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

Couch Y, Xie Q, Lundberg L, Sharp T, Anthony DC - PLoS ONE (2015)

Bottom Line: 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.However, within the brain, levels of TNF and 5-HT2A receptor mRNA within various regions increased significantly.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.

View Article: PubMed Central - PubMed

Affiliation: Department 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.

No MeSH data available.


Related in: MedlinePlus

Kynurenine and 5-HT levels in the circulation and tissues of saline and LPS treated animals at 24 hours.Animals received a single dose of LPS (0.5mg/kg) or vehicle 24 hours prior to testing for kynurenine production by IDO in the gut (A) and kynurenine levels in the plasma (B). Whole brains were assessed for 5-HT (C); 5-HIAA (D); and the ratio of 5-HT:5-HIAA (E) as well as kynurenine production by IDO in different brain regions (F). Data are mean ±SEM n = 6; *p<0.05; **p<0.01 and ***p<0.001 compared to saline injected controls.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4493081&req=5

pone.0130643.g002: Kynurenine and 5-HT levels in the circulation and tissues of saline and LPS treated animals at 24 hours.Animals received a single dose of LPS (0.5mg/kg) or vehicle 24 hours prior to testing for kynurenine production by IDO in the gut (A) and kynurenine levels in the plasma (B). Whole brains were assessed for 5-HT (C); 5-HIAA (D); and the ratio of 5-HT:5-HIAA (E) as well as kynurenine production by IDO in different brain regions (F). Data are mean ±SEM n = 6; *p<0.05; **p<0.01 and ***p<0.001 compared to saline injected controls.

Mentions: Systemic inflammation is known to alter the activity of IDO, which is strongly expressed in the gut and the CNS. This enzyme is known to metabolize tryptophan and thus reduce its availability for 5-HT synthesis. In order to determine whether inflammation affected IDO activity, and as a consequence, 5-HT and kynurenine levels in the CNS, all of the above were measured in plasma, CNS and gut. At 24 hours after an LPS challenge kynurenine concentrations in the gut were significantly increased (Student’s t-test p<0.01; Fig 2A). Concomitantly, plasma levels of kynurenine also increased in LPS-treated animals (p<0.05; Fig 3B). Total brain 5-HT, and its metabolite 5-HIAA were assessed by HPLC 24 hours after a single LPS injection (0.5mg/kg) and a ratio of 5-HT:5-HIAA was used to assess turnover (5-HIAA/5-HT). There was no significant change in either 5-HT or 5-HIAA (Student’s t-test p = 0.16 and 0.10, respectively; Fig 2C and 2D), and also no change in the ratio of 5-HT to 5-HIAA (p = 0.5; Fig 2E). Furthermore, kynurenine levels within specific regions were investigated to determine whether the immune axis within the brain had any effects on tryptophan breakdown. LPS and the region studied both had significant effects on kynurenine accumulation (two-way ANOVA region p<0.001 F4,50 = 25.71; LPS p<0.05 F1,50 = 4.15; LPS:region p<0.05 F4,50 = 3.82; Fig 4D), however, post-hoc analysis revealed no significant effect of LPS in any brain region (Bonferroni p>0.05 in all cases). The lack of change in IDO related activities was backed up by no change in IDO mRNA expression after an LPS challenge, even at acute time points where changes are likely to occur (S4 Fig).


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

Couch Y, Xie Q, Lundberg L, Sharp T, Anthony DC - PLoS ONE (2015)

Kynurenine and 5-HT levels in the circulation and tissues of saline and LPS treated animals at 24 hours.Animals received a single dose of LPS (0.5mg/kg) or vehicle 24 hours prior to testing for kynurenine production by IDO in the gut (A) and kynurenine levels in the plasma (B). Whole brains were assessed for 5-HT (C); 5-HIAA (D); and the ratio of 5-HT:5-HIAA (E) as well as kynurenine production by IDO in different brain regions (F). Data are mean ±SEM n = 6; *p<0.05; **p<0.01 and ***p<0.001 compared to saline injected controls.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493081&req=5

pone.0130643.g002: Kynurenine and 5-HT levels in the circulation and tissues of saline and LPS treated animals at 24 hours.Animals received a single dose of LPS (0.5mg/kg) or vehicle 24 hours prior to testing for kynurenine production by IDO in the gut (A) and kynurenine levels in the plasma (B). Whole brains were assessed for 5-HT (C); 5-HIAA (D); and the ratio of 5-HT:5-HIAA (E) as well as kynurenine production by IDO in different brain regions (F). Data are mean ±SEM n = 6; *p<0.05; **p<0.01 and ***p<0.001 compared to saline injected controls.
Mentions: Systemic inflammation is known to alter the activity of IDO, which is strongly expressed in the gut and the CNS. This enzyme is known to metabolize tryptophan and thus reduce its availability for 5-HT synthesis. In order to determine whether inflammation affected IDO activity, and as a consequence, 5-HT and kynurenine levels in the CNS, all of the above were measured in plasma, CNS and gut. At 24 hours after an LPS challenge kynurenine concentrations in the gut were significantly increased (Student’s t-test p<0.01; Fig 2A). Concomitantly, plasma levels of kynurenine also increased in LPS-treated animals (p<0.05; Fig 3B). Total brain 5-HT, and its metabolite 5-HIAA were assessed by HPLC 24 hours after a single LPS injection (0.5mg/kg) and a ratio of 5-HT:5-HIAA was used to assess turnover (5-HIAA/5-HT). There was no significant change in either 5-HT or 5-HIAA (Student’s t-test p = 0.16 and 0.10, respectively; Fig 2C and 2D), and also no change in the ratio of 5-HT to 5-HIAA (p = 0.5; Fig 2E). Furthermore, kynurenine levels within specific regions were investigated to determine whether the immune axis within the brain had any effects on tryptophan breakdown. LPS and the region studied both had significant effects on kynurenine accumulation (two-way ANOVA region p<0.001 F4,50 = 25.71; LPS p<0.05 F1,50 = 4.15; LPS:region p<0.05 F4,50 = 3.82; Fig 4D), however, post-hoc analysis revealed no significant effect of LPS in any brain region (Bonferroni p>0.05 in all cases). The lack of change in IDO related activities was backed up by no change in IDO mRNA expression after an LPS challenge, even at acute time points where changes are likely to occur (S4 Fig).

Bottom Line: 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.However, within the brain, levels of TNF and 5-HT2A receptor mRNA within various regions increased significantly.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.

View Article: PubMed Central - PubMed

Affiliation: Department 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.

No MeSH data available.


Related in: MedlinePlus