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

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

Unread post by Meso »

Please note: I've provided sources for this info in my other threads, so to save time I'll just type out what I think.

I'm starting to have major doubts about the SERT downregulation, presynaptic 5HT1A-GIRK uncoupling, and the serotonin flooding theory. Hear me out on this.

Presynaptic 5HT1A supersensitivity and/or upregulation causes depression, whereas postsynaptic 5HT1A upregulation/sensitivity are involved with anxiety disorders.

Many people, including myself, have experienced terrible reaction to 5HT1A full agonists. I even tried lavender extract recently and had a terrible reaction, after researching it, it turned out to be a presynaptic 5HT1A full agonist. Also, many people never improved on serotonin depleting agents and serotonin antagonists such as cyproheptadine.

Postsynaptic 5HT1A receptors activation is the main reason for MDMA's empathogenic and pro-social effects. Also, orgasms are extremely pleasurable on MDMA, but it's incredibly difficult to reach orgasms on it. MDMA abuse causes a syndrome very similar to PSSD. To recover from this syndrome, people take SJW to restore "MDMA's magic", by upregulating the postsynaptic 5HT1A, but this is a temporary solution and it doesn't upregulate it potently.

Have you ever wondered why TCAs, that have been on the market way longer than SSRIs, are rarely associated with PSSD? and post-TCA sexual dysfunction is easier to fix than post-SSRI sexual dysfunction? here's why:
"Postsynaptic 5-HT1A receptor sensitivity in the hippocampus, measured by the effect of 8-OH-DPAT to increase cAMP levels in the dialysate, was increased after chronic clomipramine."
"he lack of an effect of clomipramine on the response to 8-OH- DPAT contrasts with results obtained after long-term administration of SSRI drugs (Li et al. 1993Li et al. , 1994Li et al. , 1996Li et al. , 1997) where subsensitivity of hormonal responses was obtained. Therefore, the 5-HT uptake blocking action of a drug per se does not appear to be sufficient to induce subsensitivity of post-synaptic 5-HT 1A receptors in the hypothalamus, and indeed the finding of an increased cAMP response to 8-OH-DPAT in the hippocampus after chronic clomipramine indicates that subsensitivity of postsynaptic 5-HT 1A receptors was not obtained in this tissue either"
Clomipramine binds extremely strongly to SERT (0.14–0.28), but despite this, it doesn't cause postsynaptic 5HT1A receptors to downregulate/desensitize, but in fact it upregulates them. Whereas, SSRIs even weak binding ones to SERT can downregulate postsynaptic 5HT1A receptors. This means that SSRIs can also potently disrupt steroidogenesis and sex receptors sensitivity whereas TCAs do less of that.

Let's review what postsynaptic receptors do:
- Cortisol and ACTH release.
- Prolactin release.
- Beta-endorphin release.
- Oxytocin release.

What if these receptors are malfunctioning? you get these symptoms:
- Near complete absence of anxiety.
- Blunted affect and social anhedonia. (Low oxytocin)
- Consummatory anhedonia and non-pleasurable orgasms. (Low beta-endorphin)
- Low libido. (Blunted HPA axis)

And with the disruption of sex hormones receptor function (and levels, in some people), and the increase in allopregnanolone (causing GABA-glutamate imbalance) you end up with frank sexual dysfunction.

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.

I tried Baclofen recently, and it had ameliorated my blunted affect and anhedonia. It turns out Baclofen inhibits presynaptic 5HT1A receptors indirectly, causing postsynaptic serotonin release. It had also improved my orgasms' intensity, and libido (libido via a different mechanism: ACTH release).
Baclofen is an indirect presynaptic 5HT1A antagonist (via presynaptic GABAB receptors on non-5-HT neurons in the DRN)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943331/

This is a further proof of my theory: we could be suffering from presynaptic supersensitivity (or at least a normal sensitivity) + postsynaptic desensitization, which SSRIs are known to trigger. Cortisol desensitizes the presynaptic 5HT1A receptors, so after you take SSRIs and they blunt the HPA axis, then you withdraw from SSRIs, cortisol is still inhibited, so presynaptic 5HT1A receptors upregulate again and become supersensitive (or normal sensitivity), triggering depression on top of the symptoms of low postsynaptic function.

