Psychedelics and Neuronal Signaling Systems

[serotonin2A]

If you think about it, the endogenous system doesn't function any differently than other receptors -- serotonin itself causes 5-HT2A receptor internalization. In terms of why antagonists act weird -- I guess it is a bad thing if 5-HT2A is highly activated (probably not too surprising given how much agonists can disrupt normal function).

5-HT2A levels eventually return to normal levels when antagonists are discontinued.

 

[Cotcha Yankinov]

It seems there is this idea of therapeutic downregulation of 5-HT2A for depression and such - do most agonists accomplish this or are there any that might stand out?

 

[Nagelfar]

Serotonin2A once said the following

"5-HT2A is coupled to several G-proteins, PLC through Gq, apparently Gi/o, Rho, beta-arrestin. The activation of PLA2 involves both Gq and Gi/o (at least in certain cell types). Serotonin activates all of those pathways."

- I thought it was very curious that endogenous serotonin was able to activate all of the pathways. But I wonder if this is a good thing or bad thing in the case of drugs that increase serotonin like MDMA/SSRIs? Do you think there might be more medicinal potential in some of the biased ligands, and that maybe some of the down stream effectors are better left untouched?
[h=2][/h]

I once heard colloquially from a layman who purportedly read up on it...

...(yes, hear-say, the veracity of which I am not even now when faced with the possibility of confirming via web-access I leave to the reader, for if untrue, an interesting proposition it is: so take this very tentatively; though I'm hoping someone may know to what he was referencing if it is not patent nonsense)...

...that serotonin agonists (specifically LSD and psilocybin) cross membranes into the brain in suchwise as to activate particular serotonin receptors that are very nearly (or in specific individuals, never) ever activated / agonized by endogenous serotonin. This may perhaps I venture to guess (if indeed this is the case) only be the case with certain individuals who are, though in a neurotypical range, stunted or whose serotonergic system has a low baseline arousal. (e.g. I've heard that sociopath criminals, certain types of those inclined to violent psychopathy, have low 5-HT sensitivity due to an over-abundant exposure prenatally (praeternaturally? ;-p said attempt at verbose humor. Sehr verBöse), and it may be in a minor degree in that spectrum?

Regardless, I think if indeed such is the case, there must be some therapeutic value in reaching these *deep brained* not-reached-in-accord-with-ones-own-serotonin-reserves/pools of exogenous "psychedelic" SER agonists.

 

[serotonin2A]

Are you trying to say that the level of 5-HT2A activation is normally low or non-existent? That's not how the serotonergic system works. A low level of 5-HT2A activation is required in some cortial regions for optimal processing.

 

[Solipsis]

Partially accounting for blunting effects of consciousness from antagonists (those particular ADs and anti-psychotics)? Although.. maybe that is very hard to say since most of those have such a wide binding profile iirc, but at least it suggests that significantly lowered activity doesn't completely lobotomize a person. It also shows that since that antagonism has efficacy, the normal level of activation must be existent / significant.

I thought that for psychedelic activity you need either the IP3 / PLA2 and AA pathways or some combination? 2C-N and 2,5-DMA would be the selective extremes of that spectrum.

Only problem I see with that is that I don't even know that 2,5-DMA can be considered psychedelic, and who's to say that 2C-N's potential isn't accounted for by 5HT1a or -2c ?

 

[serotonin2A]

Lisuride activates IP3 and AA via 5-HT2A, so neither of those pathways can fully account for the hallucinogenic response. So the thinking is that there are other pathways that play a role.

5-HT1A and 5-HT2C have been eliminated as possible explainations for hallucinogenic effects because of a number of factors; trying to use them as an explaination isn't going to be particularily productive.