Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

This is for hypothesis and even educated speculation.
Jaxx
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by Jaxx »

barbaar wrote:
Postsynaptic 5HT1A receptors activation is the main reason for MDMA's empathogenic and pro-social effects.
I've read people taking MDMA shortly, maybe a month or two after getting off an SSRI, can have a complete lack of these empathogenic and pro-social effects, even with no prior history of any abuse.
This was actually what my gp thought this was in the first place; he has some patients that have pssd-like symptoms from MDMA abuse, without having any experience with SSRI's however.
Interestingly, at least one person here says he is cured from PSSD by using MDMA.
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Meso
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

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In accordance, we have shown that citalopram increases HPA axis negative feedback by glucocorticoids (measured as cortisol suppression by prednisolone) after as little as four days of administration in healthy subjects (Pariante et al. 2004).
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2982744/

Only 4 days and HPA axis blunting effect is already evident!
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TalkingAnt
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by TalkingAnt »

GR antagonists hasten 5HT1A AR desensitization with SSRI
Maybe someone could try RU-486 with low-dose SSRI to quickly desensitize 5HT1A AR?

Corticosteroids regulate 5-HT1A but not 5-HT1B receptor mRNA in rat hippocampus
Absence of the stress hormone by adrenalectomy leads to an upregulation of 5-HT1A mRNA levels in CA1 and the dentate gyrus subfields of the hippocampus. Replacement with aldosterone or high stress levels of corticosterone reverses the upregulation and brings 5-HT1A receptor levels back to normal in CA1. In the dentate gyrus treatment with high doses of corticosterone leads to a further reduction in 5-HT1A mRNA levels. Manipulation of corticosterone plasma levels does not regulate 5-HT1A mRNA levels in the median or dorsal raphe. Also, corticosterone treatment does not alter 5-HT1B mRNA levels in the dorsal raphe or the hippocampus.

CT treatment did not alter the levels of 5-HT1A mRNA in the dorsal or median raphe. Previous studies have also reported that the levels of 5-HT1A receptor and/or mRNA are not altered in the dorsal raphe [20,26] or the median raphe [39] by adrenalectomy. However, 5-HT1A receptor number is reported to be decreased 2 weeks following adrenalectomy, an effect that was not reversed by corticosterone treatment [39].
So antagonizing GR and MR could upregulate postsynaptic 5HT1A.

Glucocorticoid Receptor-Dependent Desensitization of 5-HT1A Autoreceptors by Sleep Deprivation
antidepressant effects of sleep deprivation likely result from multiple and complementary mechanisms. A sustained
increase in cortisol/corticosterone secretion during sleep deprivation would induce an enhancement of serotonergic neurotransmission, notably through desensitization of inhibitory 5-HT1A control of DRN neurons.
Some people report reduction in PSSD symptoms following sleep deprivation. Maybe those people could benefit from exogenous corticoids.

Allopregnanolone and ganaxolone increase the firing activity of dorsal raphe nucleus serotonergic neurons in female rats
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Ghost
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

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The way I view things usually is as post-synaptic receptors only really mattering in the projection sites. The Presynaptic receptors obviously matter at the projection area and in somatodendritic autoreceptors (One of the criticisms I have always had of this theory is that it was too specific - focusing only on the 1a receptors when there are many more types in the brain as well). It has been nearly impossible to find a way to agonize those 5ht1a receptors on the right side of the synapse only. That's always how I chalked up our problems getting things to work for some people. Yohimbine worked for several if I recall. Glucocorticoids no doubt play a role somewhere along the line. I'm a bit surprised though that people go into remission from mental illness if these levels remain elevated however. When tested, my levels weren't out of the ordinary. This also pushed me away from looking too much here.

For me the struggle has been taking the vast (and often contradictory) libraries of serotonin research and making it fit our model. The list of things that has contributed to recoveries is very wide. That's why I'm so happy that your findings so far oppose my theory. The theory hadn't made any progress in years and I'd started looking more into the 5ht2a receptor (psilocybin) and peripheral problems such as the pelvic floor (still important, I know - enteric nervous system i can assure you is somehow impacted as well with all the people noting that they have digestion issues now). I really think that PSSD is a collection of conditions with many possible factors. My OCD hates how up in the air that definition is, and I want nothing more than to create a manual that walks a person through what type of PSSD they likely have and how to treat it: a lifetime's work for sure.

I really wish that the SERT study had been completed a few years ago because this would have been enormous for us. If SERT is really decreased in the POA, then we have the smoking gun, but we REALLY don't know what SERT is doing, which opens the doors to countless explanations. I had the studies of increased POA SERT in transgender patients on hormone therapy, and then we had estradiol cause a temp. recovery. I thought we had it figured out two years ago. Then no one else really seemed to replicate that and then trials with T and T + aromatase inhibitors both did jerk shit. My hormones came back mostly normal and again I felt defeated on the hormone front. We do have the STRONG case for high Progesterone in PSSD cases, but like I've noted before, MOST females don't oscillate in function each month (some have noted changes in PSSD from pregnancy but it's a vast minority) - and Progesterone isn't really studied in males so we don't know if the reference levels we are given are legitimate.

