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

[Bigmum]

Maybe 3a,5 THP can develop tolerance....hence symptoms after discontinuation....????...GABA, God one knows....

[Bigmum]

https://www.google.pl/url?sa=t&source=w ... wSBkdwi5CQ

[Coraggio]

https://www.ncbi.nlm.nih.gov/pubmed/27090561
Effects of neonatal allopregnanolone manipulations and early maternal separation on adult alcohol intake and monoamine levels in ventral striatum of male rats.

Llidó A1, Bartolomé I1, Darbra S1, Pallarès M2.
Author information
Abstract
Changes in endogenous neonatal levels of the neurosteroid allopregnanolone (AlloP) as well as a single 24h period of early maternal separation (EMS) on postnatal day (PND) 9 affect the development of the central nervous system (CNS), causing adolescent/adult alterations including systems and behavioural traits that could be related to vulnerability to drug abuse. In rats, some behavioural alterations caused by EMS can be neutralised by previous administration of AlloP. Thus, the aim of the present work is to analyse if manipulations of neonatal AlloP could increase adult alcohol consumption, and if EMS could change these effects. We administered AlloP or finasteride, a 5α-reductase inhibitor, from PND5 to PND9, followed by 24h of EMS at PND9. At PND70 we measured alcohol consumption using a two-bottle free-choice model (ethanol 10% (v/v)+glucose 3% (w/v), and glucose 3% (w/v)) for 15days. Ventral striatum samples were obtained to determine monoamine levels. Results revealed that neonatal finasteride increased both ethanol and glucose consumption, and AlloP increased alcohol intake compared with neonatal vehicle-injected animals. The differences between neonatal groups in alcohol consumption were not found in EMS animals. In accordance, both finasteride and AlloP animals that did not suffer EMS showed lower levels of dopamine and serotonin in ventral striatum. Taken together, these results reveal that neonatal neurosteroids alterations affect alcohol intake; an effect which can be modified by subsequent EMS. Thus, these data corroborate the importance of the relationship between neonatal neurosteroids and neonatal stress for the correct CNS development.

this is way PFS and PSSD patients display both anhedonia.

[Coraggio]

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.]

[JayR]

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. I am going to write the explanation soon.

Yeah but the problem is we don't know how this translates to humans. It could very well be that in humans this effect is insignificant. We also can't ignore the fact that many of us have gained benefit from 5-HT2A antagonists (which like AGONISTS downregulate the receptor further) - Mianserin and Metergoline being examples. We can't ignore the fact that research/studies have shown 2A-antagonists to benefit sexual function in those taking SSRI's - and after. And lastly, the fact that Flibanserin, approved for Women with SSRI-induced sexual dysfunction, and IT being a 2A-antagonist as well - proves that the direction we would want to move in MOST LIKELY would NOT be agonism or upregulation of 2A's...not to mention the fact that it is a CORTISOL-INDUCING receptor.

Not trying to shit on your hypothesis or anything, Corragio, I just feel as though there is another element/route far more significant.

[kamikaz3]

Yes carragio i think this is definitely the pathway to fixing this, we have to normalise this system. I have ordered pregnenolone

I definitely have autism spectrum disorder, i never had a gf pre-PSSD for longer than 7 days, i never had any real friends. Terrible social skills and very awkward. People with autism spectrum have dysfunctional gene that will convert cholesterol into pregnenolone in the liver or wherever. CYP11A.

I will try preg alone, but i also want to try something else as maybe SSRI's have dysrupted other genes and making them dysfunctional or silent, etc. like this:

(1) Topical progesterone – 60 mg a day;

(2) Pregnenolone (progesterone’s precursor) – 100 mg capsules every other day;

(3) DHEA – 25 mg pill once a week,

(4) D-Aspartic acid – between 1,500 and 2,000 mg per day (usually comes in a capsule of 500mg or 750 mg).

Source: https://chestsculpting.com/how-i-booste ... rtic-acid/

(5) +5000 UI VitD3 a day

[Coraggio]

Hi guys, how are you? It's been something since I wrote last time. I hope you good.

Anyway, I write here because I feel attached to this topic. I have some news to share.


1)MELCANGI STUDIES IN MILAN:

Most of you know that I have funded a research with a professor at the university of Milan. I give a small recap for the new mmbers here.
This researcher is well known for having studied the Post Finasteride syndrome(PFS) a iatrogenic condition very very similar to PSSD caused by a 5-alpha reductase blocker.
This drug blocks the conversion of testsosterone into the most androgen hormone dihydrotestosterone(DHT) also blcks the concequent conversion into the 3-alpha diol from DHT and dihydroprogesterone(DHP) from progesterone and so allopregnanolone(THP) from DHP. This is very probable also in the PSSD. He has found decrease levels of DHT, DHP, THP and an increased levels of T (testosterone) both in animal and human brain liquor. This does it mean that there is a block in the steroidogenesis pathwayin the brain.

