Integrating the monoamine, neurotrophin and cytokine hypotheses of depression — A central role for the serotonin transporter?

Pharmacology & Therapeutics 147 (2015) 1–11

Contents lists available at ScienceDirect

Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera

Associate editor: H. Bonisch

Integrating the monoamine, neurotrophin and cytokine hypotheses of depression — A central role for the serotonin transporter? Jana Haase ⁎, Eric Brown UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin 4, Ireland

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Available online 1 November 2014 Keywords: Serotonin transporter Depression Antidepressants Brain-derived neurotrophic factor Pro-inflammatory cytokines Neuroplasticity

a b s t r a c t Monoamine, in particular serotonergic neurotransmission has long been recognized as an important factor in the aetiology of depression. The serotonin transporter (SERT) is the primary regulator of serotonin levels in the brain and a key target for widely used antidepressant drugs, such as selective serotonin reuptake inhibitors (SSRIs). In realising the limitations of current antidepressant therapy, depression research has branched out to encompass other areas such as synaptic plasticity, neurogenesis and brain structural remodelling as factors which influence mood and behaviour. More recently, the immune system has been implicated in the development of depression and various intriguing observations have inspired the cytokine hypothesis of depression. Over the past two decades evidence of in vitro and in vivo regulation of SERT function by pro-inflammatory cytokines as well as by mechanisms of synaptic plasticity has been accumulating, offering a mechanistic link between the monoamine, neurotrophin and cytokine theories of depression. This review will focus firstly on the interconnected roles of serotonin and neurotrophins in depression and antidepressant therapy, secondly on the impact of the immune system on serotonin transporter regulation and neurotrophin signalling and finally we propose a model of reciprocal regulation of serotonin and neurotrophin signalling in the context of inflammation-induced depression. © 2014 Elsevier Inc. All rights reserved.

Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Serotonin and neurotrophins in depression . . . . . . . . . . . . . . . . . . . . 3. Depression and inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . 4. The serotonin transporter and neuronal plasticity in inflammation-induced depression 5. Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Depression is a common psychological condition affecting up to 15% of the population in industrialised nations and by 2030 is projected by the World Health Organisation to be the leading cause of disease

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burden globally (Moussavi et al., 2007). Though mood disorders vary greatly in their precise symptom set and comorbidities, depression typically refers to unipolar depression, also known as clinical or major depression. This condition is characterised by several core symptoms including a persistent low mood, anhedonia, feelings of hopelessness,

Abbreviations:5-HT,5-hydroxytryptamine; BDNF,brain-derivedneurotrophicfactor; CNS,central nervoussystem; CREB, cAMP response element-bindingprotein;IL-1β, interleukin-1β; IL-6, interleukin-6; INFα, interferon-α; IDO, indolamine 2,3-dioxygenase; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; NMDA, N-methyl-D-aspartate; SERT, serotonin transporter; SSRI, selective serotonin reuptake inhibitor; TNFα, tumour necrosis factor-α. ⁎ Corresponding author at: School of Biomolecular and Biomedical Sciences, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland. Tel.: +353 1 7166754; fax: +353 1 716 6456. E-mail address: [email protected] (J. Haase).

http://dx.doi.org/10.1016/j.pharmthera.2014.10.002 0163-7258/© 2014 Elsevier Inc. All rights reserved.

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J. Haase, E. Brown / Pharmacology & Therapeutics 147 (2015) 1–11

guilt and pessimism as well as cognitive impairment. Patients may also present with other often contradictory symptoms including lethargy, insomnia, social withdrawal and sexual dysfunction among a range of others. Despite advances in the diagnosis, recognition and categorisation of depression the underlying causes of the symptoms are still poorly understood. One of the early theories attempting to explain the pathogenesis of depression was the monoamine theory which hypothesised that depression may be a result of decreased availability of monoamine neurotransmitters such as serotonin and noradrenaline in the central nervous system (CNS) (Krishnan & Nestler, 2008). The hypothesis is based on the serendipitous discovery that drugs which increase monoamine availability are effective antidepressants. This has led to the development and widespread use of the newer generation of safer, more effective selective serotonin reuptake inhibitors (SSRIs) and serotonin noradrenaline reuptake inhibitors. However, despite some successes in understanding and treating depression from a monoamine centric viewpoint many questions still remain. For example, SSRIs are not effective in treating all patients with depression. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study revealed complete remission in only about one third of patients following first-line treatment with the SSRI citalopram (Trivedi et al., 2006). The same study confirmed the previously observed latency of the antidepressant effect in patients that do respond, recording an average mean time to remission of 6–7 weeks (Trivedi et al., 2006). In conclusion, this and other studies suggest that monoamine transporter blockade is only part of the therapeutic mechanism. Emerging findings regarding the role of synaptic plasticity (Lee & Kim, 2010) and neurogenesis (Eisch & Petrik, 2012) in depression along with the discovery that the N-methyl-Daspartate (NMDA) receptor antagonist ketamine is a fast acting potent antidepressant (Berman et al., 2000), have undermined the dominant position once held by the monoamine hypothesis. However, despite the fact that the monoamine hypothesis as a sole model for the development of depressive disorders now seems dated it is undeniable that monoamine neurotransmission, in particular the action of serotonin, plays an integral role in regulating mood, and conditions that perturb monoamine networks in the brain have significant behavioural consequences. This review aims to discuss the role of the serotonin transporter (SERT), the key target for SSRI antidepressants, in the context of recent developments in depression research, such as the contribution of neuroplasticity and the role of neurotrophins. We will give particular focus to the cytokine hypothesis of depression and explore the functional consequences of cytokine-induced alterations of SERT activity on processes relevant for depression, as well as attempting to integrate the major prevailing theories of depression. 2. Serotonin and neurotrophins in depression 2.1. The serotonin transporter and serotonin signalling in depression and antidepressant therapy Serotonin or 5-hydroxytryptamine (5-HT) is a simple monoamine synthesised from tryptophan and is found in a wide variety of organisms. In mammals it is distributed throughout the body with approximately 90% of 5-HT produced in the periphery by enterochromaffin cells in the gastrointestinal tract (Berger et al., 2009). Most of the remaining 5-HT is produced in the serotonergic neurons of the raphe nuclei and although these cells are restricted to a relatively small area of the brain, their axonal projections innervate almost the entire structure (Hornung, 2003). As a wide variety of cells in the CNS express 5-HT receptors including neurons, astrocytes and microglia, raphe nuclei derived serotonin regulates a wide range of processes and behaviours including mood, memory, sleep, appetite, aggression and thermoregulation. At serotonergic nerve terminals neurotransmission is initiated by 5-HT release from the presynaptic neuron followed by diffusion of 5-HT into the synapse where it can bind pre- and postsynaptic receptors.

Duration and extent of 5-HT neurotransmission is primarily controlled by the action of the SERT, a Na+/Cl− dependent high affinity monoamine transporter (Rudnick, 2006). In addition to synaptic or wiring transmission, monoamines including 5-HT are known to modulate neuronal activity through paracrine or volume transmission (Bunin & Wightman, 1999; Fuxe et al., 2010). Indeed, the extrasynaptic location and reported substrate affinities of 5-HT receptors as well as the serotonin transporter suggest that 5-HT diffuses quite some distance from its release site before interacting with receptors and transporters (Bunin & Wightman, 1998). The large range of extracellular monoamine concentrations resulting from the volume transmission mode of action necessitates a corresponding range of mechanisms of neurotransmitter retrieval. Thus, in addition to SERT, 5-HT is a substrate for several other transporters in the brain, including OCT3 (SLC22A3) and PMAT (SLC29A4). While these low affinity, high capacity transporters contribute significantly to the bulk reuptake of monoamines (Daws, 2009), SERT as the only known high affinity transporter plays a critical role in maintaining sufficiently low extracellular 5-HT levels to ensure responsiveness of 5-HT receptors at target sites. Thus, SERT represents a key modulator of serotonergic signalling in the CNS. It is therefore perhaps unsurprising that alterations in SERT levels and activity have been associated with a range of behavioural and psychological disorders such as major depression, attention deficit hyperactivity disorder, impulsive aggressive behaviour and alcohol addiction (Torres et al., 2003; Murphy et al., 2008), while a polymorphism in the gene encoding the transporter has been shown to be a risk factor for depression under stress (Karg et al., 2011). Just as naturally occurring variations in SERT function can profoundly influence mood and behaviour so too can pharmacological agents which interfere with SERT function such as SSRIs and psychostimulants such as methylenedioxymethamphetamine (MDMA, Ecstasy). Inhibition of SERT by SSRIs results in an elevation of extracellular 5-HT, leading to enhanced signalling through postsynaptic 5-HT receptors as well as presynaptic autoreceptors. Several members of the extensive 5-HT receptor family are thought to be involved in the adaptive processes resulting from transporter blockade, which are responsible for the delayed therapeutic action of antidepressants (Artigas, 2013). 2.2. Neurotrophins and neuroplasticity in depression — link to serotonergic neurotransmission The notorious delayed onset of the therapeutic effects of antidepressants has over the past few decades led to intense research into adaptive changes induced by SSRI therapy which contribute to the normalisation of affected brain circuits. The current widely accepted hypothesis suggests that the initial elevation of monoamine transmitter levels results in enhanced gene expression and release of neurotrophic factors leading to an increase in hippocampal neurogenesis and synaptic plasticity (Krishnan & Nestler, 2008). It is now well recognised that structural and cellular changes within the hippocampus are associated with depression (Sheline et al., 1996; Campbell et al., 2004; Videbech & Ravnkilde, 2004). This is one of the few brain regions which continue to produce new neurons into adult life by the process of neurogenesis. While the hippocampus is generally understood to be involved in learning and memory (Bruel-Jungerman et al., 2007), it has also been implicated in the pathophysiology of depression. For example, human studies of depressed patients have revealed structural changes to the hippocampus, reporting a 10–15% decrease in hippocampal volume (Campbell et al., 2004; Videbech & Ravnkilde, 2004). The causes for hippocampal atrophy are currently not well understood, but a number of theories have been proposed including a loss of existing neurons, retraction of dendrites and reduced hippocampal neurogenesis (Czeh & Lucassen, 2007). Neuronal death, survival and dendritic retraction can be influenced by a range of factors but neurotrophins and in particular brain-derived neurotrophic factor (BDNF) play a critical role. BDNF is a secretory

