5-ht theory and steroidogenesis [Coraggio's corner]

This is for hypothesis and even educated speculation.
Juvo
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Re: 5-ht theory and steroidogenesis

Unread post by Juvo »

Coraggio wrote:Ok, I have attached the tab from Melcangi's article about steroids level in CNS liquor. Ghost and others see this. If we are close to PFS, ctually we need to unlock the normal testosterone metabolism in the brain and local steridogenesis (Star, 3-Beta-HSD, 17-B-HSD, 5-Alpha reductase, 3-Alpha HSD) because Abnormal high T levels come from the blood stream.
Peripherally we need more conversion of pregnenolone to progesterone so more 3 Beta -HSD. Pregnenolone is famous regulating BBB permeability.

Sorry for the abnormal size of the tab!

Maybe tumeric can do this. I m going to looking into better.
livelli neurosteroidi PFS-liquor-1.jpg
Forskolin too. Although I think that's been mentioned a time or two here
Juvo
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Re: 5-ht theory and steroidogenesis

Unread post by Juvo »

Thanks! Definitely keep us in the loop. Dr. Melcangi's work is critical to furthering our understanding.
iull1k
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Re: 5-ht theory and steroidogenesis

Unread post by iull1k »

Coraggio wrote:I think I have found the final lick to understand the situation

1. First article:

https://www.ncbi.nlm.nih.gov/m/pubmed/15936112/

"Serotonergic 5-HT2A receptor stimulation induces steroid 5alpha-reductase gene expression in rat C6 glioma cells via transcription factor Egr-1.
Morita K, et al. Brain Res Mol Brain Res. 2005.
Show full citation
Abstract
Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of depressive mood disorders and well known to inhibit the reuptake of neurotransmitter serotonin into nerve terminals. Thus, it seems conceivable that these drugs may induce the outflow of serotonin from the synapse as a consequence of inhibiting the reuptake, resulting in the stimulation of glial cells surrounding nerve terminals. On this hypothesis, the effect of serotonin on steroid 5alpha-reductase type 1 (5alpha-R) gene expression in rat C6 glioma cells was examined as one of the in vitro model experiments for investigating the indirect influence of SSRIs on glial cells. Serotonin elevated 5alpha-R mRNA and protein levels through the stimulation of serotonin 5-HT2A receptors, and also elevated Egr-1 mRNA and protein levels prior to 5alpha-R gene expression in the glioma cells. Furthermore, serotonin failed to significantly increase 5alpha-R mRNA levels in the cells preloaded with the antisense oligodeoxynucleotide targeted on Egr-1 gene. These results indicate that serotonin may stimulate 5alpha-R gene expression via transcription factor Egr-1 in glial cells, thus suggesting that serotonin flowing out of the serotonergic synapse may be implicated in SSRI-induced changes in neurosteroid metabolism in brain."

This is the link between serotonin and neurosteroids. SSRI block SERT so serotonin increases drastically in the synapses cleft. Serotonin so stimulate every 5-ht receptor, including 5-ht2a in the glial cells. Note: there are a a huge number of glial cells in the brain that they cover every part of each neurons. Glial cells have enzymes to make neurosteroids such as 5-alpha reductase.
He have previously demonstrate in another thread that SSRI can activate 3-alpha HSD in an in vitro cell study but also that SSRI can acuteley upregulate both dihydroprogesterone(DHP) and allopregnenolone in vivo. Dihydroprogesterone is made by progesterone throught 5-alpha reductase activity. DHP then is the precursor of allopregnanolone (THP). So if you increase allopregnanolone you can tune your brain because you can upregulate the alpha 4 gaba subunit receptor making gaba receptor perfect for activating a lot of neural neurotransmitter systems in an antianhedonic prosocial prosexual mode.
Let do a step behind: gaba is the main inhibitory neurotransmitter system. It account for 33% synapses in the brain( it is a huge number). Gaba neurons are mainly interneuorons that can modulate every neuron type system. For exemple, 5-ht2c receptor activity inhibits dopaminergic signal and this is done by activating a gaba neurons that inhibits the dopaminergic one. Gaba receptors are only two: gaba A and gaba B. Gaba A is very important and is well represented in the brain. But here, pay attention, there is another big complication: gaba receptor is made by 5 subunits. Each subunit can be one between alpha 1-5, Beta1-3, gamma 1-2, epsilon, delta and so on. So there a huge number of combination of Gaba A receptors. Every combination has a specific affinity to gaba activators/modulators( allopregnanolone is one of these). It has been demonstrated that alpha4 receptors subunit are necessary for a proper dopaminergic neurotransmission. Gaba A conteining Alpha 4 subunit receptors are upregulated when allopregnanolone is present. Allopregnanolone is hugely upregulated by ssri But chronic SSRI treatment downregulate and decrease allopregnanolone synthesis. Allopregnanolone withdrawal it is has been demonstrated to cause an alpha 4 gaba a downregulation in the brain. This is what happens in PTSD (post traumatic stress disorder) and why the shift to a permanent psychological state that can last forever. He have pretty the same.
With a similarity changing gaba receptors subunit expression you can alter railroad exchange in a country making trains going in a different order. This is mainly why studies has noted an altered brain connectivity after taking only few amount of SSRI.


