Post-synaptic 5HT1A receptors inhibit NMDA and genital sensitivity?

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enriqueiglesias
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Post-synaptic 5HT1A receptors inhibit NMDA and genital sensitivity?

Unread post by enriqueiglesias »

Serotonin 5-HT1A Receptors Regulate NMDA Receptor Channels through a Microtubule-Dependent Mechanism
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724987/
Here we show that serotonin, by activating 5-HT1A receptors, inhibited NMDA receptor-mediated ionic and synaptic currents in PFC pyramidal neurons, and the NR2B subunit-containing NMDA receptor is the primary target of 5-HT1A receptors. This effect of 5-HT1A receptors was blocked by agents that interfere with microtubule assembly, as well as by cellular knock-down of the kinesin motor protein KIF17 (kinesin superfamily member 17), which transports NR2B-containing vesicles along microtubule in neuronal dendrites. Inhibition of either CaMKII (calcium/calmodulin-dependent kinase II) or MEK/ERK (mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) abolished the 5-HT1A modulation of NMDAR currents. Biochemical evidence also indicates that 5-HT1A activation reduced microtubule stability, which was abolished by CaMKII or MEK inhibitors. Moreover, immunocytochemical studies show that 5-HT1A activation decreased the number of surface NR2B subunits on dendrites, which was prevented by the microtubule stabilizer. Together, these results suggest that serotonin suppresses NMDAR function through a mechanism dependent on microtubule/kinesin-based dendritic transport of NMDA receptors that is regulated by CaMKII and ERK signaling pathways.

Apparently these are postsynaptic receptors (once mentioned at another point). My theory is that presynpatic 5HT1a or autoreceptors - which are independent units with different location by my understanding - do almost nothing, except inhibit serotonin when upregulated, which improves my motivation and emotional anhedonia (terrible motivation and emotional anhedonia when downregulated with Ashwagandha).

In any case, the important thing is that NNMDAR-inhibition. And this could explain why - sometimes - St. John's Wort, which is a postsynaptic 5HT1a antagonist, temporarily inceases genital sensitivity for me (again, sometimes). Or maybe this has nothing to do with it, it is just a sidenote.
finities infinities
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Re: Post-synaptic 5HT1A receptors inhibit NMDA and genital sensitivity?

Unread post by finities infinities »

I read what the functions of this receptor are and noticed that when I got carbamazepine PAWS they disappeared.
I suspect that this receptor is also downregulated in most people on SSRIs or after discontinuation of SSRIs.
This is also anti inflammatory.
enriqueiglesias
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Re: Post-synaptic 5HT1A receptors inhibit NMDA and genital sensitivity?

Unread post by enriqueiglesias »

I don't know if carbamazepine acts on this receptor. But it is known that it is downregulated by SSRIs. I don't know the details of their positive function, aside from inhibition, and I personally don't care much and think the main effects (maybe from which other detailed effects derive) are from increasing serotonin or keeping it low. But to distinguish these autoreceptors from postsynaptic receptors, the autoreceptors are good to keep strong (and serotonin low or normal), by my experience (and I personally have good results to this effect with Sodium Butyrate), whereas the postsynaptic ones, in the above account I posted, would be good to keep weak - or to inhibit the particular action that is described in the article.
I have varying results with supplements which act on CamKII and ERK (Astragalus, Curcumin, Schisandra, Quercetin, EGCG), either to promote it in their own way or inhibit as they tested, which might have something to do with it or be unrelated...
Last edited by enriqueiglesias on Wed Sep 25, 2019 1:25 pm, edited 1 time in total.
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Re: Post-synaptic 5HT1A receptors inhibit NMDA and genital sensitivity?

Unread post by finities infinities »

It is a pity that I don't write so much about these receptors on the web. But all the information I was able to get was:
-decrease heart rate
-decrease blood pressure lead to orthostatic hypotension.
- release: beta endorphin, prolactin, acth, growth hormone
-inhibited TNF Alpha ( together with 5ht2a)
- anti pain
-weakens erection
- increase libido and sexual arousal
-decrease anhedonia, increase magical, hedonic perception
- increase dopamine in the PFC.
- Decrease hippocampal glutamate and acetylcholine.
-Decrease REM sleep.
I remember
when I ate something that strongly increased carbamazepine in plasma to extreme doses - I got rid of my PAWS symptoms and I had 2 day window without anhedonia.
Then my heart rate dropped suddenly, my penis became numb but my libido was extremely high. During these 2 days I felt a feeling I didn't feel for almost 2 years - relax, carefree, calm.
So carbamazepine appear working like- postsynaptic agonist, presynaptic antagonist ( this is less likely) or SRA like MDMA lead to fast downregulation postsynaptic 5ht1a and serotoning depletion= PAWS. Carbamazepine is in SRA listed in wikipedia.
enriqueiglesias
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Re: Post-synaptic 5HT1A receptors inhibit NMDA and genital sensitivity?

