Cytokine effects on the basal ganglia and dopamine function: The subcortical source of inflammatory malaise

Felger, Jennifer C.; Miller, Andrew H.

doi:10.1016/j.yfrne.2012.09.003

Cited by 304 publications

(249 citation statements)

References 217 publications

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“…One pathway via which increased central immune-inflammatory activity has been proposed to impact on brain function is 24 oxidative stress and neurotoxicity leading to inhibition of dopamine and serotonin function (Felger and Miller, 2012;Haroon et al, 2012;Miller et al, 2009). In this respect it is noteworthy that for AMYG, a number of the genes de-regulated by CSD express proteins that are either mediators or regulators of DA function: Drd2, Adora2a, Gpr88, Darpp-32, Rgs9, Slc29a4 and, as discussed above, Gng7 (as well as Prkcd in mPFC) ( Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…One hypothesis of depression aetio-pathophysiology is psychosocial stress 6 activation of peripheral and central immune-inflammation, leading to oxidative stress and neurotoxic disruption of several neurotransmitters including serotonin, dopamine, glutamate and GABA (Dantzer et al, 2008;Felger and Miller, 2012). The proinflammatory cytokines of tumor necrosis factor (TNF) and interleukin-6 (IL-6) are increased in a majority of depression patients relative to matched controls (Dowlati et al, 2010;Maes, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function

et al. 2014

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In neuropsychiatry, animal studies demonstrating causal effects of environmental manipulations relevant to human aetiology on behaviours relevant to human psychopathologies are valuable. Such valid models can improve understanding of aetio-pathophysiology and preclinical discovery and development of new treatments. In depression, specific uncontrollable stressful life events are major aetiological factors, and subsequent generalized increases in fearfulness, helplessness and fatigue are core symptoms or features. Here we exposed adult male C57BL/6 mice to 15-day psychosocial stress with loss of social control but minimal physical wounding. One cohort was assessed in a 3-day test paradigm of motor activity, fear conditioning and 2-way avoid-escape behaviour on days 16-18, and a second cohort was assessed in a treadmill fatigue paradigm on days 19 and 29, followed by the 3-day paradigm on days 30-32. All tests used a physical aversive stimulus, namely mild, brief electroshocks. Socially stressed mice displayed decreased motor activity, increased fear acquisition, decreased 2-way avoid-escape responding (increased helplessness) and increased fatigue. They also displayed increased plasma TNF and spleen hypertrophy, and adrenal hypertrophy without hyper-corticoidism. In a third cohort, psychosocial stress effects on brain gene expression were assessed using next generation sequencing. Gene expression was altered in pathways of inflammation and G-protein coupled receptors in prefrontal cortex and amygdala; in the latter, expression of genes important in dopamine function were de-regulated including down-regulated Drd2, Adora2a and Darpp-32. This model can be applied to identify targets for treating psychopathologies such as helplessness or fatigue, and to screen compounds/biologics developed to act at these targets. AbstractIn neuropsychiatric research, animal studies that demonstrate causal effects of environmental manipulations relevant to human aetiological factors on emotional and cognitive behaviours relevant to human psychopathologies are valuable. Such valid animal models can be useful for improved understanding of aetio-pathophysiology and preclinical discovery and development of new treatments. In depression, specific uncontrollable stressful life events are major aetiological factors, and subsequent generalized increases in fearfulness, helplessness and fatigue are core psychopathology symptoms or features. In the present study we exposed adult male C57BL/6 mice to an environmental manipulation of 15-day psychosocial stress with loss of social control but with minimal physical wounding. One cohort of stressed and control mice was assessed in a novel 3-day test paradigm of motor activity, fear conditioning and 2-way avoid-escape behaviour on days 16-18, and a second cohort was assessed in a treadmill fatigue paradigm on days 19 and 29, followed by the 3-day paradigm on days 30-32. All tests used a physical aversive stimulus, namely mild, brief electroshocks. The socially stressed mice displayed dec...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function

et al. 2014

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“…Studies in laboratory animals and humans indicate that inflammatory cytokines appear to decrease dopamine availability and ultimately decrease dopamine release (Felger and Miller, 2012). For example, using PET, administration of radiolabeled L-DOPA to humans treated with IFN-α was found to lead to increased L-DOPA uptake and decreased L-DOPA release consistent with dopamine depletion (Capuron et al, 2012).…”

