5-HT2A Desensitization Reduces Glutamate Activity

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pterostilbene
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5-HT2A Desensitization Reduces Glutamate Activity

Unread post by pterostilbene »

Gone.
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tonyareias
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Re: 5-HT2A Desensitization Reduces Glutamate Activity

Unread post by tonyareias »

Glutamatergic system mediates sexual side effects of SSRIs

Targeting the glutamatergic system could prove a winning strategy for the treatment of sexual dysfunction in patients taking selective serotonin reuptake inhibitors (SSRIs) for depression.

https://www.nature.com/articles/nrurol.2009.136
Markc1113
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Re: 5-HT2A Desensitization Reduces Glutamate Activity

Unread post by Markc1113 »

I too think this is the main reason.. I had a really long window on wellebutrin and buspirone both. I think anything that effects 5ht causes me to have a window. Even had a few days improvement with inositol. If this is the cause, how do you fix it is the big question?
cdraham
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Re: 5-HT2A Desensitization Reduces Glutamate Activity

Unread post by cdraham »

I want to note that i dont react well to psychedelics that work on 5ht2a. Could be part of the puzzle.
pterostilbene
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Re: 5-HT2A Desensitization Reduces Glutamate Activity

Unread post by pterostilbene »

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sylv
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Re: 5-HT2A Desensitization Reduces Glutamate Activity

Unread post by sylv »

Did you really expect anything else from the St. Johns Wort which is an iMAO acting antidepressant, the first and foremost ? I am not sure if the ST. John's 5-ht2a up regulation was even proven in the humans

However, there is indeed something paradoxical in the 5-ht2a receptor. Let me continue:

Blocking the 5-HT2a induces emotional blunting and that's well proven, especially in the case of modern antipsychotics. The emotional blunting and mood increasing properties are also seen in some older antidepressants. Nothing surprising, as the lowered PFC activity ( as seen with the blockade of 5-ht2a ) ultimately led to decreased emotions and to increased mood ( the leucotomy is the extreme example of this )

But I have myself noted something very unusual with the 5-Ht2a. Namely, the transient (short term) blockade of this receptor by an inverse agonist ( remember - 5ht2a is active even in the absence of an agonist ), while makes PSSD worse when the drug is acting, surprisingly improves emotion feeling, volition and anesthesia on the next day after inverse agonist withdrawal.

The above would mean that it's not the 5-HT2a which is desensitized ( not directly ) but it's second messaging system instead - the Inositol Phosphate, a signal transduction molecule through which the receptor communicate with the cell (neuron ). The Inverse agonist shuts down the always active 5-ht2a allowing the Inositol to up regulate which ultimately increases PFC reactivity and hence make PSSD better. The inverse agonist / antagonists paradoxically does not up regulate 5-ht2a receptor so you can't use this as an explanation.

That would mean why 5-HT2a agonists are not that beneficial as promised because the 5-ht2a Inositol second messaging system very quickly desensitizes. The same as glutamate
Neuroxam
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Re: 5-HT2A Desensitization Reduces Glutamate Activity

Unread post by Neuroxam »

5HT2A have no direct infuence on libido. Glutamate can potentiate feeling that is already there (see marijuana, everything feels twice as good), but if there is no feeling glutamate will do nothing.
pterostilbene
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Re: 5-HT2A Desensitization Reduces Glutamate Activity

Unread post by pterostilbene »

sylv wrote: Fri Jul 03, 2020 4:51 pm Did you really expect anything else from the St. Johns Wort which is an iMAO acting antidepressant, the first and foremost ?
That sounds like you are randomly choosing priorities, which I have never seen like that and can't explain its various effects.
I am not sure if the ST. John's 5-ht2a up regulation was even proven in the humans
A meaningless phrase one could add to most things, if one cares, it still is a proven action of St. John's Wort. (Also, your random chosen ignorance on this obligates you yourself to search out the methods of research on this, if you doubt them. Though in the worst of cases it will probably still at least point to live animals.)

sylv wrote: Fri Jul 03, 2020 4:51 pm Blocking the 5-HT2a induces emotional blunting and that's well proven, especially in the case of modern antipsychotics. The emotional blunting and mood increasing properties are also seen in some older antidepressants. Nothing surprising, as the lowered PFC activity ( as seen with the blockade of 5-ht2a ) ultimately led to decreased emotions and to increased mood ( the leucotomy is the extreme example of this )
You seem to assume that St. John's Wort acts via antagonism of 5-HT2A, of which I've actually never seen a mention. Its upregulation of it seems to occur another way. And its effect in this seems to be very linear (during and after), whereas the known 5-HT1A antagonism (always explicit) produces a marked change between acute and after-effect (also seems similar in this to Berberine or other things with 5-HT1A antagonism).
And what's "well proven" about 5HT2A no less is its involvement in OCD.