My "triad of evil" hypothesis:
1- Glutamate release dysregulation leading to mesocorticolimbic pathway dysfunction and cognitive dysfunction. This can also explain why low dose SSRI can cause symptom relief from PSSD.

2- SSRI-induced postsynaptic 5HT1A subsensitivity + presynaptic 5HT1A supersensitivity (or normal sensitivity). Blunting of HPA axis and cortisol release.

3- Androgen (and possibly estrogen) receptor subsensitivity and dysregulation, leading to sex hormone resistance.
Last edited by Meso on Tue Apr 16, 2019 8:44 am, edited 3 times in total.
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barbaar
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by barbaar »

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.

Also side note, I'm really excited (as far as I can get excited) about your theories here mesolimbo! I only used to read this forum sometimes but I signed up so I can hopefully contribute.
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by Dryed »

I'll put quietly this here...

Emerging Roles for Neurosteroids in Sexual Behavior and Function

https://onlinelibrary.wiley.com/doi/ful ... 08.005660l
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taarn
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by taarn »

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Last edited by taarn on Tue Apr 16, 2019 11:10 am, edited 2 times in total.
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by taarn »

Interesting thoughts. I'm 'tracking' myself since last summer when I started to experience sexual difficulties, although haven't touched AD meds yet, so I have some info on the development of my sexual dysfunction.

I've started abusing drugs wtih the end of 2017, mostly MDMA and some weed. I gave up on weed because it caused me to have numb genitals (except one occassion that was the opposite), I wonder what's the connection with the endocannabinoid system. MDMA sometimes caused me to have genital numbness, sometimes even caused me to have increased senitivity and libido. But there was a clear trend that my sexual function was deteriorating. That's why I started to take blood tests last summer. It turned out that I had high prolactin, high estradiol, normal-high T, and low DHT. (I have to admit that I took isotretinoin a few years ago but recovered, I also took high doses of zinc last year)
After getting those under control with dopamine agonists my sexual function has somewhat improved, although I couldn't really do anything with low DHT. But it was not the same as before drug abuse. MDMA was shown to downregulate SERT in certain brain areas and also upregulate 5-HT2A. I wonder what effects MDMA abuse has on pre or postsynaptic 5-HT1A though, and how does this compare to SSRIs.

I also had high cortisol and severe anxiety and sleep issues, with some OCD and weird sleep PTSD.
In the autumn I took a few pills of mirtazapine which gradually but in the end totally killed my sexual function. Like it became worse after each pill.
Since then my prolactin has remained the same, my estradiol shoot up even higher, my T has noticeably lowered, and DHT further decreased to land well under range. Guess what, my anxiety issues completely disappeared, my cortisol became low - normal, ACTH also in the low end.

And now try to connect the dots!
So to compare my experience with your theory:
I think the HPA axis blunting is totally in accordance with my experience. Very likely I suffer from malfunctioning postsynaptic 5-HT1A, cause I totally miss any form sexual pleasure and 'magic' also totally vanished from socializing. The most irritating is my loss of attraction towards girls.
I don't have anhedonia though, at least I don't really have problem with the anticipatory part, so I suspect no dopaminergic issues. My problem is with actually experiencing the feelings.
I had some function returning since full PSSD on 4 occasions: after alcohol + bromocriptine(3 days), alcohol + bupropion(2 days), bupropion in itself(1 day), after out of desperation MDMA use(disappeared when I woke up the next day).
I wonder how would you explain these windows?

Another thing is the stubborn genital numbness and the loss of pleasure. It's attractive to think that these two overlap. It makes sense the pleasure part is related to postsynaptic 5-HT1A and the chemicals you mentioned. But what exactly is genital anesthesia, skin numbness etc? I feel like I lost control over my pelvic muscles, urinating also feels weird, some people has even worse issues. Otherwise some people had improvements in this field with cholinergics. I suspect acetylcholine plays a role here, probably through the muscarinic receptors. But what upstream event or mechanism can impair acetylcholine release, these receptors and signaling?

