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

[Coraggio]

Hi everybody, this is my first topic here. Like Ghost I' m studing to become a doctor.
I'm 25 from Italy. I'm in pssd state since april after long use of citalopram at low doses.


I' ve read a lot about articles and discussions. I try to explain my hypotese about all our shitty condition:

1)First of all I think 5-ht receptor desensitation is true but I think also is only a part of the problem. I want to
add the problem is not only 5ht 1a desensitation but also a down regulation of SERT and Thryptophan Hydroxylase. So
what I think is we don' t have huge serotoninergic activity but a wrong qualitative firing of 5-ht neurons. Zero's researches about SERT expression are a good thing IMHO.

2)SSRI have something to do with steroidogenesis. In the first article below is explained how SSRI modulate CSN steroidogenesis
modulating GABA A activity ( well known to have inhibition action on all the brain ) and in the second article is shown how
SSRI inhibit aromatase activity, an enzime involved in sexual hormone conversion. Furthermore, like well explaned by
Area1255's articles, serotoninergic system is involved in HPA axis regulation by dirctly neurons firing activity. (I want to
stress is not all about testosterone, healthy persons can have a good sex life even if their T levels aren't huge). Hormones
themselves play a role in neurons modulating activity and receptor regulation.


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2670606/

https://www.ncbi.nlm.nih.gov/pubmed/26162595

3)Like the most part of medicine, deductive only approch is very week so let's pass to empirical evidence we have obteined from forum user reports:

--> People with PFS( Post Finasteride Syndrome): people from propeciaHelp forum report a lot of sympotms included ours like no libido, erectile dysfunction,
genital anesthesia. Finasteride upsets steroidogenesis inhibiting Alfa-5 reductase type II and III . People from propecia can have hormanal
issue or not just like us but they have a big steroidogenesis imbalance for sure.



--> Licorice Root: some anecdotal success story is reported ( like dude on dr.bob site and another one of pssd.forumotion reported on remedyspot )
they are true story? I don't know but is sure Licorice root changes steroidogenesis expression. Glycyzzhiza glabra, the main costituent,
has a lot of actions about steroidogenesis: it inhibits 11-hydroxysteroid dehydrogenase so blocks the metabolism of cortisol, shuts down
the enzime responsable of aldosterone coversion and decreases testosterone synthesis.
In addition, a metabolite of Glycyrrhiza Glabra 18Beta-Glycyrrhetinic Acid was found to be a serotoninergic modulator:
http://link.springer.com/article/10.100 ... 016-1938-5.

Licorice root could be a way to get out from pssd like reported. But prolonged high cortisol levels can lead to a permanent hypertension
and anti-hypertensive drugs are known to induce sexual dysfunction(especially ED).In fact, Licorice Root is found to mantain hypertension
after licorice suspension with a not well known pseudoaldosteronism.


--> Antimycotics: some reports claim improving after Fluconazole use. Why? we don' t konw. But Fluconazole changes normal steroidogenesis: It can low
cortisol and aldosterone through enzime conversion inhibition. It is used to treat Cushing off-label. One guy from Propeciahelp cure himself
with a prolonged therapy eith nystatin, Fluconazole and other antimycotics. Continue' s report says one of his friend is cured with 9 month of
nystatin. we must to get more info from him.

[Ghost]

One thing that I've wondered about SERT is that maybe the desensitization is only staying because SERT is down-regulated.

[Coraggio]

I thought the same. It' s like a drian hole in a swimming pool. This is why PSSD is so smilar to MDMA damage.
What do you thing about that?

Berberine and Evodiamine

https://www.ncbi.nlm.nih.gov/pubmed/21647174

"The aim of this study was to investigate the effect of berberine and evodiamine on serotonin transporter (5-HTT) expression and then test how allelic variations previously identified in the promoter region could modulate that effect in the serotonergic neuronal cell line RN46A. Both berberine and evodiamine, alone and in combination, increased 5-HTT mRNA and protein expression significantly across the various alleles. When tested against the S, XS(11), L(G), L(A), XL(17), and XL(18) alleles, respectively, 100 μM berberine increased 5-HTT promoter activities by 67%, 128.7%, 106.9%, 100.4%, 26.2% and 82%, 2 μM evodiamine increased 5-HTT promoter activities by 216.7%, 81.6%, 305.6%, 181.5%, 175.3% and 102.2%. Berberine and evodiamine increased 5-HTT promoter activity differently depending on the genetic variation of the 5-HTTLPR polymorphism. This study has provided a convincing example of how herbal compounds influence the expression of one of the most intensively studied psychiatric candidate genes, the serotonin transporter."

[Coraggio]

This an other study about evodiamine on male rats sexual behaviour. I think could be something good...

