Enhancement Of Serotonin Uptake By Cortisol

[Lokzo]

https://link.springer.com/content/pdf/10.3758/CABN.1.1.96.pdf

 

[Lokzo]

Guys I am actually trying to do a post about how SEROTONIN is actually increased during times of stress.
I need further support justifying how serotonin makes us fat, miserable, lowers metabolism etc.

 

[lampofred]

I think stresses that increase adrenaline/cortisol relative to prolactin lower serotonin (as this study shows), like sleep deprivation. Increasing serotonin uptake means lower serotonin in circulation. Whereas stresses that raise prolactin and lower adrenaline/cortisol, like alcohol, raise serotonin.

Serotonin goes up whenever metabolism is slowed. High cortisol = high metabolism, even though it's stress-driven, so it lowers serotonin even though it's stressful. Stress-free thyroid metabolism (aka metabolism that is supported by high CO2) is both low adrenaline/cortisol and low serotonin.

 

[Terma]

Yes indeed (Sci-Hub | Correlation between cortisol level and serotonin uptake in patients with chronic stress and depression. Cognitive, Affective, & Behavioral Neuroscience, 1(4), 388–393 | 10.3758/cabn.1.4.388), I think cortisol acutely increasing SERT is logical because that helps explain its role in anxiety disorders: in organisms where 5-HT2c or other 5-HT receptors that can induce anxiety are highly expressed, cortisol feels good by lowering serotonin. That is, until the feedback GR downregulate or become simply dysfunctional (their assembly/shuttling) at which point you begin to disintegrate. Likely, having sensitive 5-HT2c (and possibly others) together with feedback GR insensitivity is part of what makes people very sensitive to stress. Something similar might be true for 5-HT3 but I'm not as sure. Of course when GR feedback is dysregulated, this turns on the dynorphin system and you feel terrible followed by something like PTSD where essentially you can't stop thinking about your failures because the resulting KOR system insensitivity (due to to the higher levels of dynorphin) prevents failure memory reconsolidation.

@Astolfo
This idea might be interesting to you because you took a glucocorticoid and fluoxetine - a 5-HT2c antagonist - at the same time. It might have left you with upregulated 5-HT2c after you went off it while simultaneously GR insensitivity makes it impossible for cortisol to lower your serotonin levels:
Chronic citalopram and fluoxetine treatments upregulate 5-HT2c receptors in the rat choroid plexus. - PubMed - NCBI

 

[Lejeboca]

Thank you for the explanation @lampofred and @Terma and for bringing up this topic @Lokzo .
This makes Dr. Peat's mentioning that cortisol "can have protective effect of inhibiting the enzyme that makes serotonin" more specific, as I was curious about the process after reading the newsletter.

 

[Astolfo]

@Astolfo
This idea might be interesting to you because you took a glucocorticoid and fluoxetine - a 5-HT2c antagonist - at the same time. It might have left you with upregulated 5-HT2c after you went off it while simultaneously GR insensitivity makes it impossible for cortisol to lower your serotonin levels:
Chronic citalopram and fluoxetine treatments upregulate 5-HT2c receptors in the rat choroid plexus. - PubMed - NCBI

Thanks so much for letting me know.

I read it, but it seems the change on receptors is not permanent, or is it?

The changes in receptor characteristics were not observed consistently after the 68-hour withdrawal from fluoxetine

Nevertheless, I'm suspecting from GR insensitivity(excess feedback). I may have kynurenine problems but what made them problematic at the first place is not known.

 

[Terma]

It's not permanent but it would be being kept that way because receptors like 5-HT2c stimulate cortisol which will presumably keep feedback GR desensitized by chronic stimulation (e.g. during the night). 5-HT2c would be expected to lower allopregnanolone release, deficiency of which contributes to the cycle.

Well it's only one idea, but based on the pharmacology of the drugs taken I'd put more money on it than other things.

After a period of time you end up with:

5-HT ++ (or may vary)
5HT2c ++
Cortisol ++ (or inverted over 24h)
GR feedback sensitivity -- (delayed)
SERT --
Allopregnanolone --
Dynorphin ++
KOR sensitivity -- (delayed)
Growth Jormone --
Quinolinic acid ++
Kynurenic acid ++/--
Xanthurenic acid ++/--

 

[Terma]

Here is another aspect you can tie into that loop and into PTSD: the Dynorphin/KOR system is probably evolutionarily important because it helps organisms learn from mistakes and avoid future ones. It may help avoid energetically costly bad decisions and especially detect futile attempts to defeat stressors.

I make a bet that the KOR system is involved in the wiring of dopamine and 5-HT receptors, because it's already known to ablate dopamine and serotonin levels, but I'm not sure about the details.

KOR activation seems to be a failure "result" response following a period of stressful serotonin activation: 5HT receptors stimulated on threats release cortisol and stimulate CRH, which releases dynorphin, which stimulates KOR and lowers both dopamine and serotonin (disclaimer: may depend on brain area). It seems to be what signals a failure in an attempt to deal with a stressor or achieve something. In other words, KOR is normally the thing that stops the stress loop, because it has the power to restrain both catecholamines and serotonin. It allows you to stop so you can try something else later. It helps implement persistence. In nature, many predators fail the large majority of their hunts, but they learn from it and try again ad infinitum. This system could have evolved from such situations. KOR might be the "fishing" receptor. Not a lot of dopamine in fishing. Think about how incredibly persistent predators must be in nature in order to survive - sometimes it's mind-boggling. This is why we have things like KOR that we needed but make us feel like crap.

Its curious property is that you can benefit from both agonism for fear extinction and from antagonism to increase dopamine (as well as for upregulation).

 

[Lokzo]

Here is another aspect you can tie into that loop and into PTSD: the Dynorphin/KOR system is probably evolutionarily important because it helps organisms learn from mistakes and avoid future ones. It may help avoid energetically costly bad decisions and especially detect futile attempts to defeat stressors.

I make a bet that the KOR system is involved in the wiring of dopamine and 5-HT receptors, because it's already known to ablate dopamine and serotonin levels, but I'm not sure about the details.

KOR activation seems to be a failure "result" response following a period of stressful serotonin activation: 5HT receptors stimulated on threats release cortisol and stimulate CRH, which releases dynorphin, which stimulates KOR and lowers both dopamine and serotonin (disclaimer: may depend on brain area). It seems to be what signals a failure in an attempt to deal with a stressor or achieve something. In other words, KOR is normally the thing that stops the stress loop, because it has the power to restrain both catecholamines and serotonin. It allows you to stop so you can try something else later. It helps implement persistence. In nature, many predators fail the large majority of their hunts, but they learn from it and try again ad infinitum. This system could have evolved from such situations. KOR might be the "fishing" receptor. Not a lot of dopamine in fishing. Think about how incredibly persistent predators must be in nature in order to survive - sometimes it's mind-boggling. This is why we have things like KOR that we needed but make us feel like crap.

Its curious property is that you can benefit from both agonism for fear extinction and from antagonism to increase dopamine (as well as for upregulation).

How do you know so much?