NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice

doi:10.1038/NPP.2013.71

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NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice

Journal Article•DOI•

NMDA receptor blockade by ketamine abrogates lipopolysaccharide-induced depressive-like behavior in C57BL/6J mice

Adam K. Walker¹, David P. Budac², Stephanie Bisulco², Anna W. Lee², Robin A. Smith¹, Brent Beenders¹, Keith W. Kelley¹, Robert Dantzer - Show less +4 more•Institutions (2)

University of Illinois at Urbana–Champaign¹, Lundbeck²

01 Aug 2013-Neuropsychopharmacology (Nature Publishing Group)-Vol. 38, Iss: 9, pp 1609-1616

TL;DR: Findings indicate that LPS-induced depressive-like behavior is mediated by NMDA receptor activation, probably as a consequence of formation of quinolinic acid.

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About: This article is published in Neuropsychopharmacology.The article was published on 2013-08-01 and is currently open access. It has received 359 citations till now. The article focuses on the topics: Quinolinic acid & NMDA receptor.

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Journal Article•DOI•

The role of inflammation in depression: from evolutionary imperative to modern treatment target

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Andrew H. Miller¹, Charles L. Raison²•Institutions (2)

Emory University¹, University of Wisconsin-Madison²

01 Jan 2016-Nature Reviews Immunology

TL;DR: Current understanding of the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression are detailed.

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Abstract: Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.

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2,133 citations

Journal Article•DOI•

Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications

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Jennifer C. Felger¹, Francis E. Lotrich²•Institutions (2)

Emory University¹, University of Pittsburgh²

29 Aug 2013-Neuroscience

TL;DR: This review explores the idea that specific gene polymorphisms and neurotransmitter systems can confer protection from or vulnerability to specific symptom dimensions of cytokine-related depression and potential therapeutic strategies that target inflammatory cytokine signaling.

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771 citations

Journal Article•DOI•

Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

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Panos Zanos, Ruin Moaddel, Patrick J. Morris, Lace M. Riggs, Jaclyn N. Highland, Polymnia Georgiou, Edna F. R. Pereira, Edson X. Albuquerque, Craig J. Thomas, Carlos A. Zarate, Todd D. Gould - Show less +7 more

01 Jul 2018-Pharmacological Reviews

TL;DR: Pharmacological target deconvolution of ketamine and its metabolites will provide insight critical to the development of new pharmacotherapies that possess the desirable clinical effects of ketamines, but limit undesirable side effects.

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Abstract: Ketamine, a racemic mixture consisting of (S)- and (R)-ketamine, has been in clinical use since 1970. Although best characterized for its dissociative anesthetic properties, ketamine also exerts analgesic, anti-inflammatory, and antidepressant actions. We provide a comprehensive review of these therapeutic uses, emphasizing drug dose, route of administration, and the time course of these effects. Dissociative, psychotomimetic, cognitive, and peripheral side effects associated with short-term or prolonged exposure, as well as recreational ketamine use, are also discussed. We further describe ketamine’s pharmacokinetics, including its rapid and extensive metabolism to norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK) metabolites. Whereas the anesthetic and analgesic properties of ketamine are generally attributed to direct ketamine-induced inhibition of N-methyl-D-aspartate receptors, other putative lower-affinity pharmacological targets of ketamine include, but are not limited to, γ-amynobutyric acid (GABA), dopamine, serotonin, sigma, opioid, and cholinergic receptors, as well as voltage-gated sodium and hyperpolarization-activated cyclic nucleotide-gated channels. We examine the evidence supporting the relevance of these targets of ketamine and its metabolites to the clinical effects of the drug. Ketamine metabolites may have broader clinical relevance than was previously considered, given that HNK metabolites have antidepressant efficacy in preclinical studies. Overall, pharmacological target deconvolution of ketamine and its metabolites will provide insight critical to the development of new pharmacotherapies that possess the desirable clinical effects of ketamine, but limit undesirable side effects.

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621 citations

Cites background from "NMDA receptor blockade by ketamine ..."

...…abolishes ketamine’s effects in several animal tests of antidepressant efficacy (Maeng et al., 2008; Autry et al., 2011; Koike et al., 2011;Walker et al., 2013; Fukumoto et al., 2014; Koike and Chaki, 2014; Zhou et al., 2014; Yang et al., 2015; Zanos et al., 2016; Zanos et al., 2018b,c)....
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Journal Article•DOI•

Depression as a Microglial Disease

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Raz Yirmiya¹, Neta Rimmerman¹, R. Reshef¹•Institutions (1)

Hebrew University of Jerusalem¹

01 Oct 2015-Trends in Neurosciences

TL;DR: Some forms of depression can be considered as a microglia disease (microgliopathy), which should be treated by a personalized medical approach using microglial inhibitors or stimulators depending on the microglian status of the depressed patient.

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591 citations

Cites background from "NMDA receptor blockade by ketamine ..."

