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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

Open field and locomotor activity in saline and LPS treated animals at 24 hours.Animals received a single dose of LPS (0.5 mg/kg) or vehicle 24 hours prior to testing, and were tested using a standard 3-minute open field measuring rearing (A) and square crossing (B). Animals were also tested using a two-bottle sucrose preference test (C) and a forced swim test studying duration of floating behaviour (D), as well as a longer 2 hour locomotor activity study (E) and marble burying test (F). Data are mean ±SEM n = 6; *p<0.05, **p<0.01 and ***p<0.001 compared to saline injected controls.
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pone.0130643.g001: Open field and locomotor activity in saline and LPS treated animals at 24 hours.Animals received a single dose of LPS (0.5 mg/kg) or vehicle 24 hours prior to testing, and were tested using a standard 3-minute open field measuring rearing (A) and square crossing (B). Animals were also tested using a two-bottle sucrose preference test (C) and a forced swim test studying duration of floating behaviour (D), as well as a longer 2 hour locomotor activity study (E) and marble burying test (F). Data are mean ±SEM n = 6; *p<0.05, **p<0.01 and ***p<0.001 compared to saline injected controls.

Mentions: To determine whether basic exploratory and mood-related behaviours were altered 24 hours after an LPS challenge, animals were subjected to a standard 3-minute open field test, as well as a longer locomotor activity test, to examine both exploratory and anxiety-type behaviours. Open field behaviour was not different in terms of either rearing behaviour (Fig 1A) or distance travelled (Fig 1B) during a 3-minute window. During a longer 2 hour locomotor activity task, all animals slowed down over time, and there was an interaction between LPS-challenge and time but no main effect of LPS (RM-ANOVA time p<0.001 F11,110 = 26.90; LPS p = 0.07 F1,110 = 3.85; LPS:time p<0.001 F11,110 = 5.09; Fig 1E). It should be noted that this dose of LPS is capable of inducing sickness behaviours at an acute time point S1 and S2 Figs) as well as a hepatic acute phase response (S2 Fig). It has been previously shown that peripheral inflammation can cause depression like behaviour in mice [25]. Here, 24 hours after a single LPS challenge, mice showed significant changes in sucrose preference, forced swim behaviours and marble burying. Specifically, after 24 hours LPS-treated animals showed a decrease in sucrose preference to <65% showing main effects of both time after testing and LPS, as well as an interaction (RM-ANOVA time p<0.05 F1,6 = 6.51; LPS p<0.01 F1,6 = 13.21; LPS:time p<0.05 F1,6 = 6.30; Fig 1C). Bonferroni post-hoc tests showed a decrease in sucrose preference in LPS treated animals, compared to saline treated animals (p<0.01). In the forced swim test, floating behaviour reached almost twice saline treated levels in animals receiving LPS (p<0.001; Fig 1D). Finally, marble burying increased across time and this behaviour was significantly decreased in LPS treated animals (RM-ANOVA time p<0.001 F6,36 = 33.69; LPS p<0.05 F1,36 = 8.71; LPS:time p = 0.053 F6,36 = 2.32; Fig 1F) with post-hoc analysis showing significant differences between groups after 10 minutes of testing (Bonferroni post-hoc p<0.05). It should be noted that there was no impairment in the animals’ overall levels of locomotor activity in this test (p = 0.93; S3 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)

Open field and locomotor activity in saline and LPS treated animals at 24 hours.Animals received a single dose of LPS (0.5 mg/kg) or vehicle 24 hours prior to testing, and were tested using a standard 3-minute open field measuring rearing (A) and square crossing (B). Animals were also tested using a two-bottle sucrose preference test (C) and a forced swim test studying duration of floating behaviour (D), as well as a longer 2 hour locomotor activity study (E) and marble burying test (F). Data are mean ±SEM n = 6; *p<0.05, **p<0.01 and ***p<0.001 compared to saline injected controls.
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getmorefigures.php?uid=PMC4493081&req=5

pone.0130643.g001: Open field and locomotor activity in saline and LPS treated animals at 24 hours.Animals received a single dose of LPS (0.5 mg/kg) or vehicle 24 hours prior to testing, and were tested using a standard 3-minute open field measuring rearing (A) and square crossing (B). Animals were also tested using a two-bottle sucrose preference test (C) and a forced swim test studying duration of floating behaviour (D), as well as a longer 2 hour locomotor activity study (E) and marble burying test (F). Data are mean ±SEM n = 6; *p<0.05, **p<0.01 and ***p<0.001 compared to saline injected controls.
Mentions: To determine whether basic exploratory and mood-related behaviours were altered 24 hours after an LPS challenge, animals were subjected to a standard 3-minute open field test, as well as a longer locomotor activity test, to examine both exploratory and anxiety-type behaviours. Open field behaviour was not different in terms of either rearing behaviour (Fig 1A) or distance travelled (Fig 1B) during a 3-minute window. During a longer 2 hour locomotor activity task, all animals slowed down over time, and there was an interaction between LPS-challenge and time but no main effect of LPS (RM-ANOVA time p<0.001 F11,110 = 26.90; LPS p = 0.07 F1,110 = 3.85; LPS:time p<0.001 F11,110 = 5.09; Fig 1E). It should be noted that this dose of LPS is capable of inducing sickness behaviours at an acute time point S1 and S2 Figs) as well as a hepatic acute phase response (S2 Fig). It has been previously shown that peripheral inflammation can cause depression like behaviour in mice [25]. Here, 24 hours after a single LPS challenge, mice showed significant changes in sucrose preference, forced swim behaviours and marble burying. Specifically, after 24 hours LPS-treated animals showed a decrease in sucrose preference to <65% showing main effects of both time after testing and LPS, as well as an interaction (RM-ANOVA time p<0.05 F1,6 = 6.51; LPS p<0.01 F1,6 = 13.21; LPS:time p<0.05 F1,6 = 6.30; Fig 1C). Bonferroni post-hoc tests showed a decrease in sucrose preference in LPS treated animals, compared to saline treated animals (p<0.01). In the forced swim test, floating behaviour reached almost twice saline treated levels in animals receiving LPS (p<0.001; Fig 1D). Finally, marble burying increased across time and this behaviour was significantly decreased in LPS treated animals (RM-ANOVA time p<0.001 F6,36 = 33.69; LPS p<0.05 F1,36 = 8.71; LPS:time p = 0.053 F6,36 = 2.32; Fig 1F) with post-hoc analysis showing significant differences between groups after 10 minutes of testing (Bonferroni post-hoc p<0.05). It should be noted that there was no impairment in the animals’ overall levels of locomotor activity in this test (p = 0.93; S3 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