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protein, which is initially expressed as a proprotein and undergoes proteolytical processing as well as posttranslational modification, generating the mature form of the protein. While BDNF can be sorted to and secreted through the constitutive secretory pathway, it is predominantly targeted to dense-core vesicles of the regulated secretory pathway and released in an activity-dependent manner (reviewed by Lessmann & Brigadski, 2009). In addition to vesicle-mediated targeting of BDNF protein, BDNF mRNA is trafficked to dendrites, where it is locally translated and released from activated dendritic spines (Tongiorgi et al., 1997; Baj et al, 2013a,b). The common BDNF Val66Met polymorphism shows defects in maturation and activity-dependent secretion of BDNF (Egan et al., 2003; Chen et al., 2004) caused by at least two distinct mechanisms, an inefficient transport of mutant BDNF protein through the regulated secretory pathway and a deficient transport of BDNF mRNA to dendrites (Baj et al., 2013a). BDNF is known to be involved in the regulation of synaptic plasticity (R. S. Duman & Monteggia, 2006), including the maintenance and survival of dendrites (Gorski et al., 2003). Similarly, downregulation of the predominant BDNF receptor, TrkB, results in dendrite retraction (Schecterson et al., 2012). Decreased levels of BDNF and TrkB have been detected in the hippocampus as well as in the serum of patients with major depression (Karege et al., 2005; Sen et al., 2008; Autry & Monteggia, 2012) and BDNF levels are also downregulated in stress models of depression (R. S. Duman & Monteggia, 2006). In a mouse model of BDNF deficiency (heterozygote BDNF+/− mice), animals show increased sensitivity to stress and display depression-like behaviour upon exposure to mild stress (Duman et al., 2007; Advani et al., 2009). Treatment with SSRIs increases neurogenesis (Malberg et al., 2000), reverses hippocampal atrophy in stress models (Magarinos et al., 1999) and enhances BDNF gene expression in the hippocampus of rats (Nibuya et al., 1995). In clinical studies BDNF has also been found to be upregulated in the hippocampus of patients receiving SSRI treatment (Autry & Monteggia, 2012). In rats the positive action of SSRI treatment on BDNF expression occurs on a timescale consistent with the antidepressant effects of SSRIs in humans (R. S. Duman, 1998). In fact, the response to antidepressants appears to depend on BDNF signalling, as BDNF deficiency or impairment of its receptor diminishes antidepressant-induced behavioural changes and hippocampal neurogenesis in transgenic mouse models (Saarelainen et al., 2003; Monteggia et al., 2004; Sairanen et al., 2005; Li et al., 2008). Conversely, overexpression of TrkB or BDNF (Koponen et al., 2005; Taliaz et al., 2011) or direct application of BDNF (Shirayama et al., 2002; Hoshaw et al., 2005) results in antidepressant-like effects. BDNF signalling through TrkB is not only involved in chronic effects, but also triggers acute responses to antidepressants (Saarelainen et al., 2003; Rantamaki et al., 2007). Furthermore, the Val66Met polymorphism is associated with an increased risk of depression, increased vulnerability to stress, as well as with altered antidepressant response (Chen et al., 2006; Verhagen et al., 2010; Yu et al., 2012). Interestingly, using a transgenic mouse model expressing this mutant BDNF, Bath et al. recently provided evidence that the SSRI fluoxetine alters depression-relevant behaviour by mechanisms of synaptic plasticity other than neurogenesis (Bath et al., 2012). Taken together, the findings outlined above suggest a strong connection between BDNF, depression, and serotonergic neurotransmission. Indeed the interaction between serotonin and BDNF has been the topic of much experimental investigation (reviewed in Martinowich & Lu, 2007). BDNF gene transcription is regulated by cAMP response element-binding (CREB) protein (Conti et al., 2002), a transcription factor, which can be activated downstream of 5-HT receptors positively coupled to adenylyl cyclase (Martinowich & Lu, 2007). In particular, the 5-HT4 receptor has been implicated in CREB activation linked to enhanced neurogenesis (Lucas et al., 2007). Thus, decreased levels of extracellular 5-HT as a result of increased SERT activity would be expected to negatively regulate BDNF expression as studies utilising 5-HT depletion suggest (Zetterstrom et al., 1999). While extracellular

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serotonin levels can influence BDNF expression, BDNF in turn regulates serotonin levels by influencing transporter activity. Studies in the hippocampus of BDNF deficient (heterozygote BDNF+/−) mice demonstrated that SERT-dependent 5-HT clearance rates are reduced resulting in elevated extracellular levels of serotonin (Daws et al., 2007; Guiard et al., 2008). Conversely, BDNF infusion into the hippocampus of wild type rats decreases extracellular 5-HT levels by increasing the rate of 5-HT clearance (Benmansour et al., 2008), likely by enhancing SERT activity. Taken together these findings offer compelling evidence for a reciprocal regulatory mechanism between serotonin and BDNF which could serve as a feedback loop to keep the expression and activity of both factors in balance, thus contributing to homeostasis in neuronal activity in the hippocampus and other brain regions such as the prefrontal cortex. 3. Depression and inflammation 3.1. Cytokines hypothesis of depression Over the past two decades the links between the immune system and the CNS have become ever more apparent. The brain is no longer considered an immune privileged organ, it is now recognised that the brain has a working, highly regulated immune system, comprised of both humoral and cellular immune factors (Eyre & Baune, 2012; Ransohoff & Brown, 2012), all of which are engaged in bi-directional communication with the immune system in the periphery (Maier, 2003). Immune system challenge and inflammation in the periphery can induce inflammatory states and increased production of proinflammatory cytokines in the CNS, this, in turn, can regulate a range of processes in the CNS including neurotransmission (Szelényi, 2001), neurotransmitter metabolism (Myint & Kim, 2003; Dunn, 2006) and neurogenesis (Russo et al., 2011; Eyre & Baune, 2012). The link between the CNS and the peripheral nervous system renders the brain sensitive to fluctuations in immune system homeostasis; for this reason many psychological disorders such as depression are now being studied in the context of immune function. Indeed, there is a growing body of evidence linking the immune system to the pathogenesis of depression. The cytokine hypothesis, originally proposed by Smith in the early 1990s as the macrophage hypothesis (Smith, 1991) suggests that the chronic action of pro-inflammatory cytokines in the CNS may induce a number of behavioural responses we recognise as symptoms of depression (Dantzer et al., 2008). Inflammation is the body's normal response to infection which is known to cause a set of behavioural changes collectively called sickness behaviour in humans and animals. Many of the symptoms of sickness behaviour overlap considerably with the core symptoms of depression, for example lethargy, social withdrawal, loss of appetite and anhedonia. Sickness behaviour is thought to be an advantageous adaptive behaviour in evolutionary terms to ensure an organism's survival during periods of illness. Under normal circumstances the immune system should effectively clear the source of infection, inflammation is transient and the immune system returns to homeostasis. Sickness behaviour soon resolves as this adaptive behavioural response is no longer advantageous. The cytokine hypothesis proposes that depression in patients may be a maladaptive sickness behaviour as a result of chronic immune system activation (Dantzer et al., 2008). Indeed clinical evidence supports this idea of immune mediated depression. Some depressed patients who are otherwise healthy display increased levels of pro-inflammatory cytokines and other inflammatory biomarkers both in the periphery and in the cerebrospinal fluid compared to non-depressed individuals (Miller et al., 2009). A recent meta-analysis of cytokine levels in patients with major depression identified significantly higher levels of tumour necrosis factor α (TNFα) and interleukin-6 (IL-6), but no significant changes for other cytokines (Dowlati et al., 2010). Interestingly, SSRI antidepressant therapy appears to be associated with a normalisation of plasma cytokines levels (Hannestad et al., 2011) and patients with treatment-resistant

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depression have elevated plasma cytokine levels compared to patients in remission (O'Brien et al., 2007; Yoshimura et al., 2009). Another observation supporting the cytokine hypothesis is the higher incidence of depression among patients suffering from diseases with a chronic inflammatory component like rheumatoid arthritis, multiple sclerosis, cardiovascular diseases, type 2 diabetes and many cancers (Loftis et al., 2010). It has been recognised for many years that cytokines can exert a considerable effect on mood and behaviour as therapeutic administration of cytokines such as interleukin-2 and interferon-α (INFα) to treat cancers or viral infection often results in severe depression as a side effect (Dunn et al., 2005) and SSRIs are often co-prescribed to counteract these effects. The molecular mechanisms of cytokine-induced sickness and depression-like behaviour have been extensively studied in animal models of cytokine-induced depression, in particular peripheral administration of lipopolysaccharide (LPS) to mimic bacterial infection. One of the prominent pathways identified centres around the upregulation of indolamine 2,3-dioxygenase (IDO), an enzyme which initiates the conversion of tryptophan into kynurenine and on to quinolinic acid in microglia or kynurenic acid in astrocytes. Expression of IDO in the brain is normally very low, but can be induced by pro-inflammatory cytokines, such as TNFα and interferon-γ. Peripheral administration of LPS causes IDO-dependent depression-like behaviour in rodents, possibly via NMDA receptor agonism by quinolinic acid, a mechanism which also supports a role for glutamate in depression-like behaviour (O'Connor et al., 2009). In addition, by causing an enhanced degradation of tryptophan, IDO activation is thought to cause the depletion of the essential precursor for serotonin biosynthesis. For a detailed discussion of the role of IDO in cytokine-induced depression-like behaviour see previously published reviews (Dantzer et al., 2008, 2011). Pro-inflammatory cytokines are not only involved in mood symptoms triggered by acute or chronic central or peripheral inflammation, they are also likely to play a prominent role in stress-induced depression (Barrientos et al., 2003; Koo & Duman, 2008; Koo et al., 2010). In fact, in addition to physical and psychological stress, inflammation has been viewed as another stressor leading to depression and related mood disorders through converging and synergistic pathways (Anisman, 2009; Audet & Anisman, 2013). Furthermore, the crosstalk between the endocrine and the immune system in depression has been extensively studied (Krishnan & Nestler, 2008; Anisman, 2009). For example, studies in depression relevant animals models, such as chronic mild stress and learned helplessness show that stress induced depression is accompanied by elevated cytokine levels (Nguyen et al., 1998; Goshen et al., 2008; You et al., 2011; Couch et al., 2013). Consistent with the concept that microglia are the primary source of pro-inflammatory cytokines in the brain, there is also evidence of microglia activation upon stress exposure (reviewed in F. R. Walker et al., 2013). Interestingly, while acute stress causes microglia activation, chronic stress was found to be associated with a reduction in microglia number, in particular in the hippocampus (Kreisel et al., 2014), consistent with a distinct role for microglia in neuronal plasticity (see below). 3.2. Neuroplasticity and neurotrophins as targets in cytokine-induced depression Immune modulators in the brain affect neuroplasticity and neurotrophin expression differentially. In the CNS BDNF is predominantly expressed by neurons and under basal conditions fairly low amounts of BDNF are produced by astrocytes and microglia. However, neurotrophin expression can be upregulated in these cell types under pathophysiological conditions (Zafra et al., 1992; Dougherty et al., 2000). In particular, in microglia as the primary mediators of neuroinflammation, BDNF expression is dependent on their state of activation and thus, these cells have both protective and neurotoxic effects on neuronal plasticity (Ekdahl et al., 2009; Kettenmann et al., 2011;