[End part 1. I am going to edit the next part soon.]

Amazing! I found now this study about 5ht2a and 5areductase. I was shocked and searched the link on the site, found your comment. I read exactly my thoughts in your comment.
DrugsAreBad
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Re: 5-ht theory and steroidogenesis

Unread post by DrugsAreBad »

iull1k: It looks interesting but it's a bit over my head. Could you provide a short summary of the theory and perhaps more importantly, its implications?
iull1k
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Re: 5-ht theory and steroidogenesis

Unread post by iull1k »

DrugsAreBad wrote:iull1k: It looks interesting but it's a bit over my head. Could you provide a short summary of the theory and perhaps more importantly, its implications?
Here is a file that i wrote 3 years ago. You can read it. https://docs.google.com/file/d/0B5GlVMx ... ype=msword
Now, after 3 years, there is a lot to change and add here. A lot of new information we discovered and new studies we found. I don't have time now and my brain fog don't allow me to concentrate, but there are such interesting findings to the level that maybe SSRI are not at all SSRI and their "antidepressant" effect is mediated trough completly another patway.
Coraggio
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Re: 5-ht theory and steroidogenesis

Unread post by Coraggio »

iull1k wrote:
Coraggio wrote:I think I have found the final lick to understand the situation

1. First article:

https://www.ncbi.nlm.nih.gov/m/pubmed/15936112/

"Serotonergic 5-HT2A receptor stimulation induces steroid 5alpha-reductase gene expression in rat C6 glioma cells via transcription factor Egr-1.
Morita K, et al. Brain Res Mol Brain Res. 2005.
Show full citation
Abstract
Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of depressive mood disorders and well known to inhibit the reuptake of neurotransmitter serotonin into nerve terminals. Thus, it seems conceivable that these drugs may induce the outflow of serotonin from the synapse as a consequence of inhibiting the reuptake, resulting in the stimulation of glial cells surrounding nerve terminals. On this hypothesis, the effect of serotonin on steroid 5alpha-reductase type 1 (5alpha-R) gene expression in rat C6 glioma cells was examined as one of the in vitro model experiments for investigating the indirect influence of SSRIs on glial cells. Serotonin elevated 5alpha-R mRNA and protein levels through the stimulation of serotonin 5-HT2A receptors, and also elevated Egr-1 mRNA and protein levels prior to 5alpha-R gene expression in the glioma cells. Furthermore, serotonin failed to significantly increase 5alpha-R mRNA levels in the cells preloaded with the antisense oligodeoxynucleotide targeted on Egr-1 gene. These results indicate that serotonin may stimulate 5alpha-R gene expression via transcription factor Egr-1 in glial cells, thus suggesting that serotonin flowing out of the serotonergic synapse may be implicated in SSRI-induced changes in neurosteroid metabolism in brain."

This is the link between serotonin and neurosteroids. SSRI block SERT so serotonin increases drastically in the synapses cleft. Serotonin so stimulate every 5-ht receptor, including 5-ht2a in the glial cells. Note: there are a a huge number of glial cells in the brain that they cover every part of each neurons. Glial cells have enzymes to make neurosteroids such as 5-alpha reductase.
He have previously demonstrate in another thread that SSRI can activate 3-alpha HSD in an in vitro cell study but also that SSRI can acuteley upregulate both dihydroprogesterone(DHP) and allopregnenolone in vivo. Dihydroprogesterone is made by progesterone throught 5-alpha reductase activity. DHP then is the precursor of allopregnanolone (THP). So if you increase allopregnanolone you can tune your brain because you can upregulate the alpha 4 gaba subunit receptor making gaba receptor perfect for activating a lot of neural neurotransmitter systems in an antianhedonic prosocial prosexual mode.
Let do a step behind: gaba is the main inhibitory neurotransmitter system. It account for 33% synapses in the brain( it is a huge number). Gaba neurons are mainly interneuorons that can modulate every neuron type system. For exemple, 5-ht2c receptor activity inhibits dopaminergic signal and this is done by activating a gaba neurons that inhibits the dopaminergic one. Gaba receptors are only two: gaba A and gaba B. Gaba A is very important and is well represented in the brain. But here, pay attention, there is another big complication: gaba receptor is made by 5 subunits. Each subunit can be one between alpha 1-5, Beta1-3, gamma 1-2, epsilon, delta and so on. So there a huge number of combination of Gaba A receptors. Every combination has a specific affinity to gaba activators/modulators( allopregnanolone is one of these). It has been demonstrated that alpha4 receptors subunit are necessary for a proper dopaminergic neurotransmission. Gaba A conteining Alpha 4 subunit receptors are upregulated when allopregnanolone is present. Allopregnanolone is hugely upregulated by ssri But chronic SSRI treatment downregulate and decrease allopregnanolone synthesis. Allopregnanolone withdrawal it is has been demonstrated to cause an alpha 4 gaba a downregulation in the brain. This is what happens in PTSD (post traumatic stress disorder) and why the shift to a permanent psychological state that can last forever. He have pretty the same.
With a similarity changing gaba receptors subunit expression you can alter railroad exchange in a country making trains going in a different order. This is mainly why studies has noted an altered brain connectivity after taking only few amount of SSRI.


