Post-viral Fatigue Mice Study Surprises


Founder of Health Rising and Phoenix Rising
Staff member
It suggests that serotonin transport changes, not the kynurenine pathway plays a major role in the fatigue seen after infections - at least according to these mice. Alterations in the serotonin transporter genes have been found in ME/CFS. Not many people are willing to base the fatigue in ME/CFS on serotonin problems, however. The insignificance of the kynurenine pathway was clearly a surprise.

The IDO theory postulates that pro-inflammatory cytokines up-regulate the activity of IDO and therefore deplete the levels of tryptophan available for making 5-HT [36]. Perhaps the most surprising result therefore, was that brain tissue levels of tryptophan breakdown to kynurenine and the levels of 5-HT and 5-HT metabolites were unaltered in the depressive-like late phase of sickness (>24 hours) in these animals. The role of IDO in the breakdown of tryptophan suggests that any circulating factors altering the activity of this enzyme, should alter overall 5-HT metabolism [3739]. It is clear from the work here that peripheral IDO activity is increased by systemic inflammation and this is reflected in the increased IDO activity in the gut and the increased levels of circulating kynurenine. Others have demonstrated similarly large increases in the periphery [40], however, increases of this magnitude are rarely reflected by similarly large increases in the CNS. These data suggest that while the tryptophan/kynurenine pathway may be involved in inflammation-associated behavioural changes, this is likely to be an entirely peripheral phenomenon.

A Model of Post-Infection Fatigue Is Associated with Increased TNF and 5-HT2A Receptor Expression in Mice
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.


Well-Known Member
What's also interesting is how closely the two are connected. If there is a conversion problem in the tryptophan pathway and it doesn't go down the pathway to produce seratonin. It goes down the pathway to make quinolinic acid which is neurotoxic. Does all sorts of things when the conversion doesn't happen properly.


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