Modulation Of Tryptophan And Serotonin Metabolism As A Biochemical Basis Of The Behavioral Effects O

Terma

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I still can't properly reply on this forum, it's ******* gay. The only reason I do this is because I think this author (Abdulla) provides a decent summary about the current scientific consensus regarding the tryptophan kynurenine pathway, which is something @Travis had been talking about extensively, although he clearly did not approve of all this guy's ideas (I write that with respect to Travis; I think the main ideas put forward in this article are theoretical at best, but Abdulla provides a decent summary of the current scientific knowledge about the kynurenine pathway, and parts of this are very significant and contradict some of my own ideas - all subject to review).

Modulation of Tryptophan and Serotonin Metabolism as a Biochemical Basis of the Behavioral Effects of Use and Withdrawal of Androgenic-Anabolic Steroids and Other Image- and Performance-Enhancing Agents

Modulation of tryptophan (Trp) metabolism may underpin the behavioral effects of androgenic-anabolic steroids (AAS) and associated image and performance enhancers. Euphoria, arousal, and decreased anxiety observed with moderate use and exercise may involve enhanced cerebral serotonin synthesis and function by increased release of albumin-bound Trp and estrogen-mediated liver Trp 2,3-dioxygenase (TDO) inhibition and enhancement of serotonin function. Aggression, anxiety, depression, personality disorders, and psychosis, observed on withdrawal of AAS or with use of large doses, can be caused by decreased serotonin synthesis due to TDO induction on withdrawal, excess Trp inhibiting the 2 enzymes of serotonin synthesis, and increased cerebral levels of neuroactive kynurenines. Exercise and excessive protein and branched-chain amino acid intakes may aggravate the effects of large AAS dosage. The hypothesis is testable in humans and experimental animals by measuring parameters of Trp metabolism and disposition and related metabolic processes.

If you read only the abstract, you're doing yourself a huge disservice, because it is the "Overview of Tryptophan Metabolism and Disposition" section that provides the best information. I'm not going to do like the amazon guy and highlight a bunch of quotes, I don't have the energy.

The last article that I'm aware by this author was: Kynurenine Pathway of Tryptophan Metabolism: Regulatory and Functional Aspects [edit: fixed second link]
Regulatory and functional aspects of the kynurenine (K) pathway (KP) of tryptophan (Trp) degradation are reviewed. The KP accounts for ~95% of dietary Trp degradation, of which 90% is attributed to the hepatic KP. During immune activation, the minor extrahepatic KP plays a more active role. The KP is rate-limited by its first enzyme, Trp 2,3-dioxygenase (TDO), in liver and indoleamine 2,3-dioxygenase (IDO) elsewhere. TDO is regulated by glucocorticoid induction, substrate activation and stabilization by Trp, cofactor activation by heme, and end-product inhibition by reduced nicotinamide adenine dinucleotide (phosphate). IDO is regulated by IFN-γ and other cytokines and by nitric oxide. The KP disposes of excess Trp, controls hepatic heme synthesis and Trp availability for cerebral serotonin synthesis, and produces immunoregulatory and neuroactive metabolites, the B3 “vitamin” nicotinic acid, and oxidized nicotinamide adenine dinucleotide. Various KP enzymes are undermined in disease and are targeted for therapy of conditions ranging from immunological, neurological, and neurodegenerative conditions to cancer.
 
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Travis

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I don't see any cause for disagreement. After all, he does mention this:

'IDO is regulated by IFN-γ and other cytokines and by nitric oxide.' ―Abdulla

Which was my primary concern, and certainly a very important one. Interferon-γ is how the immune system lowers tryptophan, and does so ostensibly to restrict it from invaders. The immune system interacts with serotonin in many others ways as well: mast cells synthesize and release serotonin when they degranulate, this indole serves as a chemotactic factor for eosinophils, and the high serotonin-binding platelets have surprising immune functions too.

'Euphoria, arousal, and decreased anxiety observed with moderate use and exercise may involve enhanced cerebral serotonin synthesis and function by increased release of albumin-bound Trp and estrogen-mediated liver Trp 2,3-dioxygenase (TDO) inhibition and enhancement of serotonin function.' ―Abdulla

I didn't know about this, but since other steroids regulate tryptophan and tyrosine catabolism (in the liver) this is not surprising. I do know that estradiol increases steroyl–CoA desaturase, an enzyme who's product is oleoyl–CoA. The increased synthesis of oleic acid could be expected to lead to concomitant increase of oleamide, the only molecule more serotonergic than serotonin itself (you laugh now, but wouldn't do so after reading a few oleamide studies). In low nanomolar concentrations, oleamide potentiates the 5-HT₂ receptor fivefold; it does not complete with serotonin binding, but binds allosterically to the receptor at an adjacent site. This molecule will predictably induce sleep at low levels, and as being more potent than the endocannabinoids its biological relevance shouldn't be discounted.

