Lowering Sertonin In The Brain Abolishes Fatigue

[haidut]

There have been many studies on this, and in fact my experiments with BCAA and tyrosine to reduce serotonin in the brain were based on those studies. This study however, goes a step further and claims that exercise-derived (but probably any other as well) fatigue is fully abolished by inhibiting tryptophan hydroxylase, and thus reducing serotonin in the brain.
http://www.ncbi.nlm.nih.gov/pubmed/22540893

In addition, the study claims that reduced brain serotonin improved the ability of mice to cool off when their bodies heated up due to the exercise. So, aspirin + BCAA + tyrosine seems like a good cocktail to try and take for several days...

 

[jyb]

In addition, the study claims that reduced brain serotonin improved the ability of mice to cool off when their bodies heated up due to the exercise. So, aspirin + BCAA + tyrosine seems like a good cocktail to try and take for several days...

I think it'd only work if you keep taking this profile throughout the day so not sure if practical (because if you just take for breakfast, I would imagine that the blockage at the brain barrier only last an hour). But it's a pretty cool diagnosis, for example if my hypo symptoms disappeared after such an experiment then I'd find it informative.

 

[DaveFoster]

This is interesting. After taking tianeptine, an SSRE, I find that sleep deprivation affects me significantly less; about to the same effect as caffeine. Taking the two together and you can just forget about getting tired.

 

[Mauritio]

Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. - PubMed - NCBI

Can somebody explain me that ? Shouldn't the people that take SSRIs exactly be the ones that respond best to serotonin- depletion ?!
I think they used Fenclonin for ATD ,which reduces Serotonin to almost undetectable levels ,so go figure ...

In drug-free patients with MDD in remission, a moderate mood decrease was found for ATD, without an effect of APTD. ATD induced relapse in patients with MDD in remission who used serotonergic antidepressants. In conclusion, monoamine depletion studies demonstrate decreased mood in subjects with a family history of MDD and in drug-free patients with MDD in remission, but do not decrease mood in healthy humans. Although depletion studies usefully investigate the etiological link of 5-HT and NE with MDD, they fail to demonstrate a causal relation. They presumably clarify a vulnerability trait to become depressed. Directions for further investigation of this vulnerability trait are proposed.


@haidut @DaveFoster

 

[DaveFoster]

Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. - PubMed - NCBI

Can somebody explain me that ? Shouldn't the people that take SSRIs exactly be the ones that respond best to serotonin- depletion ?!
I think they used Fenclonin for ATD ,which reduces Serotonin to almost undetectable levels ,so go figure ...

In drug-free patients with MDD in remission, a moderate mood decrease was found for ATD, without an effect of APTD. ATD induced relapse in patients with MDD in remission who used serotonergic antidepressants. In conclusion, monoamine depletion studies demonstrate decreased mood in subjects with a family history of MDD and in drug-free patients with MDD in remission, but do not decrease mood in healthy humans. Although depletion studies usefully investigate the etiological link of 5-HT and NE with MDD, they fail to demonstrate a causal relation. They presumably clarify a vulnerability trait to become depressed. Directions for further investigation of this vulnerability trait are proposed.

So here's a more full excerpt from the study, which shows that neither 5-hydroxytryptophan (5-HT) nor norepinephrine/dopamine (NE/DA) depletion negatively impacted the mood of healthy people. In those who previously suffered from depression but had not began or had no longer taken antidepressants after their recovery, as well as in those who currently took antidepressants, tryptophan depletion had a depressive effect. In other words, only those with an inclination toward depression suffered a depressive effect from tryptophan depletion. Therefore, tryptophan depletion did not have a depressive effect per se.

"5-HT or NE/DA depletion did not decrease mood in healthy controls. 5-HT or NE/DA depletion slightly lowered mood in healthy controls with a family history of MDD. In drug-free patients with MDD in remission, a moderate mood decrease was found for ATD, without an effect of APTD. ATD induced relapse in patients with MDD in remission who used serotonergic antidepressants."​

In depressed or formerly depressed patients currently taking or who had formerly taken antidepressants of the selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) classes, the depressive effect of tryptophan depletion became even more pronounced and prompted relapse of depression.

"Additionally, a depressive relapse after monoamine depletion in remitted patients who use AD, occurs only if the target of the depletion (5-HT, NE) coincides with the working mechanism of the AD used. This emphasizes that AD indeed specifically affect their supposed target systems. However, we may only conclude that an undepleted 5-HT system is required for serotonergic AD. The same holds for the NE system and norepinephrinergic AD. "​

The study by H. G. Ruhé and others referred to another study by Delgado, who commented on the parallel between antidepressant withdrawal and the depression caused by tryptophan depletion. In both cases, it's possible that the SSRIs cause some excitatory effect in the brain tied very closely to their interactions with the serotonergic system. It could be that tryptophan depletion interfered with some mode of action for the SSRIs, which led exacerbation of depression in the short-term. Bear in mind that many antidepressants can worsen depression and even cause suicidal behavior in the short-term, whereas in the long-term, they tend to have an antidepressive effect. These drugs have a myriad of mixed effects, not all the result of serotonin.