Kohman & Rhodes, 2013). Neuroinflammatory activation of microglia as a result of LPS administration has inhibitory effects on neurogenesis (Monje et al., 2003; Ekdahl et al., 2009). Levels of neurotrophins, in particular BDNF are negatively affected by high concentrations of proinflammatory cytokines (Eyre & Baune, 2012). In the rat brain BDNF levels are downregulated as a result of peripheral administration of LPS (Guan & Fang, 2006; Schnydrig et al., 2007), intranigral LPS infusion (Hritcu & Gorgan, 2014) and polyinosinic:polycytidylic acid (poly I:C) injection (Kranjac et al., 2012; Gibney et al., 2013). BDNF downregulation associated with CNS inflammation has also been observed in the hippocampus of peripheral tumour bearing mice (Yang et al., 2014). In cancer patients, INFα therapy lowers serum BDNF levels and BDNF levels are correlated with depressive symptoms (Kenis et al., 2011). In contrast, chronic activation or the interaction with T cells promotes a protective phenotype of microglia leading to enhanced secretion of anti-inflammatory cytokines and neurotrophins (Colton, 2009; Kettenmann et al., 2011; Yirmiya & Goshen, 2011). Interestingly, neurogenesis and BDNF levels are reduced in immunodeficient mice lacking T-cells and B-cells (Ziv et al., 2006). Furthermore, physiological concentrations of cytokines such as interleukin-1β (IL-1β), IL-6, and TNFα were found to promote neurogenesis and other forms of neuroplasticity (Yirmiya & Goshen, 2011; Eyre & Baune, 2012). Recently, Parkhurst et al. showed that microglia-derived BDNF supports synaptic plasticity in a localised, activity-dependent fashion (Parkhurst et al., 2013). Furthermore, in astrocytes, pro-inflammatory cytokines activate BDNF expression (Meeuwsen et al., 2003; Saha et al., 2006). Taken together, these studies suggest an important role for immune system cells and cytokines in normal maintenance of neuroplasticity. The balance of neuroprotective versus neurotoxic effects is also likely to play a role in depression. 3.3. SERT as a target in inflammation-induced depression The fact that SSRIs are an effective treatment for depressive symptoms presenting as side effects in immunotherapy suggests a role for the serotonin transporter in immune associated depressive disorders. The first evidence that cytokines can regulate SERT came in 1995 when Ramamoorthy et al. demonstrated IL-1β regulation of SERT expression in human JAR choriocarcinoma cells (Ramamoorthy et al., 1995). Upregulation of SERT by IL-1β was shown to be dependent on the IL-1β receptor, potentially involving activation of transcription factor NFκB (Kekuda et al., 2000). A number of other cytokines were also shown to enhance SERT activity in peripheral cell lines (Morikawa et al., 1998; Mossner et al., 1998; Tsao et al., 2008). However, the question of whether cytokines regulate SERT in CNS cells has only recently been addressed. Both TNFα and IL-1β induce an acute, transient upregulation of SERT activity in vitro in cultured raphe neurons and mouse brain synaptosomes (Zhu et al., 2006). Kinetic measurements suggest that both cytokines upregulate SERT activity by reducing the the apparent substrate affinity (Km), while TNFα also increases the maximal transport capacity (Vmax) for serotonin uptake. The first study of cytokine regulation of SERT in vivo used short-term stimulation of up to two hours with LPS in mice to mimic the acute immune response to bacterial infection. The study found that LPS treatment upregulated SERT activity and was associated with a depression-like behavioural despair. Furthermore, LPS-mediated stimulation of SERT activity was abolished in IL-1β receptor knockout mice, and the associated behavioural despair was absent in SERT knockout mice (Zhu et al., 2010). A similar study in rats confirmed that LPS-induced depressionlike behaviour, specifically anhedonia, is dependent on SERT (van Heesch et al., 2013a). The notion that SERT activity is enhanced upon inflammatory challenge is consistent with observations of increased 5-HT turnover (Dunn, 2006; O'Connor et al., 2009; van Heesch et al., 2014). Similar to LPS treatment, intraperitoneal TNFα injection causes depression-

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like behaviour in mice, accompanied by an enhanced serotonin and dopamine turnover attributed to elevated activities of the respective transporters (van Heesch et al., 2013b). Furthermore, SERT activity was also found to be upregulated in other neuroinflammatory models (Katafuchi et al., 2005; Fu et al., 2011). Cytokine-mediated stimulation of neuronal SERT activity appears to be short-lived, and due to posttranslational mechanisms (Zhu et al., 2006). In contrast, the enhancement of SERT activity in peripheral cells lines mentioned above (Ramamoorthy et al., 1995; Morikawa et al., 1998; Mossner et al., 1998, 2001; Kekuda et al., 2000; Tsao et al., 2008) was found to be transcription dependent. No evidence for gene expression dependent SERT regulation in neurons has yet been reported. However, recent studies in our laboratory have shown that prolonged treatment with TNFα increases SERT mRNA levels and SERT activity in primary astrocytes and C6 glioma cells (Malynn et al., 2013), suggesting cell-type specific mechanisms of SERT regulation by pro-inflammatory cytokines. It is not yet known whether enhanced SERT activity in chronic models of cytokine-induced depression-like behaviour is due to enhanced neuronal or glial SERT expression and/or activity. To our knowledge there is, to-date, no direct evidence for enhanced SERT activity in astrocytes in vivo, and under basal conditions very little SERT appears to be expressed in astrocytes in vivo (Huang & Pickel, 2002). However, since SERT gene expression in the brain is largely restricted to serotonergic neurons in the raphe nuclei, an increase in mRNA levels in another brain region without a concomitant increase in the raphe would indicate either expression in non-serotonergic neurons or SERT expression within the local glial cell population. For example, treatment of organotypic hippocampal slices with the HIV Tat protein, a molecule that induces depression-like behaviour in mice, resulted in an increase of SERT mRNA levels at a time interval (6 to 12 h) that follows the peak of TNFα mRNA expression (2 h) (Fu et al., 2011). Also, in a chronic stress model of depression, inflammatory markers such as microglia activation and pro-inflammatory cytokine expression were found to be elevated in sensitive, but not resilient animals. SERT mRNA was significantly upregulated in the prefrontal cortex but not in the raphe, again only in sensitive animals (Couch et al., 2013). While these studies suggest stress- and/or cytokine-induced increase in SERT expression outside of serotonergic neurons, it remains to be shown if enhanced glial SERT expression contributes to alterations in the serotonergic system under chronic inflammatory conditions in vivo. Nonetheless, enhanced astrocytic SERT activity would be consistent with the observed increase in 5-HT turnover in various animal models (Dunn et al., 2005; Dantzer et al., 2011), as 5-HT taken up into astrocytes would be rapidly metabolised, leaving a smaller portion of neurotransmitter available for recycling into presynaptic nerve terminals. As a consequence, neurons are likely to enhance synthesis of 5-HT and would under these conditions have greater demands for the precursor tryptophan. Interestingly, increases in brain content of tryptophan have been observed in the LPS model (O'Connor et al., 2009), suggesting enhanced active transport of tryptophan across the blood–brain barrier. On the other hand, as already outlined in Section 3.1, LPS stimulated IDO will compete with tryptophan hydroxylase, the rate limiting enzyme for 5-HT synthesis, for the available tryptophan. And while the increase in brain tryptophan levels appears to be independent of IDO activation (O'Connor et al., 2009), prolonged diversion of tryptophan into IDO-dependent pathways could potentially diminish the rate of 5-HT synthesis, and prevent it from meeting demands under neuroinflammatory conditions. Interestingly, both the acute stimulation of neuronal SERT activity in vitro and in vivo (Zhu et al., 2006, 2010) and the gene expression regulation in astrocytes (Malynn et al., 2013) were found to be dependent on p38 MAPK activation. Despite recently published contradicting findings (Andreetta et al., 2013), these studies imply a prominent role for the p38 MAPK pathway in cytokine-mediated regulation of SERT. Furthermore, independently of cytokine activation, p38 MAPK affects SERT activity by a number of mechanisms in various cell and tissue

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models (Steiner et al., 2008). Actually, SERT activity appears to be constitutively upregulated in synaptosomes in a p38-dependent manner (Samuvel et al., 2005). Moreover, p38 MAPK has been found to be an essential mediator of stress-induced behaviour through the modulation of serotonergic functions, including SERT activity (Bruchas et al., 2011; Schindler et al., 2012). It is tempting to speculate that stress and cytokine dependent pathways converge at the level of p38 MAPK activation to bring about an increase in SERT function. As outlined in Section 3.1 above, both stress and inflammatory challenge activate microglia, thereby enhancing secretion of pro-inflammatory cytokines, which in turn trigger p38 MAPK activation downstream of cytokine receptors located on neurons and astrocytes. 4. The serotonin transporter and neuronal plasticity in inflammation-induced depression 4.1. Model of inflammation triggered perturbation of serotonin-BDNF homeostasis As outlined above, the past few years have seen a growing body of evidence regarding the regulation of CNS SERT function by peripheral and central immune system activation. However, taken in isolation, these observations of cytokine-induced alterations of SERT activity go little further toward understanding the pathogenesis of depression than the early monoamine hypothesis. A greater understanding of the molecular, cellular and structural consequences of alterations in SERT function by the immune system could hold the key towards linking immune system dysfunction to mood disorders. Neuroplastic changes, including neurogenesis were shown to be regulated both by inflammation and by serotonin. However, such findings have generally been reported in separate studies, and the link between inflammationinduced SERT regulation and altered neuroplasticity in the hippocampus and other brain regions has received little attention. This is somewhat surprising since the hippocampus is known to be highly innervated with serotonergic nerve terminals (Hensler, 2006) and on the other hand, the density of receptors for the pro-inflammatory cytokines IL-1β, IL-6, TNFα and interleukin-2 is highest in the hippocampus (Wilson et al., 2002). Thus, given that the activation of cytokine receptors results in an upregulation of SERT activity (see previous section), the high density of these receptors in the hippocampus suggests that SERT activity is likely to be influenced by immune system perturbations in this region. In addition, SERT function regulation in other brain regions may play an important role as well. For example, BDNF and TrkB levels are downregulated in depressed patients and in animal models of depression in the prefrontal cortex, which is heavily innervated by serotonergic neurons (Autry & Monteggia, 2012). In LPS and poly I:C models of infection cytokines are upregulated not only in the hippocampus, but also in the prefrontal cortex (Guan & Fang, 2006; Gibney et al., 2013). Furthermore, acute LPS treatment enhanced SERT activity in a number of brain regions, including the frontal cortex to a similar extent (Zhu et al., 2010). So, what is the relevance of serotonin transporter regulation by immune modulators for the aetiology of depression and the action of antidepressant drugs? We propose here a model for SERT dependent mechanisms of cytokine-induced changes in BDNF expression and signalling relevant for neurochemical changes and altered neuroplasticity in depression, which is illustrated in Fig. 1. As previously discussed in Section 2.2, under physiological conditions SERT activity and BDNF levels mutually regulate each other generating reciprocal feedback loops. More specifically, high levels of BDNF release result in an upregulation of SERT activity, which in turn increases 5-HT clearance and reduces activation of Gs-coupled 5-HT receptors, such as 5-HT4. Consequently, 5-HT receptor induced activation of CREB is downregulated resulting in reduced BDNF expression. Conversely, at lower BDNF levels SERT activity is attenuated, hence 5-HT clearance rates are reduced resulting in enhanced 5-HT receptor

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A) Normal physiological conditions

B) Inflammatory conditions STRESS or INFLAMMATION

serotonergic terminus

serotonergic terminus

glutamatergic terminus

resting microglia

glutamatergic terminus

p38

2

2

6

activated microglia pro-inflammatory, neurotoxic 1

5HT

?