Unread post by enriqueiglesias »

That anhedonia sounds a bit like what I get from Ashwagandha, although I'm less "carefree" (in some way satisfied) as I don't care at all. I would actually say it makes me depressed. Similar as high-dose Rhodiola, I have noticed...
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Re: Post-synaptic 5HT1A receptors inhibit NMDA and genital sensitivity?

Unread post by finities infinities »

This ,,carefree" is good feeling!
I feel very tension and anxiety always, but this magic 2 day with increase plasma level carbamazepine disappeared my anhedonia and produce calm, carefree, normal state like old healthy me.
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Re: Post-synaptic 5HT1A receptors inhibit NMDA and genital sensitivity?

Unread post by Meso »

Here we show that serotonin, by activating 5-HT1A receptors, inhibited NMDA receptor-mediated ionic and synaptic currents in PFC pyramidal neurons, and the NR2B subunit-containing NMDA receptor is the primary target of 5-HT1A receptors.
It's important to note the brain area that is being discussed. The PFC isn't involved in genital sensation; that's more the job of the postcentral gyrus and the paracentral lobule (parietal lobe regions). I would also like to note that NMDA inhibition in the PFC actually increases glutamate release since NMDAR are present on GABA interneurons.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357265/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2117556/

I also want to point out some points regarding genital numbness:
I think SSRIs mess up bodily sensations and can numb several areas of the body unrelated to the gentialia through messing up areas of the parietal lobe (centrally), and TRP channels, spinal channels/receptors like NMDAR/5HT2, and the genitals/AR (peripherally).

People who report loss of erogenous sensations but without numbness of mechanical sensations are most likely affected by the central mechanism only (parietal lobe dysfunction).
Some people also mistake loss of libido with genital numbness. If you don't have a libido, of course you won't feel pleasure from your genitals.

- If you have good libido but experience no pleasure from genitals, that's erogenous numbness (parietal lobe).
- If you have frank mechanical numbness (to touch, temperature changes, and friction) affecting your genitals and other areas of your body, then it's central and/or peripheral dysfunction.
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Re: Post-synaptic 5HT1A receptors inhibit NMDA and genital sensitivity?

Unread post by TalkingAnt »

You could try out a Jujube extract which may be a postsynaptic 5HT1A antagonist, for the purpose of upregulation. I was trying 1-5g at night for a few weeks which coincided with some symptom improvements, but I'm not sure if it was due to jujube.

CBD may be a 5HT1A agonist. Some have reported symptom improvements from it.

Baclofen is also a post synaptic 5HT1A agonist but be careful with it.
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Re: Post-synaptic 5HT1A receptors inhibit NMDA and genital sensitivity?

Unread post by ErgogenicHealth »

enriqueiglesias wrote:Serotonin 5-HT1A Receptors Regulate NMDA Receptor Channels through a Microtubule-Dependent Mechanism
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724987/
Here we show that serotonin, by activating 5-HT1A receptors, inhibited NMDA receptor-mediated ionic and synaptic currents in PFC pyramidal neurons, and the NR2B subunit-containing NMDA receptor is the primary target of 5-HT1A receptors. This effect of 5-HT1A receptors was blocked by agents that interfere with microtubule assembly, as well as by cellular knock-down of the kinesin motor protein KIF17 (kinesin superfamily member 17), which transports NR2B-containing vesicles along microtubule in neuronal dendrites. Inhibition of either CaMKII (calcium/calmodulin-dependent kinase II) or MEK/ERK (mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) abolished the 5-HT1A modulation of NMDAR currents. Biochemical evidence also indicates that 5-HT1A activation reduced microtubule stability, which was abolished by CaMKII or MEK inhibitors. Moreover, immunocytochemical studies show that 5-HT1A activation decreased the number of surface NR2B subunits on dendrites, which was prevented by the microtubule stabilizer. Together, these results suggest that serotonin suppresses NMDAR function through a mechanism dependent on microtubule/kinesin-based dendritic transport of NMDA receptors that is regulated by CaMKII and ERK signaling pathways.

Apparently these are postsynaptic receptors (once mentioned at another point). My theory is that presynpatic 5HT1a or autoreceptors - which are independent units with different location by my understanding - do almost nothing, except inhibit serotonin when upregulated, which improves my motivation and emotional anhedonia (terrible motivation and emotional anhedonia when downregulated with Ashwagandha).

In any case, the important thing is that NNMDAR-inhibition. And this could explain why - sometimes - St. John's Wort, which is a postsynaptic 5HT1a antagonist, temporarily inceases genital sensitivity for me (again, sometimes). Or maybe this has nothing to do with it, it is just a sidenote.

Dude!!!

I just noticed that you got destroyed by ashwagandha too!!

I am currently battling what seems to be PSSD symptoms from Ashwagandha KSM-66 usage
My symptoms are:
-Genital Numbness
-Reduced Sensation
-No sexual arousal
-Normal erections
-Morning wood I have every single day.
-No smell
-No good feeling after orgasm. Blunted.

It's literally lasted longer than 2 years now.

About me:
-Low Cortisol
-Low Aldosterone
-High Testosterone, DHT, And E (manageable with calcium d glucarate and nettle root).
-Excellent overall health.