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3251647/

[fasttrack1982]

Coraggion; Thank you for your input. It is great to hear about another person with our condition who is entering the medical field. I think the more theories being tested about PSSD the better.

[Coraggio]

Thank you fasttrack! I can only spend my time doing researches like all of us here..

[Ghost]

Yea I think that it could be something good too. I've looked at Bacopa for a long time becuase it increases SERT expression, but I've been worried because it also increases tryptophan hydroxylase-2 and increases 5HT levels/ decreases Dopamine levels. But if SERT is the cause, maybe bumping it up for a bit is all that is needed to break the feedback loop. I remember someone on here once said that it helped for a few days, and my only thought is that it may help by increasing SERT before the 5HT is increased overall.

"concomitant up-regulation was recorded in the mRNA expression of serotonin synthesizing enzyme tryptophan hydroxylase-2 (TPH2) and serotonin transporter (SERT)"

https://www.ncbi.nlm.nih.gov/pubmed/21129470

[Ghost]

The more that I think about this...the more that it makes sense.

http://www.jneurosci.org/content/19/23/10494.full.pdf

"Based on these results, it appears that the SERT is
downregulated by chronic administration of SSRIs but not other
types of antidepressants; furthermore, the downregulation is
not caused by decreases in SERT gene expression."

IF this continued after drug treatment, THEN desensitization would continue indefinitely. I still need to think over the regulators of G-Protein stuff, but in theory I think that this could be a result of the increased 5HT, which COULD be from decreased SERT expression.

I liked the article that I posted above, but had a few comments on it

- They addressed what they think are errors in older studies showing no change in SERT due to SSRIs, but it's still a bit unnerving that there is so much debate over it (this is also 17 years old and a lot could have changed - I haven't read recent literature).

- They mention an MAOI that they used that actually INCREASED SERT levels. That brings to mind SJW, which is a natural MAOI. I know that user beetlebum recovered after it. But they also talk about how other factors in the drug could be at play.

- I don't like how they measured SERT action in the Hippocampus, and then SERT expression in the DRN, and then concluded that SERT mRNA isn't to blame. They are measuring from 2 different brain areas and I don't think that's a fair assumption to make: that SERT changes are global. Basically, they check for function in the Hippocampus, and then expression in the DRN.

- Brings up the point that post-translational regulation could play a role.

[jaiho]

Effects of sustained serotonin reuptake inhibition on the firing of dopamine neurons in the rat ventral tegmental area

Sustained administration of escitalopram robustly decreased the firing rate and burst activity of DA neurons. There was no difference in the mean number of spontaneously active DA neurons per tract among the 3 groups (citalopram, escitalopram, control). This inhibition was reversed by the selective 5-HT2C receptor antagonist SB 242084. Citalopram, however, did not alter the overall firing rate but inhibited the burst activity of DA neurons.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674976/

This may explain why alot of you have symptoms from Lexapro. Excess 5HT transmission is reducing DA firing via 5ht2c receptors.

[Coraggio]

The more that I think about this...the more that it makes sense.

http://www.jneurosci.org/content/19/23/10494.full.pdf

"Based on these results, it appears that the SERT is
downregulated by chronic administration of SSRIs but not other
types of antidepressants; furthermore, the downregulation is
not caused by decreases in SERT gene expression."

IF this continued after drug treatment, THEN desensitization would continue indefinitely. I still need to think over the regulators of G-Protein stuff, but in theory I think that this could be a result of the increased 5HT, which COULD be from decreased SERT expression.

I liked the article that I posted above, but had a few comments on it

- They addressed what they think are errors in older studies showing no change in SERT due to SSRIs, but it's still a bit unnerving that there is so much debate over it (this is also 17 years old and a lot could have changed - I haven't read recent literature).

- They mention an MAOI that they used that actually INCREASED SERT levels. That brings to mind SJW, which is a natural MAOI. I know that user beetlebum recovered after it. But they also talk about how other factors in the drug could be at play.

- I don't like how they measured SERT action in the Hippocampus, and then SERT expression in the DRN, and then concluded that SERT mRNA isn't to blame. They are measuring from 2 different brain areas and I don't think that's a fair assumption to make: that SERT changes are global. Basically, they check for function in the Hippocampus, and then expression in the DRN.

- Brings up the point that post-translational regulation could play a role.

Yeah, but I want to say my doubts still unsolved. Maybe you can find an answer. My doubts are: 1)why so many people doesn' t improve after long term therapy of berberine if berberin can upragulates SERT. 2) maybe SERT expression is always strong linked with Thryptophan hydroxylase like bacopa. I' ve read about correlation between SERT phenotype and stress coping behavior. Good presence of SERT is linked with good stress coping and low SERT expression the opposite. This goes against what expected by researchers. Also I' ve found evodiamine can improve neurotransmitter levels of NA,DA and serotonin. It presents MAOI activity too.