3 5HT

5HIAA

BDNF

BDNF

2

1 p38

astrocyte

astrocyte

3 CREB

4

P

CREB

postsynaptic dendrite

postsynaptic dendrite

C) Antidepressant therapy Glutamate receptor

SERT TrkB

Cytokine receptor

5-HT receptor

5-HT

glutamate

BDNF

pro-inflammatory cytokine

serotonergic terminus glutamatergic terminus

p38

Resting microglia, neuroprotective 7

Ketamine

8

?

3

2

1 SSRI 1 5HT

6 BDNF

4 astrocyte

5 CREB

P

postsynaptic dendrite

5

J. Haase, E. Brown / Pharmacology & Therapeutics 147 (2015) 1–11

activity and increased CREB-dependent BDNF expression. This interdependent regulation of SERT and BDNF ensures maintenance of homeostatic balance between monoamine and neurotrophin signalling, which is highly relevant for the physiological functioning of neuronal circuits (Fig. 1A). Under inflammatory conditions, microglia become activated and cytokine-dependent signalling pathways, such as the p38 MAPK pathway, upregulate SERT activity in neurons and/or glial cells independently of BDNF levels. Enhanced SERT activity then leads to a reduction in 5-HT receptor dependent BDNF gene expression. Since microglia activation and elevation of pro-inflammatory cytokines are part of the brain's response to chronic stress as mentioned previously, this mechanism may also play a role in stress-induced depression. Hence, cytokineinduced upregulation of brain SERT activity could tip the balance toward decreased extracellular serotonin levels and ultimately result in a decrease in BDNF expression. Thus, it seems plausible to conclude that inflammation negatively influences the maintenance and survival of neurons and dendrite architecture in the hippocampus via SERTdependent downregulation of BDNF signalling (Fig. 1B). 4.2. Cytokine-enhanced serotonin transporter activity — a neuroprotective mechanism? It should be noted that SERT activity regulation may be beneficial during short-term cytokine or stress exposure. For example, SERT upregulation would help to counteract enhanced 5-HT release seen as a result of stress and cytokine treatment (Linthorst et al., 1996; Merali et al., 1997; Dunn, 2006). Furthermore, 5-HT itself may be regarded as pro-inflammatory. A large body of evidence exists for 5-HT receptor involvement in immune modulation in the periphery (Meredith et al., 2005; Ahern, 2011; Baganz & Blakely, 2013). Moreover, 5-HT by acting at 5-HT7 receptors induces cytokine expression in astrocytes (Pousset et al., 1996; Lieb et al., 2005) and microglia (Mahe et al., 2005). Serotonin appears to have distinct effects on microglia activation, i.e. serotonin receptor activation enhances injury-induced motility of microglia processes but decreases their phagocytic activity (Krabbe et al., 2012). Basal and LPS-induced cytokine levels and microglia activation are increased in the hippocampus of SERT knockout and heterozygote mice, suggesting a critical role for SERT as a regulator of 5-HT availability in the modulation of the brain's immune system and the response to peripheral infection (Macchi et al., 2013). Depending on the conditions, BDNF levels may not actually be significantly affected or may even be enhanced during immune activation (Audet & Anisman, 2013). Microglia exhibiting a neuroprotective phenotype express BDNF and may compensate for any reduction in neuronal BDNF expression and/or release (Kohman & Rhodes, 2013). As mentioned above, cytokine activated astrocytes were also found to express and release BDNF, suggesting a contribution by this cell type to neuroprotective mechanisms (Saha et al., 2006). However, as outlined in Section 3.1 chronic stress was found to result in a reduction of microglial cell numbers (Kreisel et al., 2014). While this may cause an overall decrease in cytokine levels in the affected brain region,

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neuroprotective functions of microglia, including BDNF release, would also be diminished, potentially contributing to neuronal dysfunction and the development of depressive symptoms. Thus, beneficial responses to infection or other stressors, including the increase in SERT activity may become maladaptive if not resolved in due course, for example in chronic inflammatory diseases or under conditions of chronic stress. The prolonged upregulation of SERT and the resulting modification in serotonergic signalling may ultimately contribute to depletion of BDNF levels and alterations in neuroplasticity. 4.3. Mechanism of antidepressant therapy in the context of cytokine-induced depression The increase in BDNF expression upon antidepressant therapy is a consistent finding in human and animal studies. In addition to their chronic effects, SSRI antidepressants appear to cause a rapid increase in BDNF signalling through TrkB receptors (Rantamaki et al., 2007), suggesting a role for 5-HT receptors in both the expression and also the release of BDNF. Acute increases in BDNF levels downstream of 5-HT receptors may be mostly due to indirect mechanisms, i.e. via enhancement of glutamatergic neurotransmission (Pehrson & Sanchez, 2014). Notably, the augmentation of BDNF release as a result of NMDA receptor dependent disinhibition of glutamate signalling and enhanced AMPA receptor activation is thought to underlie the fast, but transient antidepressant action of ketamine (Browne & Lucki, 2013). Interestingly, by blocking NMDA receptors, ketamine can also counteract the effects of the NMDA agonist quinolinic acid, a downstream product of IDO in LPS-induced depressive-like behaviour (A. K. Walker et al., 2013; Yang et al., 2013), supporting a role for glutamate signalling also in cytokine-induced depression (see also Section 3.1). However, despite evidence of acute effects of SSRI antidepressants, long-term treatment over a number of weeks or even months is required to achieve remission in responding patients (see also introductory remarks). Several mechanisms have been proposed to explain the delayed response to antidepressant therapy. It has long been suggested that in the early stages of SSRI antidepressant treatment the enhancement of extracellular 5-HT levels is limited due to the activation of 5-HT autoreceptors, namely 5-HT1A and 5-HT1B, which inhibit 5-HT neuronal firing and transmitter release (Artigas, 2013). In addition, the rise in extracellular 5-HT levels may also be suppressed by lowaffinity transporters, such as OCT3 and PMAT (see Section 2.1), which can compensate for the lack of 5-HT uptake through SERT. For example, OCT3 was shown to be up-regulated in SERT knockout mice (Baganz et al., 2008), and inhibition of OCT3 enhanced the antidepressant effect of SSRIs (Horton et al., 2013). An insufficient elevation of 5-HT levels is likely to be responsible for the ineffective activation of cAMP-coupled 5-HT receptors, such as 5-HT4, upstream of CREB-dependent BDNF expression. This is also consistent with recent studies reporting fastonset antidepressant action and potentiation of SSRI antidepressant effects by a 5-HT4 agonist (Lucas et al., 2007, 2010). Additional mechanisms underlying the delayed therapeutic effect of SSRIs can be deducted from our model of reciprocal regulation of BDNF

Fig. 1. Model of reciprocal regulation of SERT and BDNF activity in the context of inflammation-induced depression and antidepressant treatment. A) Under normal physiological conditions, BDNF is released from neurons in an activity dependent manner (1). BDNF via its receptor TrkB enhances SERT activity (2). Increased activity of SERT results in a reduction of extracellular 5-HT, diminishing 5-HT receptor-dependent CREB activation and BDNF gene expression (3). The reciprocal regulation of SERT activity and BDNF levels contributes to homeostatic balance between monoamine and neurotrophin signalling. B) Under inflammatory conditions (or resulting from stress exposure), microglial cells and astrocytes become activated and release large amounts of pro-inflammatory cytokines (1). Cytokine and stress dependent pathways enhance SERT activity in neurons, as well as increase SERT gene expression in astrocytes. Both processes are mediated by p38 MAPK dependent pathways. Enhanced 5-HT uptake into astrocytes promotes 5-HT degradation to 5-hydroxyindolacetic acid (5HIAA) (2). Increased SERT activity results in a reduction of extracellular 5-HT levels, causing an attenuation of signalling through pre- and postsynaptic 5-HT receptors (3). CREB-dependent BDNF gene expression is reduced (4) and as a consequence BDNF level are decreased (5), impacting on various processes of neuroplasticity and leading to depression-associated alteration of relevant brain circuits. In addition, SERT activity regulation is uncoupled from BDNF-dependent mechanisms (6). C) During antidepressant therapy, SSRI antidepressants enhance extracellular 5-HT by blocking SERT and hence reuptake (1). The resulting increase in 5-HT receptor activity positively influences neuronal activity, including glutamatergic signalling (2). Direct activation of glutamatergic signalling as a result of ketamine treatment (3) promotes a rapid, but transient activation of BDNF release (4). SSRI antidepressant mediated increases in 5-HT levels and 5-HT dependent enhancement of glutamatergic signalling is likely to be limited initially, as 5-HT autoreceptor activation negatively regulates 5-HT release. However, chronic antidepressant treatment allows for enhanced CREB dependent BDNF gene expression (5), promoting long-term recovery of BDNF levels (6). In addition, antidepressant treatment directly or indirectly facilitates the switch from a neurotoxic to a neuroprotective phenotype of microglia suppressing the release of pro-inflammatory cytokines (7). Ultimately, antidepressants contribute to the normalization of reciprocal feedback regulation between SERT and BDNF (8).