And I was always wondering by knowing about the 5-HT1A theory that how the hell things that was shown to desensitize DRN 5-HT1A but increase or restore serotonergic neurotransmission (dopaminergic too) could help people to achieve remission of PSSD. I think of Maxxbook - Pramipexole and Numby82 - Bupropion.
People also recovered with SJW, Psilocybin + MDMA, Bethanechol (that guy also took Psilocybin and MDMA though). So basically I can't match any of the recovery stories with the resensitization of presynaptic (DRN) 5-HT1A receptors.
The answer may be something like that our main problems aren't lingering around the 'desensitized' presynaptic 5-HT1AR anymore?

People also experience sexual issues while on meds, but the worst issues in most cases come after stopping the drugs. It also makes sense by reading your theory.
Blocked SERT, 5-HT1A desensitization and elevated serotonin causes sexual issues but the worst part comes when postsynaptic receptors remain desensitized and the presynaptic ones supersensitize.

Chronic SSRI intake upregulates glucocorticoid receptors and dampens HPA axis and cortisol, that makes sense. But to me further questions arise.
1) How does a single SSRI pill increase cortisol? Is it through postsynaptic 5-HT1A activation mediated by SERT blockage? Shouldn't the presynaptic autoreceptors kick in and lower serotonin levels so postsynaptic 5-HT1A activation as well?

2) By what mechanism cortisol desensitize presynaptic 5-HT1A?

3) Regarding the TCA paper you linked, the reason for postsynaptic 5-HT1A desensitization is not the SERT blockage mediated increased serotonin at the postsynaptic receptors. Then what?
Mesolimbo wrote:This is a further proof of my theory: we could be suffering from presynaptic supersensitivity (or at least a normal sensitivity) + postsynaptic desensitization, which SSRIs are known to trigger. Cortisol desensitizes the presynaptic 5HT1A receptors, so after you take SSRIs and they blunt the HPA axis, then you withdraw from SSRIs, cortisol is still inhibited, so presynaptic 5HT1A receptors upregulate again and become supersensitive (or normal sensitivity), triggering depression on top of the symptoms of low postsynaptic function.
So in the end what desensitizes presynaptic 5-HT1A? Is it cortisol or SERT blockage mediated serotonin increase, or the combination of the two?

After all these I think SERT still plays a role but the other way around. It's not the AD meds that downregulate SERT and leave it like that and you'll get stuck in the 'flooded by serotonin state' permanently. Rather people with genetic SERT disturbances are more prone to anxiety issues, that possibly means easily desensitized presynaptic 5-HT1A, more postsynaptic 5-HT1A acitvation and cortisol followed by glutamate release. That makes them more likely to trigger the cascade of events that leads to LDP and long lasting sexual issues. Even more likely if you count in other genetic variations with the HPA axis and cortisol.

Other than that it would be still good to know how do we get to disrupted steroidogenesis, steroid receptor desensitization and to neurosteroid issues from here. I guess it starts from HPA axis disregulation, so what are the next steps?

EDIT: I realized something is still not clear to me. If you have supersensitive presynaptic autreceptors that will mean overregulation of serotonin levels. In absence of ligand upregulation should be expected at postsynaptic 5-HT1A. Why does it not happen?
Last edited by taarn on Tue Apr 16, 2019 12:39 pm, edited 2 times in total.
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by TalkingAnt »

I have tested pretty low cortisol (blood and urine), and I am super sensitive to buspirone which is a 5HT1A presynaptic agonist (even 5mg makes me dizzy). So a lot of what you are saying makes sense. I wrote a post on GR a while back which may be of interest.
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by nasibi »

TCA induced PSSD Is just as bad as the SSRI induced one. And it is not limitted to just "sexual dysfunction." The entire physiology gets disrupted with numerous systems becoming dysfunctional. Patients lose all emotions/feelings and stop responding to pretty much all psychoactive drugs.
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by Meso »

