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, 0.5mg/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.
Highlights
Diseases such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are often provoked by infection and have been shown to be associated with altered expression of peripheral pro-inflammatory cytokines
A popular theory argues that circulating cytokines such as tumor necrosis factor (TNF) and interleukin(IL)-1β increase the activity of the enzyme indoleamine 2,3-dioxygenase (IDO) within the brain which reduces the availability of tryptophan, a precursor for 5-HT synthesis [3] and the overall levels of 5-HT in the CNS
The data suggest the novel idea that systemic inflammation may alter behaviour by changing the expression of 5-HT receptors, rather than by reducing the availability of 5-HT in the CNS, which is consistent with observations in CFS/ME and depressed patient cohorts [2, 27, 28]
Summary
Diseases such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are often provoked by infection and have been shown to be associated with altered expression of peripheral pro-inflammatory cytokines. The change in expression of 5-HT receptors, such as 5HT2A, is a feature of fatigue, which suggests that dysregulation of the serotonergic system may play a PLOS ONE | DOI:10.1371/journal.pone.0130643. Post-infection ME/CFS-like behaviours can be modeled by the injection of bacterial endotoxin (LPS). The peripheral injection of M.Bovis BCG has been shown to not alter the CNS kynurenine/tryptophan ratio [4], which is reported to be an indirect measure of IDO activity and it is unclear whether this is solely a peripheral phenomenon, or whether IDO activity in the brain is important in regulating these behaviours
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