Something else to consider, if one still cares: Filibanserin, for example, requires 5-HT2A antagonism for its 5-HT1A agonism to work properly for its pro-sexual effect, according to one study.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898967/

Neuroxam wrote: Sat Jul 04, 2020 10:49 am 5HT2A have no direct infuence on libido. Glutamate can potentiate feeling that is already there (see marijuana, everything feels twice as good), but if there is no feeling glutamate will do nothing.
It is not about a random "pool" of glutamate in the brain, it seems some haven't paid attention to some basic premises about PSSD symptomatology here. Your "feelings" (that are or are not already there) are in many cases produced via glutamate-receptor mediated action, regardless of whether in a complex with dopamine or something else. The main receptors of this are NMDA and AMPA (and possibly kainate, which is sometimes distinguished). No-one is talking about randomly increasing "glutamate", but to activate "feelings" in the first place via such receptors or mechanisms where they are involved.
sylv
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Re: 5-HT2A Desensitization Reduces Glutamate Activity

Unread post by sylv »

A meaningless phrase one could add to most things, if one cares, it still is a proven action of St. John's Wort. (Also, your random chosen ignorance on this obligates you yourself to search out the methods of research on this, if you doubt them. Though in the worst of cases it will probably still at least point to live animals.)

Am I am correct, this is the research you base your theory upon ? The one which lacks the brain region specificity and used an outdated, not selective enough to discriminate between 5-ht2a/b/c subtypes, radioligand Ketanserin ? The most of the older research on 5-ht2 were wrong in their findings due to the same error.
https://pubmed.ncbi.nlm.nih.gov/9342771/

Their results haven't been replicated but actually contradicted in the endocrine response to 5-ht2 agonist. ( DOI used here is a non-selective like ketanserin, but at least the endocrine response is a valid functional assay of 5-ht2a ). That's the second reason why this single study in the rodent is not enough
https://pubmed.ncbi.nlm.nih.gov/12905103/

Above all, 5-HT2 GPCR's, especially 5-ht2a, differs significantly in the regulation of their expression between humans and the rodents. It's regulation differs even within the specific brain region and cell type of the same species. Find more at (but not in the abstract):
https://pubmed.ncbi.nlm.nih.gov/12650852/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110590/

"well proven" about 5HT2A no less is its involvement in OCD
Mostly by the older research which were quite inaccurate for the reasons stated above, like failing to discriminate between 5-HT2a, 5-HT2c subtypes and by using psychedelics (5-ht2a / mGLUr2 dimer agonists ) to induce OCD in the animal models
I have never seen like that and can't explain its various effects.


IAMO +
"It competitively inhibits absorption of serotonin, noradrenaline, and dopamine; it also downregulates presynaptic membrane-adrenergic receptor density and reduces binding of neurotransmitters to presynaptic membrane-adrenergic receptors, thereby increasing their concentrations in the synaptic cleft, mimicking the effect of antidepressants"
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4946846/

Quite a lot for accurately discriminating the effects to one receptor subtype ( from 20+ others ) through introspection?

Oh, and I have not assumed that St John Wort acts via 5-ht2a antagonism. The line you cited was only in part a response to
"I no longer think 5-HT2A might be good, but that it might be one of the main factors limiting "windows", as 5-HT2A seems to be upregulated in reaction to all kinds of things."

However, I have written the above mostly to share my personal findings about 5-ht2a. Which is of course an unproven hypothesis, but nonetheless I found it interesting to share in the subject called " 5-HT2A Desensitization Reduces Glutamate Activity'.


By the way, Inositol is of course implicated in the PSSD, but in my opinion, if am allowed to represent one without being attacked, the side effects are more due to desensitizing the PKC - PI3K signal transduction.
pterostilbene
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Re: 5-HT2A Desensitization Reduces Glutamate Activity

Unread post by pterostilbene »

sylv wrote: Sun Jul 05, 2020 4:45 pm
Am I am correct, this is the research you base your theory upon ?
This is no research, you russian mental case, this is a remark on your intellectual shortcoming and corruption. If you come with random bullshit propositions (truly absurd, weak ones besides), it is your obligation to make a case for them instead of waiting for others to disprove them. Basically you're acting like an insignificant troll ever, and your egocentric issues in your pathological behaviour are clear to see.

You seem to think there would be a primitive, clear-cut difference between good and bad in 5HT2A receptors. Which one can only think if one has read nothing at all about the topic (including what I posted in the beginning), and besides understands almost nothing at all about PSSd-related issues, and prefers to make things up oneself.
If 5-HT2A didn't ever feel good (by increasing dopamine in some areas, as one can read), I would never have focused on it as possibly being positive.

Currently don't have more time, but I'll get back to your bullshit.
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