Miller AH. Norman cousins lecture. Mechanisms of cytokine-induced behavioral changes: psychoneuroimmunology at the translational interface. Brain Behav Immun 23: 149-158

Department of Psychiatry and Behavioral Sciences, Winship Cancer Institute, Emory University School of Medicine, 1701 Uppergate Drive, WCI Building C, 5th Floor, Atlanta, GA 30322, USA.
Brain Behavior and Immunity (Impact Factor: 5.89). 10/2008; 23(2):149-58. DOI: 10.1016/j.bbi.2008.08.006
Source: PubMed


Work in our laboratory has focused on the mechanisms by which cytokines can influence the brain and behavior in humans and non-human primates. Using administration of interferon (IFN)-alpha as a tool to unravel these mechanisms, we have expanded upon findings from the basic science literature implicating cytokine-induced changes in monoamine metabolism as a primary pathway to depression. More specifically, a role for serotonin metabolism has been supported by the clinical efficacy of serotonin reuptake inhibitors in blocking the development of IFN-alpha-induced depression, and the capacity of IFN-alpha to activate metabolic enzymes (indolamine 2,3 dioxygenase) and cytokine signaling pathways (p38 mitogen activated protein kinase) that can influence the synthesis and reuptake of serotonin. Our data also support a role for dopamine depletion as reflected by IFN-alpha-induced changes in behavior (psychomotor slowing and fatigue) and regional brain activity, which implicate the involvement of the basal ganglia, as well as the association of IFN-alpha-induced depressive-like behavior in rhesus monkeys with decreased cerebrospinal fluid concentrations of the dopamine metabolite, homovanillic acid. Neuroimaging data in IFN-alpha-treated patients also suggest that activation of neural circuits (dorsal anterior cingulate cortex) associated with anxiety and alarm may contribute to cytokine-induced behavioral changes. Taken together, these effects of cytokines on the brain and behavior appear to subserve competing evolutionary survival priorities that promote reduced activity to allow healing, and hypervigilance to protect against future attack. Depending on the relative balance between these behavioral accoutrements of an activated innate immune response, clinical presentations may be distinct and warrant individualized therapeutic approaches.

