Mechanism of Typical Psychedelics

[The Monkey Mantra]

Most of the typical psychedelics are 5HT 2a receptor agonists. This is an autoreceptor, so it's gonna lower the activity of serotonin throughout the brain, right? Can someone clear up how lowering serotonin activity in this case produces a euphoria and body feelings that can be considered somewhat similar to those produced by MDMA? Are there mechanisms the two share, or is the similarity of the feelings entirely coincidental? Does the effect of lowering serotonin in one place just decrease the inhibitory actions of serotonin, whereas MDMA binds and does its thing better different parts of the brain where serotonin has a more stimulatory effect? Do the analgesic effects of mescaline and psilocybin share any mechanistic similarities with the analgesic actions of MDMA? I always assumed MDMA had analgesic effects at least partially due to serotonin release in the Raphe nucleus, but I'm just pullin' that out of my ass, to be honest.

I was just hoping someone could reconcile all the *apparent* paradoxes for me, and I figured this forum might be a better place to ask. I'm fairly familiar with neuroanatomy, and my education is in biochemistry. Please feel free to dumb it down as much as you like, though. If you have any papers you think I should check out, or any papers you'd like me to grab for you for the purpose of this discussion, let me know.

Thanks a ton, guys.

Ever curious,
Greg

 

[Prea]

so it's gonna lower the activity of serotonin throughout the brain, right?

I don't know a whole lot on the subject, but I don't believe that's true.

 

[Ham-milton]

whereas MDMA binds and does its thing better different parts of the brain where serotonin has a more stimulatory effect?

MDMA isn't a 5HT2a agonist, it's a VMAT2 ligand, causing the release of SE. It also somehow stimulates 5HT1a causing oxytocin release.

I hope I got that right.

 

[MattPsy]

5-HT2A ligands like LSD or 2C-B etc. shouldn't result in SE system downregulation because 1) their duration of action is low and downregulation takes quite a while of constant overstimulation to occur AFAIK, and 2) their intrinsic activity is lower than that of 5-HT itself.

 

[The Monkey Mantra]

MDMA isn't a 5HT2a agonist, it's a VMAT2 ligand, causing the release of SE. It also somehow stimulates 5HT1a causing oxytocin release.

I hope I got that right.

Well, yeah. I mean, MDMA works like methamphetamine in that it binds to the transporter, gets taken up into the vesicle, and causes the vesicle to dump its serotonin out into the synapse. When I was referring to the 5HT2a agonists, I didn't mean MDMA - just psilocybin, DMT, 2c-b, etc.

To Prea:
Well, I'm pretty sure autoreceptors serve as a presynaptic "thermostat", lowering release of serotonin into the synapse when there are high levels out there already.

To MattPsy: If their inherent activity is less than that of serotonin itself, then do you mean they're more like partial agonists at the 5-HT2a receptor, increasing serotonin levels from baseline by blocking serotonin's access to its autoreceptor but not stimulating it with as much efficacy?

 

[MattPsy]

Correct , although re: the second part of what you said, i'm not sure that any increase in SE release would be caused by this, because the autoreceptor system is very slow to respond.

 

[5-HT2]

The 5-HT2AR is generally not considered to be an autoreceptor. The 5-HT1AR is the major serotonin autoreceptor in brain. Hallucinogens are partial agonists of both receptor types. Generally, it has been observed that hallucinogens decrease tonic serotonin levels and serotonin neuron firing, consistent with nondesensitizing activation of the 5-HT1AR (though affinity of some hallucinogens for this receptor is so low they might be acting by another mechanism). Therefore, hallucinogens turn up the gain on certain 5-HT2AR-coupled signaling pathways while simultaneously turning down the gain on most other serotonin receptors.

 

[Jabberwocky]

I know offhand that 2CE actually releases and blocks the reuptake of NE (albeit in small amounts).

Other chemicals like 2CT7 are MAOI inhibitors which may account for their positive push.

AMT actually releases as much serotonin as MDMA does! albeit over a longer course and not nearly as much dopamine or NE.

 

[Dondante]

The 5-HT2AR is generally not considered to be an autoreceptor. The 5-HT1AR is the major serotonin autoreceptor in brain. Hallucinogens are partial agonists of both receptor types. Generally, it has been observed that hallucinogens decrease tonic serotonin levels and serotonin neuron firing, consistent with nondesensitizing activation of the 5-HT1AR (though affinity of some hallucinogens for this receptor is so low they might be acting by another mechanism). Therefore, hallucinogens turn up the gain on certain 5-HT2AR-coupled signaling pathways while simultaneously turning down the gain on most other serotonin receptors.