Please view the previus pages for better undesrtanding: http://www.pssdforum.com/viewtopic.php? ... 6&start=40

Melcangi now is testing the steroid and neurosteroid levels in PSSD rats model. This test is starting right now, in these days. I will go to Milan moreless in July to join the researcher team for analizing the rat's brains. I will send you a photo, promise.
But Melcangi has also wrote a review in this months suggesting every possible connections between PSSD and PFS. I have personally spoke with him several times to give him more infos that I have found in these months from my compulsive reaserches.
So, altough I think that it could be done in different way I think that this review is very important, also because can give us a scientic proof
for reach the PFS world that is bigger than our.

Here the links. Share and send it to every professor,s researchers, reporters, etc that you want.

https://link.springer.com/article/10.10 ... 018-1593-5
Post-finasteride syndrome and post-SSRI sexual dysfunction: two sides of the same coin?

2) SPECULATIONS ABOUT PSSD.
I have reached the point that nutrition and life style are the best ways to stay alive and put ourself in the right way for healing maybe in the long term.
What you eat make the difference in the long term. PSSD like PFS is major pluri-downregulated patology involving many organs, not only the brain. Talking
about a receptor or a neurotransmitter once at once is not convenient. We should talk about systems.

I give you something I ve studied.

SSRI withdrawal causes almost a brain depletion of serotonin and dopamine. it is also probably that there is a hormanal downregulation similar to PFS patient that share our same symptoms.

These imbalance are present also in the brain of diabetic patients (Known to suffer anhedonia and sexual dysfunctions. they suffer more from anhedonia that depressed mood, just like us) and austistic people. Citalopram has been used to create rats autisric models. Both of conditions lack massively allopregnenolone(THP). THP is one of the most pro libido, prosexual, prosociality hormone we have. If there is a good levels of DHT also you can have sex normally. If you have only DHT you can have erections but low libido, if yoou have THp bit not DHT you have a quite good libido or arousal but no erections. WE lack both.

Allopreganolone conversion is made by some enzimes of the AKRC family. These enzymes are also very involved in lipid homeostasis like the caroteinoids signaling and PUFAS ( the essential fatty acid we need intake), both taken by diet, and prostaglandin and other lipid compuonds other than steroids. All these compounds bind several specific nuclar receptors in the body and in the brain. If you eat small amount of veggies and nuts and also fruits, you can have a reduced levels of all these compunds that are very important for our body.

Many reports are emerging that a optimal diet can win against a lot of disease thought unhealable by the standard medicine.
So, some exemples of essentail compunds we should eat more:

-Beta-carotene (carrots) converted into vitamin A. They bind the retinoid receptors( important in sex drive, cognition and fertility)
-Sun exposure give you vitamin D that binds his receptors and give you a rise in serotonin and dopamine. Sun exposure cause you tanning. This is allowed by a very important sensitization to melanocortin hormones. Melanortins are recently found to be strong sexual enhancers.
-Vitamin K (leafy greens) important for dopamine levels and sfingomielin synthesis, so very important to synapses
- similar for omega-3 fatty acid that are essential for the brain lipids and neurotransimmetrs. Also w-6 have their own importance. (Foods: fish and nuts, expecially walnuts)
-Lycopene(Red vegetables) is the red carotenoid.
-luthein and zeaxanthin( many veg and fruits) important for vision and brain are other imprtant carotenoids that, with lycopene, curcumine and w-3 PUFAS, can activate Nfr-2, the key gene for te expression of antioxidant enzymes(ARE, so important for brain fog!) but also for the AKRC family, so also AKR1C1-2 that are also known as 3-Alpha-HSD for allopregnanolone synthesis.
-Tocopherols and tocotrienols vitamin E(oils and nuts) for fertility.
-fibre and resitant starches. Very important for healing our microbiome and fermenting into SCFAs. SCFAs regulate HDAC enzymes and so they are good epigenetic controllers.

The only downside is the amount of bad chemicals given by pesticides. i think that they can slow a natural recovery. Try to find a solution for this. eating organic means eating a lot of organic pesticides that are also deleterius.

NOTE: eating with supplement is definively not the same. This becaus esupplement substance and very avaible for the digestive system and so they can be absorbed too quickly giving an abnormal wave of this compund that can finish to desensitze the natural transporters system of your gut. So this is way I've throwed away also my multivitamins.

What I suggest is to follow a good diet like the anti-diabetic diet or the many antidepression, anti-everything diet you can find around the web. We should increase our adiponectin in the brain and re-upregulate every single enzymes taht we have turned-off. This keeping attention to not starve or drop too much weight. I think that this is not a cure but a good habit for predisposing our body for a slow but effective switching.

ANOTHER NOTE: if you take too much of vit D this can deplate others vitamins like A and K. The same with the others. So, for exemple, eat a good amount of carrots but do not eat only carrots (also because they are addictive in large amounts).

Personally I find more energy and somekind of improvements following what I eat.

Hope to graduate in this summer, fingers cross.


Best

Coraggio

[Coraggio]

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

[Ghost]

Very interesting. How is the study progressing? Interesting that we'd want more conversion to progesterone. Didn't we previous think we wanted to decrease that level?

[kamikaz3]

Coraggio can you forward the pdf upload here, it's 35 eur to buy with your link...