Meta-Chlorophenylpiperazine (mCPP), a metabolite of the antidepressant and sleep-aid trazodone, suggests some of the negative effects of serotonin on one's mood.

"mCPP possesses significant affinity for the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, and 5-HT7 receptors, as well as the SERT.[23] It also has some affinity for α1-adrenergic, α2-adrenergic, H1, I1, and NET.[23][32] It behaves as an agonist at most serotonin receptors.[33][34] mCPP has been shown to act not only as a serotonin reuptake inhibitor but as a serotonin releasing agent as well.[35]

mCPP's strongest actions are at the 5-HT2B and 5-HT2C receptors and its discriminative cue is mediated primarily by 5-HT2C.[23][36][37] Its negative effects such as anxiety, headaches, and appetite loss are likely mediated by its actions on the 5-HT2C receptor.[8][19][38] Other effects of mCPP include nausea, hypoactivity, and penile erection, the latter two the result of increased 5-HT2C activity and the former likely via 5-HT3 stimulation.[39][40][41]"​

References
1. meta-Chlorophenylpiperazine - Wikipedia [Internet]. [cited 2019 Jan 1]. Available from: meta-Chlorophenylpiperazine - Wikipedia
2. Delgado PL. Monoamine depletion studies: implications for antidepressant discontinuation syndrome. J Clin Psychiatry. 2006;67 Suppl 4:22–6.
3. Ruhé HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry. 2007 Apr;12(4):331–59.

 

[Mauritio]

So here's a more full excerpt from the study, which shows that neither 5-hydroxytryptophan (5-HT) nor norepinephrine/dopamine (NE/DA) depletion negatively impacted the mood of healthy people. In those who previously suffered from depression but had not began or had no longer taken antidepressants after their recovery, as well as in those who currently took antidepressants, tryptophan depletion had a depressive effect. In other words, only those with an inclination toward depression suffered a depressive effect from tryptophan depletion. Therefore, tryptophan depletion did not have a depressive effect per se.

"5-HT or NE/DA depletion did not decrease mood in healthy controls. 5-HT or NE/DA depletion slightly lowered mood in healthy controls with a family history of MDD. In drug-free patients with MDD in remission, a moderate mood decrease was found for ATD, without an effect of APTD. ATD induced relapse in patients with MDD in remission who used serotonergic antidepressants."​

In depressed or formerly depressed patients currently taking or who had formerly taken antidepressants of the selective serotonin reuptake inhibitor (SSRI) and serotonin-norepinephrine reuptake inhibitor (SNRI) classes, the depressive effect of tryptophan depletion became even more pronounced and prompted relapse of depression.

"Additionally, a depressive relapse after monoamine depletion in remitted patients who use AD, occurs only if the target of the depletion (5-HT, NE) coincides with the working mechanism of the AD used. This emphasizes that AD indeed specifically affect their supposed target systems. However, we may only conclude that an undepleted 5-HT system is required for serotonergic AD. The same holds for the NE system and norepinephrinergic AD. "​

The study by H. G. Ruhé and others referred to another study by Delgado, who commented on the parallel between antidepressant withdrawal and the depression caused by tryptophan depletion. In both cases, it's possible that the SSRIs cause some excitatory effect in the brain tied very closely to their interactions with the serotonergic system. It could be that tryptophan depletion interfered with some mode of action for the SSRIs, which led exacerbation of depression in the short-term. Bear in mind that many antidepressants can worsen depression and even cause suicidal behavior in the short-term, whereas in the long-term, they tend to have an antidepressive effect. These drugs have a myriad of mixed effects, not all the result of serotonin.

Meta-Chlorophenylpiperazine (mCPP), a metabolite of the antidepressant and sleep-aid trazodone, suggests some of the negative effects of serotonin on one's mood.

"mCPP possesses significant affinity for the 5-HT1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, and 5-HT7 receptors, as well as the SERT.[23] It also has some affinity for α1-adrenergic, α2-adrenergic, H1, I1, and NET.[23][32] It behaves as an agonist at most serotonin receptors.[33][34] mCPP has been shown to act not only as a serotonin reuptake inhibitor but as a serotonin releasing agent as well.[35]

mCPP's strongest actions are at the 5-HT2B and 5-HT2C receptors and its discriminative cue is mediated primarily by 5-HT2C.[23][36][37] Its negative effects such as anxiety, headaches, and appetite loss are likely mediated by its actions on the 5-HT2C receptor.[8][19][38] Other effects of mCPP include nausea, hypoactivity, and penile erection, the latter two the result of increased 5-HT2C activity and the former likely via 5-HT3 stimulation.[39][40][41]"​

References
1. meta-Chlorophenylpiperazine - Wikipedia [Internet]. [cited 2019 Jan 1]. Available from: meta-Chlorophenylpiperazine - Wikipedia
2. Delgado PL. Monoamine depletion studies: implications for antidepressant discontinuation syndrome. J Clin Psychiatry. 2006;67 Suppl 4:22–6.
3. Ruhé HG, Mason NS, Schene AH. Mood is indirectly related to serotonin, norepinephrine and dopamine levels in humans: a meta-analysis of monoamine depletion studies. Mol Psychiatry. 2007 Apr;12(4):331–59.