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and SERT activity. Firstly, it seems plausible that sustained SERT inhibition is necessary to maintain elevated 5-HT levels over a long period of time to allow for de-novo synthesis and the accumulation of sufficiently high levels of BDNF. However, as long as stress or inflammation dependent pathways that enhance SERT activity, such as the p38 MAPK pathway, remain active, premature discontinuation of SERT blockage could cause counter-productive feedback regulation between SERT and BDNF as described above. Therefore, secondly, a sustained therapeutic antidepressant effect necessitates the normalisation of the microglia activation state, i.e. the suppression of the neurotoxic phenotype and a switch to the neuroprotective phenotype, hence the downregulation of pro-inflammatory SERT activating pathways (Fig. 1C). Various antidepressants may have a direct inhibitory effect on microglia (see for example Tynan et al., 2012), although in this and other in vitro studies relatively high antidepressant concentrations were required to reduce pro-inflammatory activities of LPS stimulated microglia. The effective antidepressant concentrations were actually above the upper plasma concentration for these drugs (Haenisch et al., 2012), raising doubts that SSRIs could directly suppress cytokine release from microglia in vivo. However, serotonin itself and several other neurotransmitters are known to affect microglia phenotypes (Krabbe et al., 2012; Pannell et al., 2014). So perhaps by increasing 5-HT levels, SSRI antidepressants influence microglia activation states indirectly. Alternatively, microglia phenotypes may be altered by recovering neuronal activity, as the microglia activation state is strongly dependent on the interaction with neurons, i.e. physiological neuronal activity keeps microglia in a quiescent state (Biber et al., 2007; Kettenmann et al., 2013). In particular, the chemokine CX3CL1 (also known as fractalkine), which is constitutively released from neurons under physiological conditions inhibits neurotoxic microglia activation (Cardona et al., 2006). Interestingly, in CX3CL1 knockout mice the duration of LPS-induced depression-like behaviour was prolonged and associated with persistent microglia activation (Corona et al., 2010). Thus, the normalisation of neuronal network activity in the course of long-term antidepressant therapy may also promote the downregulation of the pro-inflammatory, neurotoxic phenotype of microglia. Several studies have tested the efficacy of anti-inflammatory drugs as antidepressants. For example, in a clinical trial of anti-TNFα (etanercept) treatment for psoriasis, a significant alleviation of depressive symptoms was observed, an effect that was in fact largely uncorrelated to the improvement of skin inflammation (Tyring et al., 2006). However, in another study, among patients with treatment-resistant depression who were treated using infliximab (anti-TNFα), only those who had high baseline TNFα levels showed a significant response (Raison et al., 2013). Moreover, nonsteroidal anti-inflammatory drugs (NSAID) may even antagonize the response to SSRI antidepressants (Warner-Schmidt et al., 2011). So, perhaps the restoration of “healthy”, i.e. proneurogenic cytokine levels, rather than the complete blockage of certain cytokines could hold the key to successful antidepressant therapy. 4.4. SERT and BDNF polymorphisms modulating susceptibility to inflammation-induced depression and response to antidepressants The proposed model of reciprocal regulation of SERT and BDNF activities described above also provides a framework towards a better molecular understanding of consequences of commonly occurring polymorphisms of the SLC6A4 (SERT) gene and the Bdnf gene in relation to the susceptibility of individuals to develop depression or to respond to antidepressant therapy. Variants of the SLC6A4 gene and their combination result in substantial differences in SERT expression and/or activity. These variants are linked to a number of neuropsychiatric disorders as well as conferring susceptibility in particular to depression through interaction with environmental factors such as stressful life events (Murphy & Moya, 2011). The common Val66Met polymorphism of the Bdnf gene was found to be associated with increased susceptibility to

depression and with altered response to antidepressant treatment in combination with stress (Yu et al., 2012; Hosang et al., 2014). As mentioned earlier (see Section 2.2), the Val66Met mutant is characterised by impaired BDNF mRNA trafficking and posttranslational maturation, hence reduced secretion of mature BDNF protein. The limited availability of dendritic, locally releasable BDNF in this mutant is thought to underlie the lack of response to the fast acting antidepressant ketamine (Liu et al., 2012). In relation to immune stressors, women with the SLC6A4 5-HTTLPR SS genotype had a more pronounced pro-inflammatory phenotype at baseline and following acute stress exposure compared to individuals with the LL phenotype (Fredericks et al., 2010). Furthermore, a number of studies report a link between genetic variants of SLC6A4 and susceptibility to develop depression in the course of INFα treatment in hepatitis C patients (Lotrich et al., 2009; Pierucci-Lagha et al., 2010; Smith et al., 2011). Interestingly, in patients undergoing INFα treatment, the SLC6A4 5-HTTLPR and the Bdnf Val66Met polymorphisms were independently correlated with depression-relevant or neurovegetative symptoms respectively, and lower pretreatment levels of BDNF were associated with higher depression symptoms (Lotrich et al., 2013). Taken together, it seems plausible that SLC6A4 and Bdnf polymorphisms contribute to an individual's susceptibility to develop depression in response to an immune challenge, i.e. genetically determined variations in expression levels and activity of SERT and BDNF are likely to impact on the robustness of the reciprocal regulatory pathways and thus, the ability to adequately respond to perturbations caused by immune activation. 5. Future directions While the model we proposed here is consistent with published findings, the finer details of the molecular mechanisms of SERT activity regulation by BDNF and how these relate to alterations observed in inflammatory conditions, including microglia activation are largely unknown. While several studies have demonstrated that BDNF enhances SERT activity (Daws et al., 2007; Benmansour et al., 2008; Guiard et al., 2008), the signalling pathways involved remain obscure. Presumably BDNF acts through TrkB, however, the downstream effectors involved in SERT regulation are still unknown. Future studies will also need to address the role of glial cells in the regulation of serotonin homeostasis during immune activation and in response to other stressors. So far, cytokine triggered functional expression of SERT in astrocytes has only been shown in vitro (Malynn et al., 2013). While the idea of pathophysiological and perhaps neuroprotective upregulation of SERT in astrocytes is intriguing, suitable in vivo approaches are needed to test this hypothesis. It is likely that changes in SERT expression play a role in human depression induced by chronic inflammatory disorders. A clinical proof of concept study in human rheumatoid arthritis patients has shown that peripheral TNFα blockade reduced SERT density in the brain (Cavanagh et al., 2010). Furthermore, in multiple sclerosis patients SERT availability appears to be altered in a brain region and disease subtype dependent manner. For example, in patients with primary progressive disease SERT density was increased in prefrontal brain areas (Hesse et al., 2014). These studies indicate that the state of peripheral and central inflammation can affect SERT density in the human brain. Clearly, more research is needed to uncover clinically relevant molecular mechanisms of SERT regulation in chronic inflammatory disorders. However, to-date most studies using animal models rely on administration of LPS and poly I:C or direct application of pro-inflammatory cytokines, representing relatively acute disease models lasting only hours to a few days. Given that chronic inflammatory diseases, as well as depression, develop over a much longer time period, these acute models may not be suitable to address outstanding questions. Future studies should therefore also utilise animal models of chronic inflammatory disorders, such as rheumatoid arthritis, multiple sclerosis, diabetes and others,

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which are well established and widely used to study molecular mechanisms of immune system perturbation but have so far seen limited application to study inflammation-induced depression. Conflict of interest The authors declare there are no conflicts of interest. Acknowledgment EB is funded by the MolCellBiol PhD Programme, under the Programme for Research in Third-Level Institutions, co-funded under the European Regional Development Fund. References Advani, T., Koek, W., & Hensler, J.G. (2009). Gender differences in the enhanced vulnerability of BDNF+/− mice to mild stress. Int J Neuropsychopharmacol 12, 583–588. Ahern, G.P. (2011). 5-HT and the immune system. Curr Opin Pharmacol 11, 29–33. Andreetta, F., Barnes, N.M., Wren, P.B., & Carboni, L. (2013). p38 MAP kinase activation does not stimulate serotonin transport in rat brain: Implications for sickness behaviour mechanisms. Life Sci 93, 30–37. Anisman, H. (2009). Cascading effects of stressors and inflammatory immune system activation: Implications for major depressive disorder. J Psychiatry Neurosci 34, 4–20. Artigas, F. (2013). Serotonin receptors involved in antidepressant effects. Pharmacol Ther 137, 119–131. Audet, M.C., & Anisman, H. (2013). Interplay between pro-inflammatory cytokines and growth factors in depressive illnesses. Front Cell Neurosci 7, 68. Autry, A.E., & Monteggia, L.M. (2012). Brain-derived neurotrophic factor and neuropsychiatric disorders. Pharmacol Rev 64, 238–258. Baganz, N.L., & Blakely, R.D. (2013). A dialogue between the immune system and brain, spoken in the language of serotonin. ACS Chem Neurosci 4, 48–63. Baganz, N.L., Horton, R.E., Calderon, A.S., Owens, W.A., Munn, J.L., Watts, L.T., et al. (2008). Organic cation transporter 3: Keeping the brake on extracellular serotonin in serotonin-transporter-deficient mice. Proc Natl Acad Sci U S A 105, 18976–18981. Baj, G., Carlino, D., Gardossi, L., & Tongiorgi, E. (2013a). Toward a unified biological hypothesis for the BDNF Val66Met-associated memory deficits in humans: A model of impaired dendritic mRNA trafficking. Front Neurosci 7, 188. Baj, G., Del Turco, D., Schlaudraff, J., Torelli, L., Deller, T., & Tongiorgi, E. (2013b). Regulation of the spatial code for BDNF mRNA isoforms in the rat hippocampus following pilocarpine-treatment: A systematic analysis using laser microdissection and quantitative real-time PCR. Hippocampus 23, 413–423. Barrientos, R.M., Sprunger, D.B., Campeau, S., Higgins, E.A., Watkins, L.R., Rudy, J.W., et al. (2003). Brain-derived neurotrophic factor mRNA downregulation produced by social isolation is blocked by intrahippocampal interleukin-1 receptor antagonist. Neuroscience 121, 847–853. Bath, K.G., Jing, D.Q., Dincheva, I., Neeb, C.C., Pattwell, S.S., Chao, M.V., et al. (2012). BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity. Neuropsychopharmacology 37, 1297–1304. Benmansour, S., Deltheil, T., Piotrowski, J., Nicolas, L., Reperant, C., Gardier, A.M., et al. (2008). Influence of brain-derived neurotrophic factor (BDNF) on serotonin neurotransmission in the hippocampus of adult rodents. Eur J Pharmacol 587, 90–98. Berger, M., Gray, J.A., & Roth, B.L. (2009). The expanded biology of serotonin. Annu Rev Med 60, 355–366. Berman, R.M., Cappiello, A., Anand, A., Oren, D.A., Heninger, G.R., Charney, D.S., et al. (2000). Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47, 351–354. Biber, K., Neumann, H., Inoue, K., & Boddeke, H.W. (2007). Neuronal ‘on’ and ‘off’ signals control microglia. Trends Neurosci 30, 596–602. Browne, C.A., & Lucki, I. (2013). Antidepressant effects of ketamine: Mechanisms underlying fast-acting novel antidepressants. Front Pharmacol 4, 161. Bruchas, M.R., Schindler, A.G., Shankar, H., Messinger, D.I., Miyatake, M., Land, B.B., et al. (2011). Selective p38alpha MAPK deletion in serotonergic neurons produces stress resilience in models of depression and addiction. Neuron 71, 498–511. Bruel-Jungerman, E., Rampon, C., & Laroche, S. (2007). Adult hippocampal neurogenesis, synaptic plasticity and memory: Facts and hypotheses. Rev Neurosci 18, 93–114. Bunin, M.A., & Wightman, R.M. (1998). Quantitative evaluation of 5-hydroxytryptamine (serotonin) neuronal release and uptake: An investigation of extrasynaptic transmission. J Neurosci 18, 4854–4860. Bunin, M.A., & Wightman, R.M. (1999). Paracrine neurotransmission in the CNS: Involvement of 5-HT. Trends Neurosci 22, 377–382. Campbell, S., Marriott, M., Nahmias, C., & MacQueen, G.M. (2004). Lower hippocampal volume in patients suffering from depression: A meta-analysis. Am J Psychiatry 161, 598–607. Cardona, A.E., Pioro, E.P., Sasse, M.E., Kostenko, V., Cardona, S.M., Dijkstra, I.M., et al. (2006). Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9, 917–924. Cavanagh, J., Paterson, C., McLean, J., Pimlott, S., McDonald, M., Patterson, J., et al. (2010). Tumour necrosis factor blockade mediates altered serotonin transporter availability in rheumatoid arthritis: A clinical, proof-of-concept study. Ann Rheum Dis 69, 1251–1252.

