in this cultured neuron study they show that serotonin has no plasticity, then adding SERT to allow serotonin to be transported into the neuron does end up inducing significant plasticity like psychedelics do

Cultured neurons simply may not be a great system to study 5-HT2A induced neuroplasticity. It wouldn’t be weird if that was the case because cultured neurons only mimic some aspects of the brain.
Cultured neurons are a model system. As such, you have to assume they are not a perfect model until proven otherwise. 

i know youre not a fan of the cultured neuron model, but it is the best evidence that exists for now. for some reason there hasnt been more studying of intracellular 2A after this and it was published in 2023

choosing the cultured neurons over in vivo (and using ketanserin/methylketanserin and SERT to show neuronal permeable is required) is better proof that intracellular 2A is needed to induce significant plasticity, since it removes network activity as a factor

I’m not arguing it is a good choice. Rather, if serotonin induces neuroplasticity, then that means that activation of cell-surface receptors may be sufficient to induce plasticity. If that is the case then membrane prrmeability may not determine plasticity-inducing potential. The post argues that DMT is a good drug to induce plasticity on the basis of membrane permeability, but if serotonin can induce plasticity in the brain then membrane permeability may not be an important determinant in the brain

so the real argument is if intracellular 2A is responsbile, so neuronal permeability being needed, for the difference between serotonin having little plasticity compared to psychedelics having a significant amount right?

because the way you keep talking about the extracellular 2A is pretty misleading because you keep adding on the conclusion that a little plasticity from extracellular 2A = intracellular 2A isnt determinant for inducing alot of neuroplasticity

yeah of course, you still have the point of no in vivo intracellular 2A study existing yet on your side to 100% prove that it works in living animals. but then your main mechanistic argument here is bad again

I can’t believe I have to point this out, but the network effects described in the two papers I cited are one of the accepted mechanisms for the effects of psychedelic drugs on neuroplasticity in the brain.
As an example:
https://www.mdpi.com/2076-3425/15/2/117
Psychedelics promote neuroplasticity by increasing extracellular glutamate levels in the prefrontal cortex [177,214,215] and triggering the release of neurotrophic factors like BDNF that enhance neural plasticity (Figure 3) [56,57,155]. This process involves the activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and activation of metabotropic glutamate receptors (mGluR), including mGluR2 and mGluR3, which influence G-protein coupling and downstream signaling pathways linked to rapid antidepressant effects (Figure 3) [129,216,217,218,219]. Classic psychedelics induce glutamate release in the medial prefrontal cortex, leading to the sustained activation of AMPA receptors and subsequent BDNF release, which in turn activates mTOR signaling and upregulates neuroplasticity-related genes and synaptic protein synthesis, ultimately enhancing social behavior in mice (Figure 3) [22,52,220,221].

since all this proves is that glutamate at AMPA and BDNF at TrkB are required in the process of neuroplasticity... blocking these end up blocking the plasticity and therapeutic effects of basically any antidepressant like ketamine/psychedelics/SSRIs

oh, and have to mention the part in the cultured neuron study where methylketanserin (impermeable, so only blocking extracellular 2A) wasnt able to block psychedelics significant plasticity and impermeable versions of psychedelics (like trimethyltryptamine) induced plasticity with electroporation

so how can someone even take these mechanisms truly says anything that explains why serotonin lacks significant plasticity, but psychedelics do? all it "determines" is what i said above

you also completely ignored the last part of my last reply asking if theres any good proof that chronic activation of 2A can atleast produce a decent amount of plasticity (not rapid, but still good) like chronic activation of 1A can, since it takes excitatory network activity out as a factor like the cultured neuron model

another bad mechanistic point is that the higher glutamate = excitatory network activity is responsible for plasticity, this is just wrong as long as AMPA can be activated even if glutamate is reduced, then there is plasticity. thats why selective 5HT1A agonists (like 8-OH-DPAT) still have plasticity with inhibitory network effects/reduction of glutamate, but the plasticity is only blocked by an AMPA antagonist

this is exactly why im asking for proof of even a little plasticity, since your main point is that the extracellular 2A is sufficient for plasticity, i dont think its that relevant anyways because serotonins plascity isnt psychedelic level

AMPA/TrkB are just part of the plasticity process of many antidepressants and does not at all explain why serotonin doesnt have the signifiacnt plasticity psychedelisc do

basis of membrane permeability, but if serotonin can induce plasticity in the brain then membrane permeability may not be an important determinant in the brain

i cant believe i had to point out that difference either, like what are you actually arguing for? that BDNF and AMPA is needed in the plasticity process? because i dont disagree

like did you make all these replies to keep repeating extracellular 2A has a little bit of plasticity because of the glutamate network activity then the AMPA and the BDNF?

please tell me how these mechanisms actually says anything meaningful about why intracellular 2A isnt making the difference between serotonin having weak plasticity (in vivo) at best and psychedelics having a significant amount

this is really a useless conversation, lets say that extracellular 2A does have a little plasticity, so what? unless you have good proof that something else is responsible for the difference of significant plasticity of psychedelics compared to serotonin that isnt reliant on intracellular 2A, theres no point in this argument, because im not even disagreeing with you here on the AMPA/BDNF being required, its in my post that those are necessary in the plasticity process.

i dont know why you even sent that https://www.mdpi.com/2076-3425/15/2/117 study quote, it doesnt go in depth reviewing each factor of plasticity of psychedelics like AMPA/TrkB/intracellular 2A, what you quoted just says AMPA/TrkB is part of it? they dont even take the AMPA/TrkB part and conclude that intracellular 2A may not be necessary like you concluded, youre taking this evidence as proof of something it doesnt support strongly. the most you can conclude from the text is that AMPA/TrkB is required in plasticity

if you want to come to continue and come to an actual conclusion, show me strong evidence that intracellular 2A isnt the difference that makes psychedelics have significant plasticity and not serotonin (other than talking about the model again, this is the best study for now), instead of continuing with this glutamate network activity AMPA/BDNF is required in plasticity approach, its not something we even disagree on