Section: Inflammation Effects On Neurotransmitter Metabolismmentioning

confidence: 99%

“…Moreover, in the context of inflammation-induced oxidative stress, BH4 is very sensitive to being oxidized to the inactive compound dihydroxyanthopterin (Neurauter et al, 2008). Of relevance to dopamine as well as other monoamines, BH4 also serves as an essential cofactor for the ratelimiting enzymes that synthesize dopamine and serotonin including tyrosine hydroxylase and tryptophan hydroxylase, respectively (Neurauter et al, 2008;Felger and Miller, 2012;Haroon et al, 2012). BH4 is also a cofactor for phenylalanine hydroxylase that converts phenylalanine to tyrosine, the primary precursor for L-DOPA that is converted to dopamine.…”

Section: Inflammation Effects On Neurotransmitter Metabolismmentioning

confidence: 99%

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

Miller

Haroon

Felger

2016

Neuropsychopharmacol

118

124

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A wealth of data has been amassed that details a complex, yet accessible, series of pathways by which the immune system, notably inflammation, can influence the brain and behavior. These data have opened the window to a diverse array of novel targets whose potential efficacy is tied to specific neurotransmitters and neurocircuits as well as specific behaviors. What is clear is that the impact of inflammation on the brain cuts across psychiatric disorders and engages dopaminergic and glutamatergic pathways that regulate motivation and motor activity as well as the sensitivity to threat. Given the ability to identify patient populations with increased inflammation, the precision of interventions can be further tuned, in conjunction with the ability to establish target engagement in the brain through the use of multiple neuroimaging strategies. After a brief overview of the mechanisms by which inflammation affects the brain and behavior, this review examines the extant literature on the efficacy of anti-inflammatory treatments, while forging guidelines for future intelligent clinical trial design. An examination of the most promising therapeutic strategies is also provided, along with some of the most exciting clinical trials that are currently being planned or underway.

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“…DA neurotransmission, especially synthesis of DA, can be modified by cytokines and inflammatory signaling pathways, via various means [105].…”

Section: Dopamine (Da) and Norepinephrine (Ne)mentioning

confidence: 99%

The Role of Immune System in Depression Disorder

Hoseinzadeh¹,

Abadi²,

Agheltar³

et al. 2016

Health

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In order to diagnose a major depressive disorder, patients must have at least 5 depressive symptoms out of 9 criteria, present for at least two weeks. Depressive symptoms include absence of concentration, fatigue and suicidal ideation. The intensity of depression symptoms affects the severity of depression and the degree of the impact on the quality of life. Major depressive disorders (MDD) are defined as a significant health problem, and are estimated to rise in prevalence in the future years. Immune cytokine, associated with major depression for instance, is the interleukin IL-6 and tumor necrosis factor (TNF-α) which is defined as pro-inflammatory cytokines, can activate an inflammatory response. The effects of other inflammatory cytokines on the central nervous system are of controversy. There is an increasing interest about the effect of cytokines derived from innate immune system on the brain and behavior. Cytokines are defined as large sized proteins, mainly produced by immune cells. Two subtypes of cytokines exist: pro-inflammatory cytokines, facilitating inflammatory responses and neural activities; and anti-inflammatory cytokines, inhibiting inflammatory processes. Besides microglia and astrocytes, immune cells such as monocytes, macrophages, and lymphocytes also produce cytokines. At the times of immunological alterations, infections or inflammation, cytokines will be in an activated form. The main goal of the current review study is to investigate the role of the immune system in the depression disorder.

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Cytokine effects on the basal ganglia and dopamine function: The subcortical source of inflammatory malaise

Cited by 304 publications

References 217 publications

Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function

Mouse social stress induces increased fear conditioning, helplessness and fatigue to physical challenge together with markers of altered immune and dopamine function

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

The Role of Immune System in Depression Disorder

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