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Chen, Z.Y., Jing, D., Bath, K.G., Ieraci, A., Khan, T., Siao, C.J., et al. (2006). Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science 314, 140–143. Chen, Z.Y., Patel, P.D., Sant, G., Meng, C.X., Teng, K.K., Hempstead, B.L., et al. (2004). Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci 24, 4401–4411. Colton, C.A. (2009). Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimmune Pharmacol 4, 399–418. Conti, A.C., Cryan, J.F., Dalvi, A., Lucki, I., & Blendy, J.A. (2002). cAMP response elementbinding protein is essential for the upregulation of brain-derived neurotrophic factor transcription, but not the behavioral or endocrine responses to antidepressant drugs. J Neurosci 22, 3262–3268. Corona, A.W., Huang, Y., O'Connor, J.C., Dantzer, R., Kelley, K.W., Popovich, P.G., et al. (2010). Fractalkine receptor (CX3CR1) deficiency sensitizes mice to the behavioral changes induced by lipopolysaccharide. J Neuroinflammation 7, 93. Couch, Y., Anthony, D.C., Dolgov, O., Revischin, A., Festoff, B., Santos, A.I., et al. (2013). Microglial activation, increased TNF and SERT expression in the prefrontal cortex define stress-altered behaviour in mice susceptible to anhedonia. Brain Behav Immun 29, 136–146. Czeh, B., & Lucassen, P.J. (2007). What causes the hippocampal volume decrease in depression? Are neurogenesis, glial changes and apoptosis implicated? Eur Arch Psychiatry Clin Neurosci 257, 250–260. Dantzer, R., O'Connor, J.C., Lawson, M.A., & Kelley, K.W. (2011). Inflammation-associated depression: From serotonin to kynurenine. Psychoneuroendocrinology 36, 426–436. Dantzer, R., O'Connor, J.C., Freund, G.G., Johnson, R.W., & Kelley, K.W. (2008). From inflammation to sickness and depression: When the immune system subjugates the brain. Nat Rev Neurosci 9, 46–56. Daws, L.C. (2009). Unfaithful neurotransmitter transporters: Focus on serotonin uptake and implications for antidepressant efficacy. Pharmacol Ther 121, 89–99. Daws, L.C., Munn, J.L., Valdez, M.F., Frosto-Burke, T., & Hensler, J.G. (2007). Serotonin transporter function, but not expression, is dependent on brain-derived neurotrophic factor (BDNF): In vivo studies in BDNF-deficient mice. J Neurochem 101, 641–651. Dougherty, K.D., Dreyfus, C.F., & Black, I.B. (2000). Brain-derived neurotrophic factor in astrocytes, oligodendrocytes, and microglia/macrophages after spinal cord injury. Neurobiol Dis 7, 574–585. Dowlati, Y., Herrmann, N., Swardfager, W., Liu, H., Sham, L., Reim, E.K., et al. (2010). A meta-analysis of cytokines in major depression. Biol Psychiatry 67, 446–457. Duman, R.S. (1998). Novel therapeutic approaches beyond the serotonin receptor. Biol Psychiatry 44, 324–335. Duman, R.S., & Monteggia, L.M. (2006). A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59, 1116–1127. Duman, C.H., Schlesinger, L., Kodama, M., Russell, D.S., & Duman, R.S. (2007). A role for MAP kinase signaling in behavioral models of depression and antidepressant treatment. Biol Psychiatry 61, 661–670. Dunn, A.J. (2006). Effects of cytokines and infections on brain neurochemistry. Clin Neurosci Res 6, 52–68. Dunn, A.J., Swiergiel, A.H., & de Beaurepaire, R. (2005). Cytokines as mediators of depression: What can we learn from animal studies? Neurosci Biobehav Rev 29, 891–909. Egan, M.F., Kojima, M., Callicott, J.H., Goldberg, T.E., Kolachana, B.S., Bertolino, A., et al. (2003). The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell 112, 257–269. Eisch, A.J., & Petrik, D. (2012). Depression and hippocampal neurogenesis: A road to remission? Science 338, 72–75. Ekdahl, C.T., Kokaia, Z., & Lindvall, O. (2009). Brain inflammation and adult neurogenesis: The dual role of microglia. Neuroscience 158, 1021–1029. Eyre, H., & Baune, B.T. (2012). Neuroplastic changes in depression: A role for the immune system. Psychoneuroendocrinology 37, 1397–1416. Fredericks, C.A., Drabant, E.M., Edge, M.D., Tillie, J.M., Hallmayer, J., Ramel, W., et al. (2010). Healthy young women with serotonin transporter SS polymorphism show a proinflammatory bias under resting and stress conditions. Brain Behav Immun 24, 350–357. Fu, X., Lawson, M.A., Kelley, K.W., & Dantzer, R. (2011). HIV-1 Tat activates indoleamine 2,3 dioxygenase in murine organotypic hippocampal slice cultures in a p38 mitogen-activated protein kinase-dependent manner. J Neuroinflammation 8, 88. Fuxe, K., Dahlstrom, A.B., Jonsson, G., Marcellino, D., Guescini, M., Dam, M., et al. (2010). The discovery of central monoamine neurons gave volume transmission to the wired brain. Prog Neurobiol 90, 82–100. Gibney, S.M., McGuinness, B., Prendergast, C., Harkin, A., & Connor, T.J. (2013). Poly I:C-induced activation of the immune response is accompanied by depression and anxietylike behaviours, kynurenine pathway activation and reduced BDNF expression. Brain Behav Immun 28, 170–181. Gorski, J.A., Zeiler, S.R., Tamowski, S., & Jones, K.R. (2003). Brain-derived neurotrophic factor is required for the maintenance of cortical dendrites. J Neurosci 23, 6856–6865. Goshen, I., Kreisel, T., Ben-Menachem-Zidon, O., Licht, T., Weidenfeld, J., Ben-Hur, T., et al. (2008). Brain interleukin-1 mediates chronic stress-induced depression in mice via adrenocortical activation and hippocampal neurogenesis suppression. Mol Psychiatry 13, 717–728. Guan, Z., & Fang, J. (2006). Peripheral immune activation by lipopolysaccharide decreases neurotrophins in the cortex and hippocampus in rats. Brain Behav Immun 20, 64–71. Guiard, B.P., David, D.J., Deltheil, T., Chenu, F., Le Maitre, E., Renoir, T., et al. (2008). Brainderived neurotrophic factor-deficient mice exhibit a hippocampal hyperserotonergic phenotype. Int J Neuropsychopharmacol 11, 79–92. Haenisch, B., Drescher, E., Thiemer, L., Xin, H., Giros, B., Gautron, S., et al. (2012). Interaction of antidepressant and antipsychotic drugs with the human organic cation

