mediated by an increase in the release of the anti-inflammatory cytokine IL-10 [44]. Thus it must be concluded that the antidepressant-induced normalisation of the behavioural deficits of the OB rat is not necessarily accompanied by a complete restoration of the immunocompetence.

Antidepressants as Immunomodulators It is not unreasonable to hypothesise that if cytokines play a causative role in the pathophysiology of depression then antidepressants should counteract their effects. There is evidence from in vitro studies that when human monocytes are incubated with different classes of antidepressants together with LPS that stimulates the release of the pro-inflammatory cytokines, the synthesis and release of IL-1, IL-6 and TNF- is markedly inhibited [45]. Furthermore, the enhanced lymphocyte proliferation and stimulated synthesis of IL-1 and IL-2 from spleen cells that occurs in rats that had been subject to chronic mild stress is reversed following chronic treatment with imipramine [46]. More recently, Kubera et al. [47] have shown that an increase in the concentration of serotonin, which would occur following the administration of an SSRI antidepressant for example, is associated with an increase in the release of the anti-inflammatory cytokine IL-10 and a decrease in the synthesis of interferon- . Similar findings have been reported to occur in rats that have been challenged with LPS after chronic treatment with desipramine, but not following treatment with paroxetine or venlafaxine [28]. The mechanisms whereby tricyclic antidepressants impair cytokine release is unknown. However, elevation of the intracellular concentration of cyclic adenosine monophosphate is thought to play an important role in decreasing the synthesis of cytokines in LPS-stimulated monocytes [45] and

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it may be speculated that tricyclic antidepressants produce their immunoregulatory effects by this mechanism. While there is evidence from experimental studies in intact rats that the tricyclic antidepressants differ from the SSRIs in their effects on the production of pro-inflammatory cytokines, in the OB model of depression [12] it has been shown that the elevated acute phase protein response (which is similar to that seen in patients with major depression) is attenuated by both tricyclic antidepressants and SSRIs [37]. The chronic administration of desipramine to OB rats was also found to attenuate IL-1 and TNF- release initiated by an acute LPS challenge [43]. There would appear to be some contradiction between the results for the effects of antidepressants on the immune system of intact rats and the results obtained from clinical studies in which it has been shown that effective antidepressant treatment, irrespective of the type of antidepressant used, usually normalises the changes in both cellular and humoral immunity that occur in depression [48]. For example, SSRIs have been shown to decrease the release of IL-6 and reduce the increase in acute phase proteins in depressed patients [49]. Furthermore, there are other mechanisms whereby antidepressants could indirectly attenuate the effects of pro-inflammatory cytokines. These include changes in the HPA axis whereby the sensitivity of the glucocorticoid receptors to feedback inhibition is re-established following chronic antidepressant treatment [50]. If this also occurs on immune cells, it seems possible that immune function would be suppressed by circulating glucocorticoids as occurs in nondepressed subjects. In addition, there is evidence that both noradrenaline and serotonin act as immunomodulators so that the functional increase in the activities of these neurotransmitter systems by effective antidepressants could contribute to the normalisation of the immune function that occurs in depresed patients following effective treatment [51]. Lastly, different classes of antidepressants increase the concentration of the anti-inflammaory cytokine IL-10 [52] and also differentially increase the concentration of the IL-1 receptor antagonist [53] which contribute to the reduction in the impact of the proinflammatory cytokines. In addition to the effects of antidepressants on the immune, endocrine and neurotransmitter systems, it is also possible that these drugs, by inhibiting the activity of COX in the brain and periphery, reduce the concentration of the inflammatory mediator PGE2. The concentration of PGE2 has been shown to be raised in the plasma and cerebrospinal fluid of depressed patients [54, 55]. Following a challenge with LPS it has been shown that the concentration of PGE2 in brain interstitial fluid is increased [56], and is attenuated by the administration of COX inhibitors which concurrently reduce the activation of the HPA axis and normalise both noradrenergic and serotonergic neurotransmission. The increased synthesis of PGE2 in the brain is therefore critically

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involved in the central effects of pro-inflammatory cytokines [57]. Of the two types of COX which are important in the synthesis of PGE2, COX2 is believed to play an important role in the elevation of PGE2 concentrations in response to the administration of LPS [58]. It is now apparent that LPS induces a rapid increase in COX2 activity throughout the vasculature of the brain which could impact on the neuronal activity brain by elevating the concentration of PGE2, a situation which would also presumably apply in depressed patients. Over 20 years ago it was shown that clomipramine inhibited the pressor responses to potassium ions and vasopressin in the rat mesenteric vascular bed, an effect which was attributed to an inhibition in the synthesis of PGE2 [59]; indomethacin was shown to have a similar effect. This led Horrobin [60] to propose that a range of antidepressants act as COX inhibitors in the brain and thereby decrease the concentration of PGE2 which is primarily responsible for many of the neurotransmitter changes which underlie depression. Conversely drugs such as reserpine and -methyl dopa, which can precipitate depression in some hypertensive patients, activate COX; oral contraceptives have qualitatively similar effects [61]. This prostaglandin hypothesis serves to unify the observed actions of antidepressants on central monoamine transmission, the changes in the HPA axis and the attenuation of pro-infammatory cytokines. Conclusions Despite the substantial evidence implicating a disorder in immune function in the aetiology of depression, controversy exists regarding the causal relationship between the increase in the various inflammatory processes and the resulting pathological changes. For example, are the changes in the immune system a reflection of a stress-induced pathological state or are they directly responsible for the changes in central neurotransmission that, following the activation of the immune system, cause the behavioural changes? Clearly more research of these interrelationships is needed. Nevertheless, such considerations have been important in stimulating new concepts regarding both the biology of depression and the mechanisms of action of antidepressants [62]. References
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Dr. Brian E. Leonard, Pharmacology Department, National University of Ireland, Galway (Ireland) Tel. 353 91 524411 2350, Fax 353 91 525300, E-Mail belucg@iol.ie

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