Meso please keep going on this! It will take some hashing out but I think with enough feedback and time you'll get some actionable findings from it. Your access to medications is key and I'm hoping you are still largely in remission. I'll get you those gene results ASAP and this summer after the MCAT I am going to go at this 1000% once again. The summer is when I always make the most research traction.
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Meso
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by Meso »

Ghost wrote:The way I view things usually is as post-synaptic receptors only really mattering in the projection sites. The Presynaptic receptors obviously matter at the projection area and in somatodendritic autoreceptors (One of the criticisms I have always had of this theory is that it was too specific - focusing only on the 1a receptors when there are many more types in the brain as well). It has been nearly impossible to find a way to agonize those 5ht1a receptors on the right side of the synapse only. That's always how I chalked up our problems getting things to work for some people. Yohimbine worked for several if I recall.
There are selective postsynaptic 5HT1A agonists, but they are research chemicals. Nearly all serotonin receptor subtypes behave paradoxically when it comes to transcriptional adaptation. It is very difficult to predict how those receptors regulate when faced with serotonin flooding after autoreceptor desensitization (and worse: when faced with an exogenous ligand). And these receptors modulate many neurotransmitters and hormones. The serotonin system is very complex, so I stick with my past experiences with drugs, which brings me to 5HT1A and 5HT2A as the two main prominent receptors involved with my own PSSD subtype.
Ghost wrote:Glucocorticoids no doubt play a role somewhere along the line. I'm a bit surprised though that people go into remission from mental illness if these levels remain elevated however. When tested, my levels weren't out of the ordinary. This also pushed me away from looking too much here.
People with mental illnesses often have a degree of glucocorticoid resistance. Even when they introduce supraphysiological level of corticosteroids, these patients never develop symptoms of Cushing's. Antidepressants solve this issue by modulating GR function, usually through upregulation, to trigger a negative feedback. Patients with treatment-resistant conditions don't experience this effect, and SSRIs fail as a treatment. So, I agree that GR are involved in some PSSD cases.

Many of PSSD patients, me included, have a cortisol level on the lower side. I agree with what you've said, that there are interpersonal variations when it comes to PSSD and every person would need a tailored regimen.
Ghost wrote:Meso please keep going on this! It will take some hashing out but I think with enough feedback and time you'll get some actionable findings from it. Your access to medications is key and I'm hoping you are still largely in remission. I'll get you those gene results ASAP and this summer after the MCAT I am going to go at this 1000% once again. The summer is when I always make the most research traction.
It gets very frustrating sometimes, but life is incredibly bland with PSSD around. And even on a symptomatic treatment, it's too heavy on the wallet and may not be sustainable on the longer run. I need to attempt reversing my own PSSD soon.
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Ghost
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

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I posted the results of those SNPs here: http://www.pssdforum.com/viewtopic.php? ... 964#p26964
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Tree
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

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5ht1a agonism, initially, increases my sensitivities, similar to pssd state. I feel less numb and coffee gives me more of a euphoria effect like it used to before taking Sertraline. However, long-term use, 5ht1a agonism always causes the same extreme symptoms, no libido, extreme erectile dysfunction, little/no semen discharge, massive headaches, (hurts when shaking head/moving eyes). It's a nightmare.
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Ghost
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

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@Meso,

Karpinski et al suggests that my entire SERT/E2 theory could be a bit off (rather, more complex). However, they make a claim about the transgender studies as being only short term, and longer term studies showing E2 leading to a decrease in SERT.

"Overall, estrogen and progesterone appear to enhance serotonin signaling, which has been associated with improved OC symptoms."

"Estradiol administration has been shown to have vari- able effects on SERT – the protein involved in reuptake of serotonin from the synaptic cleft. In studies of acute estradiol exposure in rats, SERT proteins were shown to be upregulated in both the raphe nuclei and the hypothalamus [39, 40]. In contrast, chronic estradiol administration in macaques was associated with decreased levels of SERT in the raphe nuclei [41] and increased SERT activity in the basal ganglia and hypothalamic nuclei in several animal studies [30, 42]." - As long as SERT is increased in the projection areas then that is what I had expected for a few years now and this supports the theory.

But it's clearly more complex than that:

"Other recent studies in transsexual and postmenopausal patient cohorts report an inverse association between estradiol levels and SERT activity - increasing estradiol results in a downregulation of SERT [45, 46]."

"Estradiol has also been suggested to desensitize signaling via the 5-HT1A receptor in the paraventricular nucleus" - also interesting. Maybe this is why the results weren't lasting?"

... There's a lot more for me to read here and this article is proving to be really important so I'm going to try to soak it in more.
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DrugsAreBad
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by DrugsAreBad »

SSRIs cause HPA axis blunting through upregulating the glucocorticoid receptors, and this causes negative feedback inhibition of cortisol and the adrenals. To reverse this, we need to downregulate those receptors again.
@Mesolimbo: How about dexamethasone?
https://academic.oup.com/mend/article-p ... nd1256.pdf
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Meso
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by Meso »

DrugsAreBad wrote:
SSRIs cause HPA axis blunting through upregulating the glucocorticoid receptors, and this causes negative feedback inhibition of cortisol and the adrenals. To reverse this, we need to downregulate those receptors again.
@Mesolimbo: How about dexamethasone?
https://academic.oup.com/mend/article-p ... nd1256.pdf
I've considered Prednisolone, but you know that corticosteroids can induce depression by their own right if we downregulate GR too much. It's too risky. I think we better just let life stresses handle our GR regulation, imo.
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