taarn wrote:I had some function returning since full PSSD on 4 occasions: after alcohol + bromocriptine(3 days), alcohol + bupropion(2 days), bupropion in itself(1 day), after out of desperation MDMA use(disappeared when I woke up the next day).
I wonder how would you explain these windows?
Glutamate rebound on the first. Bupropion is an nNOS inhibitor, a weak DAT/NET inhibitor, but I haven't researched it almost at all so I'm not sure why it would cause a window other than these effects. MDMA causes serotonin release and activation of postsynaptic 5HT1A receptors, and causes desensitization of them.
taarn wrote:But what exactly is genital anesthesia, skin numbness etc? I feel like I lost control over my pelvic muscles, urinating also feels weird, some people has even worse issues. Otherwise some people had improvements in this field with cholinergics. I suspect acetylcholine plays a role here, probably through the muscarinic receptors. But what upstream event or mechanism can impair acetylcholine release, these receptors and signaling?
I think it's due to the chronic effects of SSRI on androgen receptor expression, with involvement of both cholinergic and glutamatergic neurotransmission. I haven't researched this much to be honest. I need to research pelvic floor dysfunction in order to reply with links to sources.
taarn wrote:The answer may be something like that our main problems aren't lingering around the 'desensitized' presynaptic 5-HT1AR anymore?
This is the main reason that made me suspicious of the serotonin flooding theory. I actually think that our problem is sensitive or even supersensitive presynaptic 5HT1A receptors. Many people, including myself, report feeling much worse on presynaptic 5HT1A full agonists.
taarn wrote:Chronic SSRI intake upregulates glucocorticoid receptors and dampens HPA axis and cortisol, that makes sense. But to me further questions arise.
1) How does a single SSRI pill increase cortisol? Is it through postsynaptic 5-HT1A activation mediated by SERT blockage? Shouldn't the presynaptic autoreceptors kick in and lower serotonin levels so postsynaptic 5-HT1A activation as well?
https://www.sciencedirect.com/science/a ... 9383911897
https://www.ncbi.nlm.nih.gov/pubmed/12605289
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3594819/
It's mediated through 5HT2 activation.
taarn wrote:2) By what mechanism cortisol desensitize presynaptic 5-HT1A?
In the studies that confirmed this finding say via GR-mediated pathways.
taarn wrote:3) Regarding the TCA paper you linked, the reason for postsynaptic 5-HT1A desensitization is not the SERT blockage mediated increased serotonin at the postsynaptic receptors. Then what?
It could be epigenetic modification. It's never mentioned. It is also possible that TCAs don't desensitize postsynaptic 5HT1A receptors because they upregulate them via another mechanism, and SSRIs desensitize them due to elevation of serotonin. But as I said, the mechanisms are not mentioned.
taarn wrote:So in the end what desensitizes presynaptic 5-HT1A? Is it cortisol or SERT blockage mediated serotonin increase, or the combination of the two?
Combination of both.
taarn wrote:Other than that it would be still good to know how do we get to disrupted steroidogenesis, steroid receptor desensitization and to neurosteroid issues from here. I guess it starts from HPA axis disregulation, so what are the next steps?
I haven't researched this more in-depth yet, but beta-endorphin has a significant control over many hormones. SSRIs can also directly alter androgen receptor expression in the prostate. There are many factors at work here, but needs further researching.
taarn wrote:EDIT: I realized something is still not clear to me. If you have supersensitive presynaptic autreceptors that will mean overregulation of serotonin levels. In absence of ligand upregulation should be expected at postsynaptic 5-HT1A. Why does it not happen?
In normal people, postsynaptic receptors would upregulate again and they experience no PSSD. For us, they remain desensitized for some reason, I'm guessing genetic polymorphism controlling these receptors expression, or inability to reverse epigenetic changes caused by SSRI treatment. PSSD is still an under-researched topic, so we can only speculate.
Last edited by Meso on Tue Apr 16, 2019 4:20 pm, edited 1 time in total.
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by Meso »

barbaar wrote: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.

Also side note, I'm really excited (as far as I can get excited) about your theories here mesolimbo! I only used to read this forum sometimes but I signed up so I can hopefully contribute.
This is interesting. SSRIs cause desensitization of postsynaptic 5HT1A receptors, but for some reason we can't recover like normal people.
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Re: Postsynaptic 5HT1A desensitization and my "triad of evil" hypothesis

Unread post by barbaar »

Mesolimbo wrote:
barbaar wrote: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.

Also side note, I'm really excited (as far as I can get excited) about your theories here mesolimbo! I only used to read this forum sometimes but I signed up so I can hopefully contribute.
This is interesting. SSRIs cause desensitization of postsynaptic 5HT1A receptors, but for some reason we can't recover like normal people.
Yeah I've always thought PSSD like symptoms are pretty common while *on* SSRIs, we're just "special" in the sense that our body gets stuck in this state somehow.
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