What seems to "cure" me is a drug called Cyproheptadine (Periactin), which is a known serotonin antagonist. But the weird component is this. When I take 1mg of this drug, I will be sleepy (normal response) and wake up feeling tired. The following day I feel the same. BUT it's day 3 and 4 AFTER that first dose, I feel "Cured". I will literally wake up feeling fucking NORMAL again. Its like that vibrational rush is back. My symptoms of Genital numbness, No orgasm, No sexual arousal, no feeling, muscle weakness, all disappear on day 3-4. This stays like this for a week. But slowly slowly, I return back to my numb state.

So the question arises... HOW/WHY? I suspect looking into the 5-HT1a receptor, 5-HT2a receptor and the 5-HT2c receptors.

Is it just a Cortisol rebound following Cypro? Rebound elevation of cortisol following cyproheptadine withdrawal in Cushing's disease from a pituitary macroadenoma. - PubMed - NCBI

Ashwagandha Lowers cortisol and can cause anhedonia/laziness for some people.

So what else makes my symptoms worse:
-High dose Zinc Supplements
-Apigenin rich foods
-Ginger
-Potatoes (nightshades)
ErgogenicHealth
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Re: Post-synaptic 5HT1A receptors inhibit NMDA and genital sensitivity?

Unread post by ErgogenicHealth »

enriqueiglesias wrote:Serotonin 5-HT1A Receptors Regulate NMDA Receptor Channels through a Microtubule-Dependent Mechanism
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724987/
Here we show that serotonin, by activating 5-HT1A receptors, inhibited NMDA receptor-mediated ionic and synaptic currents in PFC pyramidal neurons, and the NR2B subunit-containing NMDA receptor is the primary target of 5-HT1A receptors. This effect of 5-HT1A receptors was blocked by agents that interfere with microtubule assembly, as well as by cellular knock-down of the kinesin motor protein KIF17 (kinesin superfamily member 17), which transports NR2B-containing vesicles along microtubule in neuronal dendrites. Inhibition of either CaMKII (calcium/calmodulin-dependent kinase II) or MEK/ERK (mitogen-activated protein kinase kinase/extracellular signal-regulated kinase) abolished the 5-HT1A modulation of NMDAR currents. Biochemical evidence also indicates that 5-HT1A activation reduced microtubule stability, which was abolished by CaMKII or MEK inhibitors. Moreover, immunocytochemical studies show that 5-HT1A activation decreased the number of surface NR2B subunits on dendrites, which was prevented by the microtubule stabilizer. Together, these results suggest that serotonin suppresses NMDAR function through a mechanism dependent on microtubule/kinesin-based dendritic transport of NMDA receptors that is regulated by CaMKII and ERK signaling pathways.

Apparently these are postsynaptic receptors (once mentioned at another point). My theory is that presynpatic 5HT1a or autoreceptors - which are independent units with different location by my understanding - do almost nothing, except inhibit serotonin when upregulated, which improves my motivation and emotional anhedonia (terrible motivation and emotional anhedonia when downregulated with Ashwagandha).

In any case, the important thing is that NNMDAR-inhibition. And this could explain why - sometimes - St. John's Wort, which is a postsynaptic 5HT1a antagonist, temporarily inceases genital sensitivity for me (again, sometimes). Or maybe this has nothing to do with it, it is just a sidenote.

Dude!!!

I just noticed that you got destroyed by ashwagandha too!!

I am currently battling what seems to be PSSD symptoms from Ashwagandha KSM-66 usage
My symptoms are:
-Genital Numbness
-Reduced Sensation
-No sexual arousal
-Normal erections
-Morning wood I have every single day.
-No smell
-No good feeling after orgasm. Blunted.

It's literally lasted longer than 2 years now.

About me:
-Low Cortisol
-Low Aldosterone
-High Testosterone, DHT, And E (manageable with calcium d glucarate and nettle root).
-Excellent overall health.

What seems to "cure" me is a drug called Cyproheptadine (Periactin), which is a known serotonin antagonist. But the weird component is this. When I take 1mg of this drug, I will be sleepy (normal response) and wake up feeling tired. The following day I feel the same. BUT it's day 3 and 4 AFTER that first dose, I feel "Cured". I will literally wake up feeling fucking NORMAL again. Its like that vibrational rush is back. My symptoms of Genital numbness, No orgasm, No sexual arousal, no feeling, muscle weakness, all disappear on day 3-4. This stays like this for a week. But slowly slowly, I return back to my numb state.

So the question arises... HOW/WHY? I suspect looking into the 5-HT1a receptor, 5-HT2a receptor and the 5-HT2c receptors.

Is it just a Cortisol rebound following Cypro? Rebound elevation of cortisol following cyproheptadine withdrawal in Cushing's disease from a pituitary macroadenoma. - PubMed - NCBI

Ashwagandha Lowers cortisol and can cause anhedonia/laziness for some people.

So what else makes my symptoms worse:
-High dose Zinc Supplements
-Apigenin rich foods
-Ginger
-Potatoes (nightshades)
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