Thank you!

 

[DaveFoster]

Thank you!

No problem. Let me know if you have any other questions.

 

[Mauritio]

I will ;=)

 

[Terma]

Can't help it, I think the study in OP probably had experimental specific circumstances or a flaw, I'm not sold on it thanks to these guys:

Tryptophan circuit in fatigue: From blood to brain and cognition. - PubMed - NCBI
https://www.researchgate.net/public...ryptophan_and_its_Neurometabolites_in_Fatigue

It's more logical for kynurenine (kynurenic acid) to mediate fatigue because it is more directly related to energy regulation (evolutionarily: Kynurenic acid is a nutritional cue that enables behavioral plasticity) while serotonin is more like a higher-level signal for perceived threats. KYNA behaves like a "brake" or possibly "full" signal.

For example: KYNA decreases dopamine and NMDA, together with QUIN they ruin cognition in hippocampus, and it's even possible xanthurinic acid decreases BH4 synthesis: Tetrahydrobiopterin Biosynthesis as a Potential Target of the Kynurenine Pathway Metabolite Xanthurenic Acid

KYNA is produced in muscles during exercise, so less KYN crosses the BBB forming an indirect signal to the CNS. Serotonin can't communicate as much across the BBB since it can't cross it and the conversions only consume as small amount of Trp compared to KYN pathway.

It goes on like this.

It may be worse in males or slightly dependent on sex because some estrogens lower the KYN pathway in favor of serotonin, while cortisol triggers KYN.

The picture changes in chronic illness, but even there, increased serotonin (sensitivity) feeds back via cortisol to enhance KYN production.

The article in the OP doesn't even mention kynurenine once (not even a title in the references), much like the original tests with fenclonine, so I find it questionable. In the first 2 studies I posted they criticize the serotonin hypothesis of fatigue directly (don't just read abstract).

 

[Hans]

From the first study:
"These findings suggest that uptake of periphery-derived kynurenine (produced via indoleamine-2,3- dioxygenase (IDO)) and tryptophan into the brain enhances kynurenic acid production in the brain, and the three factors produce amplification effect involved in the role of central-peripheral linkage in central fatigue, triggering cognitive dysfunction"

IDO is activated by inflammation and also nitric oxide, so those two would then also play a big path in fatigue and cognitive deficits.

 

[Terma]

Yes, but the contribution could have as much or more to do with the KYN->KYNA conversion in exercise in muscles as the TRP->KYN; meanwhile the KYN may also come from TDO as it's the biggest producer especially under high cortisol.

Just a warning, in the first article there was a typo, in:

Peripheral kynurenine is first produced by the catalytic reaction of free tryptophan with indoleamine-2,3-dioxygenase (IDO) in the liver (Schrocksnadel et al., 2006), and then crosses the blood-brain barrier to be rapidly taken up into the brain (Fukui et al., 1991).

Here he meant to say TDO in the liver, not IDO (you can verify this against other papers such as Abdulla's).

You can see half of what I wrote in this convenient study:
Inhibition of stress-induced hepatic tryptophan 2,3-dioxygenase exhibits antidepressant activity in an animal model of depressive behaviour

The role of hepatic tryptophan 2,3 dioxygenase (TDO) was assessed in the provocation of stress-induced depression-related behaviour in the rat. TDO drives tryptophan metabolism via the kynurenine pathway (KP) and leads to the production of neuroactive metabolites including kynurenine. A single 2 h period of restraint stress in adult male Sprague–Dawley rats provoked an increase in circulating concentrations of the glucocorticoid corticosterone and induction of hepatic TDO expression and activity. Repeated exposure to stress (10 d of 2 h restraint each day) provoked an increase in immobility in the forced swimming test (FST) indicative of depression-related behaviour. Immobility was accompanied by an increase in the circulating corticosterone concentrations, expression and activity of hepatic TDO and increase in the expression of TDO in the cerebral cortex. Increased TDO activity was associated with raised circulating kynurenine concentrations and a reduction in circulating tryptophan concentrations indicative of KP activation. Co-treatment with the TDO inhibitor allopurinol (20 mg/kg, i.p.), attenuated the chronic stress-related increase in immobility in the FST and the accom- panying increase in circulating kynurenine concentrations. These findings indicate that stress-induced corticosterone and consequent activation of hepatic TDO, tryptophan metabolism and production of kynurenine provoke a depression-related behavioural phenotype. Inhibition of stress-related hepatic TDO activity promotes antidepressant activity. TDO may therefore represent a promising target for the treatment of depression asso- ciated with stress-related disorders in which there is evidence for KP activation.