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Available from: Andrew H Miller, Dec 22, 2013
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    • "In fact, several studies have reported a clear interaction between the CNS and the immune system in mental disorders such as depression (Miller, Maletic & Raison 2009; Sukoff Rizzo et al. 2012), anxiety (Salim, Chugh & Asghar 2012) and neurodegenerative diseases (Li et al. 2011; Montgomery & Bowers 2012), suggesting that the neuroinflammation is a component of mental diseases. However, not all the inflammatory mediators that participate in the brain have been studied [i.e. "
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    ABSTRACT: The treatment for cocaine use constitutes a clinical challenge because of the lack of appropriate therapies and the high rate of relapse. Recent evidence indicates that the immune system might be involved in the pathogenesis of cocaine addiction and its co-morbid psychiatric disorders. This work examined the plasma pro-inflammatory cytokine and chemokine profile in abstinent cocaine users (n = 82) who sought outpatient cocaine treatment and age/sex/body mass-matched controls (n = 65). Participants were assessed with the diagnostic interview Psychiatric Research Interview for Substance and Mental Diseases according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Tumor necrosis factor-alpha, chemokine (C-C motif) ligand 2/monocyte chemotactic protein-1 and chemokine (C-X-C motif) ligand 12 (CXCL12)/stromal cell-derived factor-1 (SDF-1) were decreased in cocaine users, although all cytokines were identified as predictors of a lifetime pathological use of cocaine. Interleukin-1 beta (IL-1β), chemokine (C-X3 -C motif) ligand 1 (CX3CL1)/fractalkine and CXCL12/SDF-1 positively correlated with the cocaine symptom severity when using the DSM-IV-TR criteria for cocaine abuse/dependence. These cytokines allowed the categorization of the outpatients into subgroups according to severity, identifying a subgroup of severe cocaine users (9-11 criteria) with increased prevalence of co-morbid psychiatric disorders [mood (54%), anxiety (32%), psychotic (30%) and personality (60%) disorders]. IL-1β was observed to be increased in users with such psychiatric disorders relative to those users with no diagnosis. In addition to these clinical data, studies in mice demonstrated that plasma IL-1β, CX3CL1 and CXCL12 were also affected after acute and chronic cocaine administration, providing a preclinical model for further research. In conclusion, cocaine exposure modifies the circulating levels of pro-inflammatory mediators. Plasma cytokine/chemokine monitoring could improve the stratification of cocaine consumers seeking treatment and thus facilitate the application of appropriate interventions, including management of heightened risk of psychiatric co-morbidity. Further research is necessary to elucidate the role of the immune system in the etiology of cocaine addiction.
    Full-text · Article · May 2014 · Addiction Biology
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    • "This mechanism was supported by many studies. Miller [75] proved that administration of IFN-α could influence the synthesis and reuptake of serotonin. Felger et al. [76] established a nonhuman primate model of cytokine-induced depression with rhesus monkeys and observed a lower dopamine metabolite concentration in CSF. "
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    ABSTRACT: Poststroke depression (PSD) is an important consequence after stroke, with negative impact on stroke outcome. The pathogenesis of PSD is complicated, with some special neurobiological mechanism, which mainly involves neuroanatomical, neuron, and biochemical factors and neurogenesis which interact in complex ways. Abundant studies suggested that large lesions in critical areas such as left frontal lobe and basal ganglia or accumulation of silent cerebral lesions might interrupt the pathways of monoamines or relevant pathways of mood control, thus leading to depression. Activation of immune system after stroke produces more cytokines which increase glutamate excitotoxicity, results in more cell deaths of critical areas and enlargement of infarctions, and, together with hypercortisolism induced by stress or inflammation after stroke which could decrease intracellular serotonin transporters, might be the key biochemical change of PSD. The interaction among cytokines, glucocorticoid, and neurotrophin results in the decrease of hippocampal neurogenesis which has been proved to be important for mood control and pharmaceutical effect of selective serotonin reuptake inhibitors and might be another promising pathway to understand the pathogenesis of PSD. In order to reduce the prevalence of PSD and improve the outcome of stroke, more relevant studies are still required to clarify the pathogenesis of PSD.
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    • "It has been demonstrated that IFN-α, a pro-inflammatory cytokine used as treatment for a variety of chronic viral infections and malignant disorders, induces depressive symptoms in 30–50% of the patients undergoing a long lasting treatment. The IFN-associated depression may reach higher degree in the case of HCV patients, leading even to the development of suicidal ideation and behavior [5], [6]. As IFN-α treatment acts as external inducer of pro-inflammatory cytokine production, it has been suggested that its neurotoxic effects may derive from alterations in peripheral pro-inflammatory cytokines, reduction of neurotransmitter biosynthesis in the central nervous system (CNS) and the alteration of the hypothalamic-pituitary-adrenal axis. "
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    ABSTRACT: We have previously identified 15 genes that are associated with the development of severe depressive side effects during the standard therapy with interferon alpha and ribavirin in the peripheral blood of hepatitis C virus infected patients. An enhanced expression of these genes was also found in the blood of psychiatric patients suffering severe depressive episode. Herein, we demonstrate that the same depression-related interferon-inducible genes (DRIIs) are also upregulated in post-mortem brains of suicidal individuals. Using cultured mouse hippocampal and prefrontal neurons we show that costimulation with murine IFN (mIFN) and the TLR3 agonist poly(I:C) promotes the expression of the described DRIIs, at the same time inducing pro-inflammatory cytokine expression through Stat1 and Stat3 activation, promoting neuronal apoptosis. Consequently, the upregulation of selective DRIIs, production of inflammatory cytokines and inhibition of neuronal plasticity may be involved in the pathogenesis of IFN-associated depression.
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