10

J. Haase, E. Brown / Pharmacology & Therapeutics 147 (2015) 1–11

transporters hOCT1, hOCT2 and hOCT3. Naunyn Schmiedebergs Arch Pharmacol 385, 1017–1023. Hannestad, J., DellaGioia, N., & Bloch, M. (2011). The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: A meta-analysis. Neuropsychopharmacology 36, 2452–2459. Hensler, J.G. (2006). Serotonergic modulation of the limbic system. Neurosci Biobehav Rev 30, 203–214. Hesse, S., Moeller, F., Petroff, D., Lobsien, D., Luthardt, J., Regenthal, R., et al. (2014). Altered serotonin transporter availability in patients with multiple sclerosis. Eur J Nucl Med Mol Imaging 41, 827–835. Hornung, J.P. (2003). The human raphe nuclei and the serotonergic system. J Chem Neuroanat 26, 331–343. Horton, R.E., Apple, D.M., Owens, W.A., Baganz, N.L., Cano, S., Mitchell, N.C., et al. (2013). Decynium-22 enhances SSRI-induced antidepressant-like effects in mice: Uncovering novel targets to treat depression. J Neurosci 33, 10534–10543. Hosang, G.M., Shiles, C., Tansey, K.E., McGuffin, P., & Uher, R. (2014). Interaction between stress and the BDNF Val66Met polymorphism in depression: A systematic review and meta-analysis. BMC Med 12, 7. Hoshaw, B.A., Malberg, J.E., & Lucki, I. (2005). Central administration of IGF-I and BDNF leads to long-lasting antidepressant-like effects. Brain Res 1037, 204–208. Hritcu, L., & Gorgan, L.D. (2014). Intranigral lipopolysaccharide induced anxiety and depression by altered BDNF mRNA expression in rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry 51, 126–132. Huang, J., & Pickel, V.M. (2002). Serotonin transporters (SERTs) within the rat nucleus of the solitary tract: Subcellular distribution and relation to 5HT2A receptors. J Neurocytol 31, 667–679. Karege, F., Vaudan, G., Schwald, M., Perroud, N., & La Harpe, R. (2005). Neurotrophin levels in postmortem brains of suicide victims and the effects of antemortem diagnosis and psychotropic drugs. Brain Res Mol Brain Res 136, 29–37. Karg, K., Burmeister, M., Shedden, K., & Sen, S. (2011). The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: Evidence of genetic moderation. Arch Gen Psychiatry 68, 444–454. Katafuchi, T., Kondo, T., Take, S., & Yoshimura, M. (2005). Enhanced expression of brain interferon-alpha and serotonin transporter in immunologically induced fatigue in rats. Eur J Neurosci 22, 2817–2826. Kekuda, R., Leibach, F.H., Furesz, T.C., Smith, C.H., & Ganapathy, V. (2000). Polarized distribution of interleukin-1 receptors and their role in regulation of serotonin transporter in placenta. J Pharmacol Exp Ther 292, 1032–1041. Kenis, G., Prickaerts, J., van Os, J., Koek, G.H., Robaeys, G., Steinbusch, H.W., et al. (2011). Depressive symptoms following interferon-alpha therapy: Mediated by immune-induced reductions in brain-derived neurotrophic factor? Int J Neuropsychopharmacol 14, 247–253. Kettenmann, H., Hanisch, U.K., Noda, M., & Verkhratsky, A. (2011). Physiology of microglia. Physiol Rev 91, 461–553. Kettenmann, H., Kirchhoff, F., & Verkhratsky, A. (2013). Microglia: New roles for the synaptic stripper. Neuron 77, 10–18. Kohman, R.A., & Rhodes, J.S. (2013). Neurogenesis, inflammation and behavior. Brain Behav Immun 27, 22–32. Koo, J.W., & Duman, R.S. (2008). IL-1beta is an essential mediator of the antineurogenic and anhedonic effects of stress. Proc Natl Acad Sci U S A 105, 751–756. Koo, J.W., Russo, S.J., Ferguson, D., Nestler, E.J., & Duman, R.S. (2010). Nuclear factorkappaB is a critical mediator of stress-impaired neurogenesis and depressive behavior. Proc Natl Acad Sci U S A 107, 2669–2674. Koponen, E., Rantamaki, T., Voikar, V., Saarelainen, T., MacDonald, E., & Castren, E. (2005). Enhanced BDNF signaling is associated with an antidepressant-like behavioral response and changes in brain monoamines. Cell Mol Neurobiol 25, 973–980. Krabbe, G., Matyash, V., Pannasch, U., Mamer, L., Boddeke, H.W., & Kettenmann, H. (2012). Activation of serotonin receptors promotes microglial injury-induced motility but attenuates phagocytic activity. Brain Behav Immun 26, 419–428. Kranjac, D., McLinden, K.A., Koster, K.M., Kaldenbach, D.L., Chumley, M.J., & Boehm, G.W. (2012). Peripheral administration of poly I:C disrupts contextual fear memory consolidation and BDNF expression in mice. Behav Brain Res 228, 452–457. Kreisel, T., Frank, M.G., Licht, T., Reshef, R., Ben-Menachem-Zidon, O., Baratta, M.V., et al. (2014). Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis. Mol Psychiatry 19, 699–709. Krishnan, V., & Nestler, E.J. (2008). The molecular neurobiology of depression. Nature 455, 894–902. Lee, B. -H., & Kim, Y. -K. (2010). The roles of BDNF in the pathophysiology of major depression and in antidepressant treatment. Psychiatry Investig 7, 231. Lessmann, V., & Brigadski, T. (2009). Mechanisms, locations, and kinetics of synaptic BDNF secretion: An update. Neurosci Res 65, 11–22. Li, Y., Luikart, B.W., Birnbaum, S., Chen, J., Kwon, C.H., Kernie, S.G., et al. (2008). TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment. Neuron 59, 399–412. Lieb, K., Biersack, L., Waschbisch, A., Orlikowski, S., Akundi, R.S., Candelario-Jalil, E., et al. (2005). Serotonin via 5-HT7 receptors activates p38 mitogen-activated protein kinase and protein kinase C epsilon resulting in interleukin-6 synthesis in human U373 MG astrocytoma cells. J Neurochem 93, 549–559. Linthorst, A.C., Flachskamm, C., Holsboer, F., & Reul, J.M. (1996). Activation of serotonergic and noradrenergic neurotransmission in the rat hippocampus after peripheral administration of bacterial endotoxin: Involvement of the cyclo-oxygenase pathway. Neuroscience 72, 989–997. Liu, R.J., Lee, F.S., Li, X.Y., Bambico, F., Duman, R.S., & Aghajanian, G.K. (2012). Brainderived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry 71, 996–1005.

Loftis, J.M., Huckans, M., & Morasco, B.J. (2010). Neuroimmune mechanisms of cytokineinduced depression: Current theories and novel treatment strategies. Neurobiol Dis 37, 519–533. Lotrich, F.E., Albusaysi, S., & Ferrell, R.E. (2013). Brain-derived neurotrophic factor serum levels and genotype: Association with depression during interferon-alpha treatment. Neuropsychopharmacology 38, 985–995. Lotrich, F.E., Ferrell, R.E., Rabinovitz, M., & Pollock, B.G. (2009). Risk for depression during interferon-alpha treatment is affected by the serotonin transporter polymorphism. Biol Psychiatry 65, 344–348. Lucas, G., Du, J., Romeas, T., Mnie-Filali, O., Haddjeri, N., Pineyro, G., et al. (2010). Selective serotonin reuptake inhibitors potentiate the rapid antidepressant-like effects of serotonin4 receptor agonists in the rat. PLoS One 5, e9253. Lucas, G., Rymar, V.V., Du, J., Mnie-Filali, O., Bisgaard, C., Manta, S., et al. (2007). Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action. Neuron 55, 712–725. Macchi, F., Homberg, J.R., Calabrese, F., Zecchillo, C., Racagni, G., Riva, M.A., et al. (2013). Altered inflammatory responsiveness in serotonin transporter mutant rats. J Neuroinflammation 10, 116. Magarinos, A.M., Deslandes, A., & McEwen, B.S. (1999). Effects of antidepressants and benzodiazepine treatments on the dendritic structure of CA3 pyramidal neurons after chronic stress. Eur J Pharmacol 371, 113–122. Mahe, C., Loetscher, E., Dev, K.K., Bobirnac, I., Otten, U., & Schoeffter, P. (2005). Serotonin 5-HT7 receptors coupled to induction of interleukin-6 in human microglial MC-3 cells. Neuropharmacology 49, 40–47. Maier, S.F. (2003). Bi-directional immune–brain communication: Implications for understanding stress, pain, and cognition. Brain Behav Immun 17, 69–85. Malberg, J.E., Eisch, A.J., Nestler, E.J., & Duman, R.S. (2000). Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci 20, 9104–9110. Malynn, S., Campos-Torres, A., Moynagh, P., & Haase, J. (2013). The pro-inflammatory cytokine TNF-α regulates the activity and expression of the serotonin transporter (SERT) in astrocytes. Neurochem Res 38, 694–704. Martinowich, K., & Lu, B. (2007). Interaction between BDNF and serotonin: Role in mood disorders. Neuropsychopharmacology 33, 73–83. Meeuwsen, S., Persoon-Deen, C., Bsibsi, M., Ravid, R., & van Noort, J.M. (2003). Cytokine, chemokine and growth factor gene profiling of cultured human astrocytes after exposure to proinflammatory stimuli. Glia 43, 243–253. Merali, Z., Lacosta, S., & Anisman, H. (1997). Effects of interleukin-1beta and mild stress on alterations of norepinephrine, dopamine and serotonin neurotransmission: A regional microdialysis study. Brain Res 761, 225–235. Meredith, E.J., Chamba, A., Holder, M.J., Barnes, N.M., & Gordon, J. (2005). Close encounters of the monoamine kind: Immune cells betray their nervous disposition. Immunology 115, 289–295. Miller, A.H., Maletic, V., & Raison, C.L. (2009). Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression. Biol Psychiatry 65, 732–741. Monje, M.L., Toda, H., & Palmer, T.D. (2003). Inflammatory blockade restores adult hippocampal neurogenesis. Science 302, 1760–1765. Monteggia, L.M., Barrot, M., Powell, C.M., Berton, O., Galanis, V., Gemelli, T., et al. (2004). Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc Natl Acad Sci U S A 101, 10827–10832. Morikawa, O., Sakai, N., Obara, H., & Saito, N. (1998). Effects of interferon-alpha, interferon-gamma and cAMP on the transcriptional regulation of the serotonin transporter. Eur J Pharmacol 349, 317–324. Mossner, R., Daniel, S., Schmitt, A., Albert, D., & Lesch, K.P. (2001). Modulation of serotonin transporter function by interleukin-4. Life Sci 68, 873–880. Mossner, R., Heils, A., Stober, G., Okladnova, O., Daniel, S., & Lesch, K.P. (1998). Enhancement of serotonin transporter function by tumor necrosis factor alpha but not by interleukin-6. Neurochem Int 33, 251–254. Moussavi, S., Chatterji, S., Verdes, E., Tandon, A., Patel, V., & Ustun, B. (2007). Depression, chronic diseases, and decrements in health: Results from the World Health Surveys. Lancet 370, 851–858. Murphy, D.L., Fox, M.A., Timpano, K.R., Moya, P.R., Ren-Patterson, R., Andrews, A.M., et al. (2008). How the serotonin story is being rewritten by new gene-based discoveries principally related to SLC6A4, the serotonin transporter gene, which functions to influence all cellular serotonin systems. Neuropharmacology 55, 932–960. Murphy, D.L., & Moya, P.R. (2011). Human serotonin transporter gene (SLC6A4) variants: Their contributions to understanding pharmacogenomic and other functional GxG and GxE differences in health and disease. Curr Opin Pharmacol 11, 3–10. Myint, A.M., & Kim, Y.K. (2003). Cytokine-serotonin interaction through IDO: A neurodegeneration hypothesis of depression. Med Hypotheses 61, 519–525. Nguyen, K.T., Deak, T., Owens, S.M., Kohno, T., Fleshner, M., Watkins, L.R., et al. (1998). Exposure to acute stress induces brain interleukin-1beta protein in the rat. J Neurosci 18, 2239–2246. Nibuya, M., Morinobu, S., & Duman, R.S. (1995). Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15, 7539–7547. O'Brien, S.M., Scully, P., Fitzgerald, P., Scott, L.V., & Dinan, T.G. (2007). Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J Psychiatr Res 41, 326–331. O'Connor, J.C., Lawson, M.A., Andre, C., Moreau, M., Lestage, J., Castanon, N., et al. (2009). Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol Psychiatry 14, 511–522. Pannell, M., Szulzewsky, F., Matyash, V., Wolf, S.A., & Kettenmann, H. (2014). The subpopulation of microglia sensitive to neurotransmitters/neurohormones is modulated by stimulation with LPS, interferon-gamma, and IL-4. Glia 62, 667–679.