..., LPS, CpG, HIV Tat protein, and Bacillus Calmette–Guérin (BCG)] [21,125,126]), as well as by psychological stress and glucocorticoids [127] (Figure 2)....
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Journal Article•DOI•

Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment

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Gulam Khandaker¹, Gulam Khandaker², Gulam Khandaker³, Lesley Cousins¹, Lesley Cousins², Lesley Cousins³, Julia Deakin¹, Julia Deakin³, Julia Deakin², Belinda R Lennox⁴, Robert H. Yolken⁵, Peter B. Jones¹, Peter B. Jones³, Peter B. Jones² - Show less +10 more•Institutions (5)

University of Cambridge¹, National Institute for Health Research², National Health Service³, University of Oxford⁴, Johns Hopkins University⁵

01 Mar 2015-The Lancet Psychiatry

TL;DR: Some of the important areas of research regarding innate and adaptive immune response in schizophrenia and related psychotic disorders that, it is thought, will be of interest to psychiatric clinicians and researchers are described.

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586 citations

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References

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Journal Article•DOI•

From inflammation to sickness and depression: when the immune system subjugates the brain

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Robert Dantzer¹, Jason C. O'Connor¹, Gregory G. Freund¹, Rodney W. Johnson¹, Keith W. Kelley¹ - Show less +1 more•Institutions (1)

University of Illinois at Urbana–Champaign¹

01 Jan 2008-Nature Reviews Neuroscience

TL;DR: In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour, which can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals.

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Abstract: In response to a peripheral infection, innate immune cells produce pro-inflammatory cytokines that act on the brain to cause sickness behaviour. When activation of the peripheral immune system continues unabated, such as during systemic infections, cancer or autoimmune diseases, the ensuing immune signalling to the brain can lead to an exacerbation of sickness and the development of symptoms of depression in vulnerable individuals. These phenomena might account for the increased prevalence of clinical depression in physically ill people. Inflammation is therefore an important biological event that might increase the risk of major depressive episodes, much like the more traditional psychosocial factors.

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5,665 citations

"NMDA receptor blockade by ketamine ..." refers background in this paper

...The neurovegetative symptoms of depression are similar to the behavioral signs of sickness that can be observed in rodents of which the peripheral immune system has been activated (Dantzer et al, 2008)....
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Journal Article•DOI•

The HPA axis in major depression: classical theories and new developments

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Carmine M. Pariante¹, Stafford L. Lightman²•Institutions (2)

King's College London¹, University of Bristol²

01 Sep 2008-Trends in Neurosciences

TL;DR: It is shown that hyperactivity of the hypothalamic-pituitary-adrenal axis is one of the most consistent biological findings in major depression psychiatry, but the mechanisms underlying this abnormality are still unclear.

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1,621 citations

"NMDA receptor blockade by ketamine ..." refers background in this paper

...Immune activation activates IDO and TDO (O’Connor et al, 2009a, b, c; Park et al, 2011), with the increase in the activity of this last enzyme probably being mediated indirectly by increased glucocorticoid receptor activation (Bhagwagar et al, 2003; Pariante and Lightman, 2008)....
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Journal Article•DOI•

NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses

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Anita E. Autry¹, Megumi Adachi¹, Elena Nosyreva, Elisa S. Na¹, Maarten F. Los¹, Pengfei Cheng¹, Ege T. Kavalali, Lisa M. Monteggia - Show less +4 more•Institutions (1)

University of Texas Southwestern Medical Center¹

07 Jul 2011-Nature

TL;DR: It is shown that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor, suggesting the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast- acting antidepressants.

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Abstract: Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear. Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks, unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients. The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.

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1,551 citations

"NMDA receptor blockade by ketamine ..." refers background in this paper

...In view of the ability of ketamine to increase brain-derived neurotrophic factor (BDNF) at antidepressant doses (Autry et al, 2011), we also checked that ketamine does not interfere with the decrease in BDNF that has been reported in response to LPS (Guan and Fang, 2006; Wu et al, 2011)....
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...There is already evidence that the antidepressant-like activity of ketamine is blocked by the AMPA antagonist NBQX (Maeng and Zarate, 2007; Maeng et al, 2008; Autry et al, 2011)....
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...…been responsible for the antidepressant-like activity of ketamine on LPS-induced depressive-like behavior in the context of a LPS-induced decrease of BDNF. Ketamine has been shown to increase BDNF in the hippocampus and prefrontal cortex (Garcia et al, 2008; Ibla et al, 2009; Autry et al, 2011)....
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...…to the consideration of the possible alleviating effects of ketamine on LPS-induced decreases in brain BDNF. Ketamine did not alter LPS-induced decreases of BDNF at 6 h after treatment, probably because the acute stimulating effect of ketamine on BDNF had already ended (Autry et al, 2011)....
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Journal Article•DOI•

Cytokine-Associated Emotional and Cognitive Disturbances in Humans

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Abraham Reichenberg¹, Raz Yirmiya, Andreas Schuld², Thomas Kraus, Monika Haack, Abraham Morag, Thomas Pollmächer² - Show less +3 more•Institutions (2)

Hebrew University of Jerusalem¹, Max Planck Society²

01 May 2001-Archives of General Psychiatry

TL;DR: In humans, a mild stimulation of the primary host defense has negative effects on emotional and memory functions, which is probably caused by cytokine release, and cytokines represent a novel target for neuropsychopharmacological research.