[End part 1. I am going to edit the next part soon.]

Amazing! I found now this study about 5ht2a and 5areductase. I was shocked and searched the link on the site, found your comment. I read exactly my thoughts in your comment.
Glad to see anyone going deep and finding the same results.
Now I am searching about bdnf(Brain Derived Nwurotrophic factor) and how it is linked qith serotoninergic, dopaminergic e gabaergic system. We are close to autism spectrum disorder and PTSD. In both there is a bdnf signiling problem and in both there is a gaba alpha4 downregulation and in both there is a marked decrease in allopregnanolone.

Now I am finding that bdnf in the mature form(m-bdnf), throught the Trk-B pathway, can increase the g-protein receptor affinity(so the dopamine and serotonin ones) and also can increase the gaba alpha4 receptor subunits.

I found that one of the best way to increase bdnf in the brain is eating an high flavonoids diet. It sounds very promising and I will follow this hope.
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TalkingAnt
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Re: 5-ht theory and steroidogenesis [Coraggio's corner]

Unread post by TalkingAnt »

Has anyone tried anything related to allopregnanolone? I know some PFS guys were helped by progesterone which metabolizes into allo. A guy from the RayPeatForum sells 5a-DHP which is a precursor to allo. If you have low 3a-HSD activity (which converts 5a-DHP to allo), supposedly you can increase 5a-DHP conversion with a few things, like low dose SSRI (fuck that though), glycine, or mirtazapine. It would be interesting to see what happens when we raise allo with 5a-DHP and glycine/mirtazapine. There are also new drugs that are basically allo itself but they are still in clinical trials and research labs that sell them charge thousands for a single dose (Ganaxolone, SAGE-547).


Relevant discussions:
https://raypeatforum.com/community/thre ... vity.9361/

https://raypeatforum.com/community/thre ... 43/page-41

5a-DHP source:

http://www.idealabsdc.com/lab/
Cured | PSSD 2012-2020 | Log thread
DrugsAreBad
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Re: 5-ht theory and steroidogenesis [Coraggio's corner]

Unread post by DrugsAreBad »

Great work iull1k.
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TalkingAnt
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Re: 5-ht theory and steroidogenesis [Coraggio's corner]

Unread post by TalkingAnt »

Also looks like Sulforaphane raises 3a-HSD. A good source is broccoli seed preparations like this one:

https://www.amazon.com/Jarrow-Formulas- ... =srch&th=1

I may try something like 5mg every morning of 5a-DHP with 1 dose of sulforaphane for two weeks.
Cured | PSSD 2012-2020 | Log thread
Juvo
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Re: 5-ht theory and steroidogenesis [Coraggio's corner]

Unread post by Juvo »

TalkingAntColony wrote:Has anyone tried anything related to allopregnanolone? I know some PFS guys were helped by progesterone which metabolizes into allo. A guy from the RayPeatForum sells 5a-DHP which is a precursor to allo. If you have low 3a-HSD activity (which converts 5a-DHP to allo), supposedly you can increase 5a-DHP conversion with a few things, like low dose SSRI (fuck that though), glycine, or mirtazapine. It would be interesting to see what happens when we raise allo with 5a-DHP and glycine/mirtazapine. There are also new drugs that are basically allo itself but they are still in clinical trials and research labs that sell them charge thousands for a single dose (Ganaxolone, SAGE-547).


Relevant discussions:
https://raypeatforum.com/community/thre ... vity.9361/

https://raypeatforum.com/community/thre ... 43/page-41

5a-DHP source:

http://www.idealabsdc.com/lab/
Yeah I tried high dose progesterone with great temporary benefits. Wether or not GABA is a culprit, messing with it seems to produce the biggest effects versus anything else I've tried
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