J. Haase, E. Brown / Pharmacology & Therapeutics 147 (2015) 1–11 Parkhurst, C.N., Yang, G., Ninan, I., Savas, J.N., Yates, J.R., 3rd, Lafaille, J.J., et al. (2013). Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155, 1596–1609. Pehrson, A.L., & Sanchez, C. (2014). Serotonergic modulation of glutamate neurotransmission as a strategy for treating depression and cognitive dysfunction. CNS Spectr 19, 121–133. Pierucci-Lagha, A., Covault, J., Bonkovsky, H.L., Feinn, R., Abreu, C., Sterling, R.K., et al. (2010). A functional serotonin transporter gene polymorphism and depressive effects associated with interferon-alpha treatment. Psychosomatics 51, 137–148. Pousset, F., Fournier, J., Legoux, P., Keane, P., Shire, D., & Soubrie, P. (1996). Effect of serotonin on cytokine mRNA expression in rat hippocampal astrocytes. Brain Res Mol Brain Res 38, 54–62. Raison, C.L., Rutherford, R.E., Woolwine, B.J., Shuo, C., Schettler, P., Drake, D.F., et al. (2013). A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: The role of baseline inflammatory biomarkers. JAMA Psychiatry 70, 31–41. Ramamoorthy, S., Ramamoorthy, J.D., Prasad, P.D., Bhat, G.K., Mahesh, V.B., Leibach, F.H., et al. (1995). Regulation of the human serotonin transporter by interleukin-1 beta. Biochem Biophys Res Commun 216, 560–567. Ransohoff, R.M., & Brown, M.A. (2012). Innate immunity in the central nervous system. J Clin Invest 122, 1164–1171. Rantamaki, T., Hendolin, P., Kankaanpaa, A., Mijatovic, J., Piepponen, P., Domenici, E., et al. (2007). Pharmacologically diverse antidepressants rapidly activate brain-derived neurotrophic factor receptor TrkB and induce phospholipase-Cgamma signaling pathways in mouse brain. Neuropsychopharmacology 32, 2152–2162. Rudnick, G. (2006). Serotonin transporters—Structure and function. J Membr Biol 213, 101–110. Russo, I., Barlati, S., & Bosetti, F. (2011). Effects of neuroinflammation on the regenerative capacity of brain stem cells. J Neurochem 116, 947–956. Saarelainen, T., Hendolin, P., Lucas, G., Koponen, E., Sairanen, M., MacDonald, E., et al. (2003). Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J Neurosci 23, 349–357. Saha, R.N., Liu, X., & Pahan, K. (2006). Up-regulation of BDNF in astrocytes by TNFalpha: A case for the neuroprotective role of cytokine. J Neuroimmune Pharmacol 1, 212–222. Sairanen, M., Lucas, G., Ernfors, P., Castren, M., & Castren, E. (2005). Brain-derived neurotrophic factor and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation, and survival in the adult dentate gyrus. J Neurosci 25, 1089–1094. Samuvel, D.J., Jayanthi, L.D., Bhat, N.R., & Ramamoorthy, S. (2005). A role for p38 mitogenactivated protein kinase in the regulation of the serotonin transporter: Evidence for distinct cellular mechanisms involved in transporter surface expression. J Neurosci 25, 29–41. Schecterson, L.C., Sanchez, J.T., Rubel, E.W., & Bothwell, M. (2012). TrkB downregulation is required for dendrite retraction in developing neurons of chicken nucleus magnocellularis. J Neurosci 32, 14000–14009. Schindler, A.G., Messinger, D.I., Smith, J.S., Shankar, H., Gustin, R.M., Schattauer, S.S., et al. (2012). Stress produces aversion and potentiates cocaine reward by releasing endogenous dynorphins in the ventral striatum to locally stimulate serotonin reuptake. J Neurosci 32, 17582–17596. Schnydrig, S., Korner, L., Landweer, S., Ernst, B., Walker, G., Otten, U., et al. (2007). Peripheral lipopolysaccharide administration transiently affects expression of brain-derived neurotrophic factor, corticotropin and proopiomelanocortin in mouse brain. Neurosci Lett 429, 69–73. Sen, S., Duman, R., & Sanacora, G. (2008). Serum brain-derived neurotrophic factor, depression, and antidepressant medications: Meta-analyses and implications. Biol Psychiatry 64, 527–532. Sheline, Y.I., Wang, P.W., Gado, M.H., Csernansky, J.G., & Vannier, M.W. (1996). Hippocampal atrophy in recurrent major depression. Proc Natl Acad Sci U S A 93, 3908–3913. Shirayama, Y., Chen, A.C., Nakagawa, S., Russell, D.S., & Duman, R.S. (2002). Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J Neurosci 22, 3251–3261. Smith, R.S. (1991). The macrophage theory of depression. Med Hypotheses 35, 298–306. Smith, K.J., Norris, S., O'Farrelly, C., & O'Mara, S.M. (2011). Risk factors for the development of depression in patients with hepatitis C taking interferon-alpha. Neuropsychiatr Dis Treat 7, 275–292. Steiner, J.A., Carneiro, A.M., & Blakely, R.D. (2008). Going with the flow: Traffickingdependent and -independent regulation of serotonin transport. Traffic 9, 1393–1402. Szelényi, J. (2001). Cytokines and the central nervous system. Brain Res Bull 54, 329–338. Taliaz, D., Loya, A., Gersner, R., Haramati, S., Chen, A., & Zangen, A. (2011). Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor. J Neurosci 31, 4475–4483. Tongiorgi, E., Righi, M., & Cattaneo, A. (1997). Activity-dependent dendritic targeting of BDNF and TrkB mRNAs in hippocampal neurons. J Neurosci 17, 9492–9505. Torres, G.E., Gainetdinov, R.R., & Caron, M.G. (2003). Plasma membrane monoamine transporters: Structure, regulation and function. Nat Rev Neurosci 4, 13–25.

11

Trivedi, M.H., Rush, A.J., Wisniewski, S.R., Nierenberg, A.A., Warden, D., Ritz, L., et al. (2006). Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: Implications for clinical practice. Am J Psychiatry 163, 28–40 (United States). Tsao, C.W., Lin, Y.S., Cheng, J.T., Lin, C.F., Wu, H.T., Wu, S.R., et al. (2008). Interferon-alphainduced serotonin uptake in Jurkat T cells via mitogen-activated protein kinase and transcriptional regulation of the serotonin transporter. J Psychopharmacol 22, 753–760. Tynan, R.J., Weidenhofer, J., Hinwood, M., Cairns, M.J., Day, T.A., & Walker, F.R. (2012). A comparative examination of the anti-inflammatory effects of SSRI and SNRI antidepressants on LPS stimulated microglia. Brain Behav Immun 26, 469–479. Tyring, S., Gottlieb, A., Papp, K., Gordon, K., Leonardi, C., Wang, A., et al. (2006). Etanercept and clinical outcomes, fatigue, and depression in psoriasis: Double-blind placebocontrolled randomised phase III trial. Lancet 367, 29–35. van Heesch, F., Prins, J., Konsman, J.P., Korte-Bouws, G.A., Westphal, K.G., Rybka, J., et al. (2014). Lipopolysaccharide increases degradation of central monoamines: An in vivo microdialysis study in the nucleus accumbens and medial prefrontal cortex of mice. Eur J Pharmacol 725, 55–63. van Heesch, F., Prins, J., Konsman, J.P., Westphal, K.G., Olivier, B., Kraneveld, A.D., et al. (2013a). Lipopolysaccharide-induced anhedonia is abolished in male serotonin transporter knockout rats: An intracranial self-stimulation study. Brain Behav Immun 29, 98–103. van Heesch, F., Prins, J., Korte-Bouws, G.A., Westphal, K.G., Lemstra, S., Olivier, B., et al. (2013b). Systemic tumor necrosis factor-alpha decreases brain stimulation reward and increases metabolites of serotonin and dopamine in the nucleus accumbens of mice. Behav Brain Res 253, 191–195. Verhagen, M., van der Meij, A., van Deurzen, P.A., Janzing, J.G., Arias-Vasquez, A., Buitelaar, J.K., et al. (2010). Meta-analysis of the BDNF Val66Met polymorphism in major depressive disorder: Effects of gender and ethnicity. Mol Psychiatry 15, 260–271. Videbech, P., & Ravnkilde, B. (2004). Hippocampal volume and depression: A metaanalysis of MRI studies. Am J Psychiatry 161, 1957–1966. Walker, A.K., Budac, D.P., Bisulco, S., Lee, A.W., Smith, R.A., Beenders, B., et al. (2013). NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6 J mice. Neuropsychopharmacology 38, 1609–1616. Walker, F.R., Nilsson, M., & Jones, K. (2013). Acute and chronic stress-induced disturbances of microglial plasticity, phenotype and function. Curr Drug Targets 14, 1262–1276. Warner-Schmidt, J.L., Vanover, K.E., Chen, E.Y., Marshall, J.J., & Greengard, P. (2011). Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans. Proc Natl Acad Sci U S A 108, 9262–9267. Wilson, C.J., Finch, C.E., & Cohen, H.J. (2002). Cytokines and cognition—The case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc 50, 2041–2056. Yang, M., Kim, J., Kim, J. -S., Kim, S. -H., Kim, J. -C., Kang, M. -J., et al. (2014). Hippocampal dysfunctions in tumor-bearing mice. Brain Behav Immun 36, 147–155. Yang, C., Shen, J., Hong, T., Hu, T.T., Li, Z.J., Zhang, H.T., et al. (2013). Effects of ketamine on lipopolysaccharide-induced depressive-like behavior and the expression of inflammatory cytokines in the rat prefrontal cortex. Mol Med Rep 8, 887–890. Yirmiya, R., & Goshen, I. (2011). Immune modulation of learning, memory, neural plasticity and neurogenesis. Brain Behav Immun 25, 181–213. Yoshimura, R., Hori, H., Ikenouchi-Sugita, A., Umene-Nakano, W., Ueda, N., & Nakamura, J. (2009). Higher plasma interleukin-6 (IL-6) level is associated with SSRI- or SNRIrefractory depression. Prog Neuropsychopharmacol Biol Psychiatry 33, 722–726. You, Z., Luo, C., Zhang, W., Chen, Y., He, J., Zhao, Q., et al. (2011). Pro- and antiinflammatory cytokines expression in rat's brain and spleen exposed to chronic mild stress: Involvement in depression. Behav Brain Res 225, 135–141. Yu, H., Wang, D.D., Wang, Y., Liu, T., Lee, F.S., & Chen, Z.Y. (2012). Variant brain-derived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants. J Neurosci 32, 4092–4101. Zafra, F., Lindholm, D., Castren, E., Hartikka, J., & Thoenen, H. (1992). Regulation of brainderived neurotrophic factor and nerve growth factor mRNA in primary cultures of hippocampal neurons and astrocytes. J Neurosci 12, 4793–4799. Zetterstrom, T.S., Pei, Q., Madhav, T.R., Coppell, A.L., Lewis, L., & Grahame-Smith, D.G. (1999). Manipulations of brain 5-HT levels affect gene expression for BDNF in rat brain. Neuropharmacology 38, 1063–1073. Zhu, C. -B., Blakely, R.D., & Hewlett, W.A. (2006). The proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Neuropsychopharmacology 31, 2121–2131. Zhu, C. -B., Lindler, K.M., Owens, A.W., Daws, L.C., Blakely, R.D., & Hewlett, W.A. (2010). Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters. Neuropsychopharmacology 35, 2510–2520. Ziv, Y., Ron, N., Butovsky, O., Landa, G., Sudai, E., Greenberg, N., et al. (2006). Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nat Neurosci 9, 268–275.