The more direct androgen/estrogen effects in this article certainly are interesting, and could do alot to explain the sex differential in psychology. This looks like something I ought to read.
 
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Terma

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Oleamide potentiates 5-HT2? That's surprising...

About estradiol and SCD, I've been reading mixed messages on that: Biochemical and physiological function of stearoyl-CoA desaturase
In ovariectomized rats, in which the ligand 17β-estradiol is absent, or estrogen receptor knockout mice, there is a profound increase in lipogenic gene expression in liver and adipose tissue. Under these conditions, SCD-1 expression has been shown to increase more than fivefold, with concomitant increases in adiposity and insulin resistance (7, 46). Until recently, the underlying mechanism by which estrogen reduced lipogenesis was unknown; however, Bryzgalova et al. (8) were able to demonstrate direct repression of SCD-1 promoter activity in the presence of estrogen. In addition, they were also able to demonstrate the ability of estrogen therapy in high-fat-fed mice to repress SCD-1 expression by ∼80%. However, it remains unresolved whether this is a direct effect of estrogen receptor-α binding to SCD-1 promoter or whether an indirect partner is involved.
I think it might be only in cancer cells that it increases SCD1
 

Travis

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Oleamide potentiates 5-HT2? That's surprising...

About estradiol and SCD, I've been reading mixed messages on that: Biochemical and physiological function of stearoyl-CoA desaturase

I think it might be only in cancer cells that it increases SCD1
That's really far out, because everything I've read shows an increase; I have even seen microarray data showing a significant upregulation in mRNA.

But steroyl–CoA desaturase could be a a thing induced by all growth hormones because both this enzyme in tandem with fatty acid synthesase is needed to create new unsaturated membrane lipids; the cell membrane must double in surface area upon each mitosis cycle, and the increased membrane fluidity caused by the stearate ⟶ oleate desaturation appears to be a prerequisite for this. On second thought: focusing on how just one growth hormone (estrogen) induces steroyl–CoA desaturase could be missing the point altogether . . . or growth/cancer-mongering on just one hormone out of many. Increased cell membrane desaturation also increases volume—or lowers density—which causes increased glucose permeability, and I think just this one fact alone could go a ways in understanding how growth hormones stimulate cell growth and/or mitosis—along with the induction of ornithine decarboxylase (polyamines are needed to replicate DNA; the nucleus also needs to double in size).

Ntambi, J. "Regulation of stearoyl-CoA desaturase by polyunsaturated fatty acids and cholesterol." Journal of lipid research (1999)

It would make more sense from a teleological perspective to have this enzyme controlled by lipids and lipid hormones, as the cell shouldn't have much use for it in times of a high oleic acid diet—for instance. There is some indication of this (Ntambi, 1999), and I don't think it would be unreasonable to suppose that the promoter region on the steroyl–CoA desaturase gene has a PPAR domain.
 
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Terma

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Yeah there's got to be some factor that's not accounted for.

I read a study not long ago where mRNA expression of something in liver (forgot) was different depending on whether estrogen, progesterone, or (estrogen + progesterone) were administered [as in, not additive]. I think that's common actually?

But I saw various studies where estrogen could be lipotropic, so I'm not that surprised about that.
 
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Perhaps estrogen might behave in a way similar to Growth Hormone vs IGF-1, since GH itself promotes fat oxidation, and it's the following IGF-1 increase that should increase SCD1 (e.g. Insulin-like growth factor-1 coordinately induces the expression of fatty acid and cholesterol biosynthetic genes in murine C2C12 myoblasts)... Tied into the context of food intake/restriction (and then methionine intake, so it's hopelessly convoluted)...

Or alternatively something tissue-specific, since the hormones often redistribute storage instead of acting equally on all tissues. Given the increase of SCD1 by estrogen in cancer cells...
 
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Now that you mentioned it, you're right, some link to/from PPARalpha and PPARgamma seems highly plausible.

[This has almost nothing to do with the original topic, but it's my thread damnit! I can derail it if I want!]
 

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