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Abstract: Background: Infectious, autoimmune, and neurodegenerative diseases are associated with profound psychological disturbances. Studies in animals clearly demonstrate that cytokines mediate illness-associated behavioral changes. However, the mechanisms underlying the respective psychological alterations in humans have not been established yet. Therefore, we investigated the effects of low-dose endotoxemia, a well-established and safe model of host-defense activation, on emotional, cognitive, immunological, and endocrine parameters. Methods: In a double-blind, crossover study, 20 healthy male volunteers completed psychological questionnaires and neuropsychological tests 1, 3, and 9 hours after intravenous injection of Salmonella abortus equi endotoxin (0.8 ng/kg) or saline in 2 experimental sessions. Blood samples were collected hourly, and rectal temperature and heart rate were monitored continuously. Results: Endotoxin had no effects on physical sickness symptoms, blood pressure, or heart rate. Endotoxin caused a mild increase in rectal temperature (0.5°C), and increased the circulating levels of tumor necrosis factor a (TNF-a), soluble TNF receptors, interleukin (IL)-6, IL-1 receptor antagonist, and cortisol. After endotoxin administration, the subjects showed a transient significant increase in the levels of anxiety (effect size [ES]=0.55) and depressed mood (ES=0.66). Verbal and nonverbal memory functions were significantly decreased (ES=0.55 to 0.64). Significant positive correlations were found between cytokine secretion and endotoxin-induced anxiety (r= 0.49 to r= 0.60), depressed mood (r= 0.40 to r=0.75), and decreases in memory performance (r=0.46 to r=0.68). Conclusions: In humans, a mild stimulation of the primary host defense has negative effects on emotional and memory functions, which are probably caused by cytokine release. Hence, cytokines represent a novel target for neuropsychopharmacological research. Arch Gen Psychiatry. 2001;58:445-452

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1,256 citations

"NMDA receptor blockade by ketamine ..." refers background in this paper

...Inflammation induces depressive symptoms in at-risk individuals (Capuron et al, 2002; Reichenberg et al, 2001; Wright et al, 2005)....
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Journal Article•DOI•

Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice

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Jason C. O'Connor¹, Marcus A. Lawson¹, Caroline André², Maïté M. Moreau², Jacques Lestage², Nathalie Castanon², Keith W. Kelley¹, Keith W. Kelley³, Robert Dantzer - Show less +5 more•Institutions (3)

University of Illinois at Urbana–Champaign¹, University of Bordeaux², University of Illinois at Chicago³

01 May 2009-Molecular Psychiatry

TL;DR: Results implicate IDO as a critical molecular mediator of inflammation-induced depressive-like behavior, probably through the catabolism of tryptophan along the kynurenine pathway.

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Abstract: Although elevated activity of the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) has been proposed to mediate comorbid depression in inflammatory disorders, its causative role has never been tested. We report that peripheral administration of lipopolysaccharide (LPS) activates IDO and culminates in a distinct depressive-like behavioral syndrome, measured by increased duration of immobility in both the forced-swim and tail suspension tests. Blockade of IDO activation either indirectly with the anti-inflammatory tetracycline derivative minocycline, that attenuates LPS-induced expression of proinflammatory cytokines, or directly with the IDO antagonist 1-methyltryptophan (1-MT), prevents development of depressive-like behavior. Both minocycline and 1-MT normalize the kynurenine/tryptophan ratio in the plasma and brain of LPS-treated mice without changing the LPS-induced increase in turnover of brain serotonin. Administration of L-kynurenine, a metabolite of tryptophan that is generated by IDO, to naive mice dose dependently induces depressive-like behavior. These results implicate IDO as a critical molecular mediator of inflammation-induced depressive-like behavior, probably through the catabolism of tryptophan along the kynurenine pathway.

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1,069 citations

"NMDA receptor blockade by ketamine ..." refers background or methods in this paper

...More specifically, genetic or pharmaceutical blockade of IDO abrogates the onset of depressive-like behavior without affecting sickness (O’Connor et al, 2009b)....
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...Immune activation activates IDO and TDO (O’Connor et al, 2009a, b, c; Park et al, 2011), with the increase in the activity of this last enzyme probably being mediated indirectly by increased glucocorticoid receptor activation (Bhagwagar et al, 2003; Pariante and Lightman, 2008)....
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...This dose of LPS was chosen for its ability to reliably induce the acute sickness response and subsequent depressive-like behaviors across the time points examined here (Mormède et al, 2004; O’Connor et al, 2009c)....
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...Expression of the other tryptophan-degrading enzyme, TDO, in the brain and liver also increased significantly by LPS at 6 h after treatment (Supplementary Figure S7)....
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...The activation of IDO by LPS induces the formation of kynurenine, both at the periphery and in the brain (O’Connor et al, 2009c)....
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