Interleukin-1 Receptor Activation by Systemic Lipopolysaccharide Induces Behavioral Despair Linked to MAPK Regulation of CNS Serotonin Transporters
Open accessAbstract
Serotonin (5-hydroxytryptamine, 5-HT) has long been implicated in regulation of mood. Medications that block the neuronal 5-HT transporter (SERT) are used as major pharmacological treatment for mood disorders. Conversely, stimuli that enhance SERT activity might be predicted to diminish synaptic 5-HT availability and increase the risk for 5-HT-related CNS disorders. We have shown that the inflammatory cytokines enhance brain SERT activity in cultured serotonergic cells and nerve terminal preparations in vitro. In this study, we establish that intraperitoneal injection of the cytokine-inducer lipopolysaccharide (LPS) stimulates brain SERT activity, acting at doses below those required to induce overt motor suppression. SERT stimulation by LPS is paralleled by increased immobility in both the tail suspension test (TST) and the forced swim test (FST); antidepressant-sensitive alterations are thought to model aspects of behavioral despair. Both the stimulation of SERT activity and induced immobility are absent when LPS is administered to interleukin-1 receptor (IL-1R)-deficient mice and in the presence of SB203580, an inhibitor of IL-1R-stimulated p38 MAPK. Moreover, the ability of LPS to enhance immobility in TST is lost in SERT knockout mice. These findings reveal an ability of peripheral inflammatory stimuli to enhance brain SERT activity through IL-1R and p38 MAPK pathways in vivo and identify a requirement for SERT expression in immune-system-modulated despair behaviors. Our studies identify IL-1R- and p38 MAPK-dependent regulation of SERT as one of the mechanisms by which environmentally driven immune system activation can trigger despair-like behavior in an animal model, encouraging future analysis of the pathway for risk factors in neuropsychiatric disorders.
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IL-1β and TNF induction of p38 MAPK increases the expression and function of serotonin reuptake pumps, leading to decreased synaptic serotonin and depressive-like behaviour in laboratory animals.
“IL-1β and TNF induction of p38 mitogen-activated protein kinase (MAPK) has been shown to increase the expression and function of the reuptake pumps for serotonin, leading to decreased synaptic availability of serotonin and depressive-like behaviour in laboratory animals72.”
From The role of inflammation in depression: from evolutionary imperative to modern treatment target (2016) · cites this paper as [72]
The Introduction (page not provided) reports that IL-1β and TNF-α activate serotonin transporter function through p38 MAPK, while the Abstract links IL-1 receptor– and p38-dependent transporter activity to despair-like behavior in LPS-treated mice. The paper does not show that this pathway increases transporter expression in those animals, or that either cytokine causes the behavior by measurably reducing synaptic serotonin; it describes reduced synaptic availability as a prediction. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCytokines influence the synthesis of monoamines through disruption of tetrahydrobiopterin.
“Cytokines also influence the synthesis of monoamines through disruption of tetrahydrobiopterin, an essential enzyme co-factor to hydroxylases involved in monoamine synthesis.”
From Cytokine Research in Depression: Principles, Challenges, and Open Questions (2019) · cites this paper as [91]
Cytokines can modulate serotonin signaling by increasing the expression and function of monoamine transporters.
“Furthermore, they can modulate serotonin signaling by increasing the expression and function of monoamine transporters which perform the re-uptake of synaptic serotonin (89–92).”
From Cytokine Research in Depression: Principles, Challenges, and Open Questions (2019) · cites this paper as [91]
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“29–31 Moreover, drugs that block serotonin transporter function can significantly reduce depression during IFN-α treatment.”
BackgroundNeuroinflammatory basis of depression: learning from experimental models
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Serotonin is a common thread linking different classes of antidepressants
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- Authors
- Zhu, C.-B., Lindler, K. M., Owens, A. W., Daws, L. C., Blakely, R. D., & Hewlett, W. A.
- Affiliations
- Vanderbilt University (US)
- The University of Texas at San Antonio Health Science Center (US)
- Corresponding author
- Blakely, Randy D
- Hewlett, William A
- Venue
- Neuropsychopharmacology
- Published
- 2010-09-08
- Volume
- 35
- Issue
- 13
- Pages
- 2510-2520
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- PMC
- PMC3055584
- OpenAlex
- W2164423986
- Cited by
- 317
- References
- 68
- Citations by year
- 2026: 9 · 2025: 16 · 2024: 28 · 2023: 14 · 2022: 24 · 2021: 27 · 2020: 27 · 2019: 25 · 2018: 23 · 2017: 11 · 2016: 17 · 2015: 22 · 2014: 14 · 2013: 19 · 2012: 21
- FWCI
- 6.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Vanderbilt University
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health (MH078028)
- National Institute of Mental Health (P50MH078028, MH078028)
- National Institute on Drug Abuse (DA-07390, R01DA007390)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- interleukin-1 receptor, lipopolysaccharide, serotonin transporter, behavioral despair, p38 MAPK, neuroinflammation, depression, immobility, tail suspension test, forced swim test, serotonin, mood disorders, immune activation
- MeSH terms
- Animals, Behavior, Animal, Brain, Depression, Disease Models, Animal, Dose-Response Relationship, Drug, Enzyme Inhibitors, Imidazoles, Lipopolysaccharides, Male, Mice, Inbred C57BL, Pyridines, Synaptosomes, Receptors, Interleukin-1, Mice, Knockout, p38 Mitogen-Activated Protein Kinases, Serotonin Plasma Membrane Transport Proteins, Mice
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