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A Model of Post-Infection Fatigue Is Associated with Increased TNF and 5-HT2A Receptor Expression in Mice
Yvonne Couch1, Qin Xie1, Louise Lundberg2
1Department of Pharmacology, Mansfield Road, Oxford, OX1 3QT, United Kingdom.
Abstract:
It is well documented that serotonin (5-HT) plays an important role in psychiatric illness. For example, myalgic encephalomyelitis (ME/CFS), which is often provoked by infection, is a disabling illness with an unknown aetiology and diagnosis is based on symptom-specific criteria. However, 5-HT2A receptor expression and peripheral cytokines are known to be upregulated in ME. We sought to examine the relationship between the 5-HT system and cytokine expression following systemic bacterial endotoxin challenge (LPS, 0.5 mg/kg i.p.), at a time when the acute sickness behaviours have largely resolved. At 24 hours post-injection mice exhibit no overt changes in locomotor behaviour, but do show increased immobility in a forced swim test, as well as decreased sucrose preference and reduced marble burying activity, indicating a depressive-like state. While peripheral IDO activity was increased after LPS challenge, central activity levels remained stable and there was no change in total brain 5-HT levels or 5-HIAA/5-HT. However, within the brain, levels of TNF and 5-HT2A receptor mRNA within various regions increased significantly. This increase in receptor expression is reflected by an increase in the functional response of the 5-HT2A receptor to agonist, DOI. These data suggest that regulation of fatigue and depressive-like moods after episodes of systemic inflammation may be regulated by changes in 5-HT receptor expression, rather than by levels of enzyme activity or cytokine expression in the CNS.
Insights
Systemic inflammation can induce depressive-like states by altering serotonin (5-HT) 2A receptor expression in the brain, not central enzyme activity. This impacts fatigue and mood regulation following infection.
Area of Science:
- Neuroscience
- Psychiatry
- Immunology
Background:
- Serotonin (5-HT) is implicated in psychiatric disorders.
- Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) involves infection and unknown etiology.
- ME/CFS patients exhibit upregulated 5-HT2A receptors and peripheral cytokines.
Purpose of the Study:
- To investigate the relationship between the serotonin system and cytokine expression after bacterial endotoxin challenge.
- To understand the neurobiological underpinnings of depressive-like states post-inflammation.
Main Methods:
- Mice were challenged with lipopolysaccharide (LPS).
- Behavioral tests (forced swim, sucrose preference, marble burying) assessed depressive-like states.
- Central and peripheral levels of serotonin, 5-HIAA, IDO activity, TNF, and 5-HT2A receptor mRNA were measured.
- Functional response of 5-HT2A receptors to DOI was assessed.
Main Results:
- LPS challenge induced depressive-like behaviors 24 hours post-injection.
- Peripheral IDO activity increased, but central serotonin levels and enzyme activity remained unchanged.
- Brain levels of TNF and 5-HT2A receptor mRNA significantly increased.
- Increased 5-HT2A receptor expression correlated with enhanced functional response.
Conclusions:
- Depressive-like moods and fatigue following systemic inflammation may be regulated by altered central 5-HT2A receptor expression.
- Changes in receptor expression, rather than CNS enzyme activity or cytokine levels, appear critical.
- This suggests a novel mechanism for mood regulation in post-infectious syndromes.