DOx's are pretty much full agonists at the 5-HT2A/C receptors AFAIK. Or if they're not full agonists, they're much closer to it than tryptamines and LSD.

DOx's also have very low affinity for 1AR (like 1000-fold lower) ... I assume that's what you were referring to. Trypts have much higher affinity for 1AR (even higher than for 5-HT2AR), which is likely a mechanism for the subjective differences between the groups, since the two receptors have opposing roles on prefrontal pyrimidal neurons.

I like the idea that tryptamines "turn up the gain on certain 5-HT2AR-coupled signaling pathways while simultaneously turning down the gain on most other serotonin receptors." Maybe this is a key mechanism for explaining the subjective differences between tryptamines and 2C-x/DOx hallucinogens. The fact that trypts are weaker partial agonist could play a role as well.

From a great review on 5-HT receptors:

"Not only 5-HT1A auto-receptors, but also post-synaptic
5-HT1ARs inhibit neuronal firing. This inhibition is
attributable to the activation of G-protein-gated inwardly
rectifying potassium (GIRK) currents and the inhibition of
Ca2+ channels (Andrade et al. 1986; Oleskevich 1995;
Sodickson and Bean 1998; Fig. 4)."

"5-HT1ARs are negatively coupled to adenylyl
cyclase (AC) via pertussis-toxin-sensitive Gαi and/or Gαo
proteins (De Vivo and Maayani 1986; Weiss et al. 1986;
Fig. 4). However, 5-HT1ARs do not seem to be coupled to
AC inhibition in dorsal raphe nuclei, in spite of their high
density within these nuclei."

Bockaert J, Claeysen S, Bécamel C, Dumuis A, Marin P. Neuronal 5-HT metabotropic receptors: fine-tuning of their structure, signaling, and roles in synaptic modulation. Cell Tissue Res (2006) 326:553–572.

AMT actually releases as much serotonin as MDMA does! albeit over a longer course and not nearly as much dopamine or NE.

I remember it being a fairly similar ratio of 5-HT: DA. AMT is a more potent MAOI though if I remember that correctly.

 

[Xaratoostrah]

MDMA isn't a 5HT2a agonist, it's a VMAT2 ligand, causing the release of SE. It also somehow stimulates 5HT1a causing oxytocin release.

I hope I got that right.

I would like a further clarification please from anyone knowledgable enough. While VMAT2 is implicated in the mechanism of action of amphetamines ,for MDMA specifically i have heard that more important to its effects is that it binds to the SERT (serotonin transporter) making it act "in reverse".

Since Hammilton ,which i consider to know his stuff, didnt mention the SERT on MDMA mode of action it made me wary that i may not know the full story of MDMA action or even worse have it completely wrong.

Anyone?

 

[vecktor]

I would like a further clarification please from anyone knowledgable enough. While VMAT2 is implicated in the mechanism of action of amphetamines ,for MDMA specifically i have heard that more important to its effects is that it binds to the SERT (serotonin transporter) making it act "in reverse".

Since Hammilton ,which i consider to know his stuff, didnt mention the SERT on MDMA mode of action it made me wary that i may not know the full story of MDMA action or even worse have it completely wrong.

Anyone?

no one knows the full story least of all me....

its a pretty promiscuous substance, MDMA does a whole load of things, it acts to reverse DAT SERT and NERT which pump cytoplasmic DA SE and NE into the synaptic cleft. it blocks reuptake to a degree also.
it appears to effect VMAT-2 to cause the storage vesicles to dump monoamines into the cytoplasm but there are plenty of other mechnisms that could explain this without involving VMAT 2 for example the weak amine theory and hydrogen ion balance across the vesicle wall.
it has 5ht2a agonist activity, it binds to other receptors too but off the top of my head I dont remember what they are, indirectly it effects oxytocin and various other things too.
it seems to effect somehow the mechanism which moves vesicles around in the neuron
it is a competitive inhibitor though a bad one for MAO and that is just the start.
and somehow it manages to quite effectively damage serotinergic neurons.

 

[Ham-milton]

I thought that it's effect on VMAT2 (which I always thought was somehow rather SE specific) and that SERT effects weren't as responsible for the unique effects.

I've always thought that the psychedelic effect (not the uniquely pro-social effect) was due mostly to an altered VMAT2 affinity- that caused it to pump out SE instead of the usual amphetamine DA dump; and attributed the pro-social effects to it's ability to release oxytocin.


This is definitely not something I know a whole lot about, however, having never studied it a whole lot. That probably is the result of never really using it. I don't honestly even know if a VMAT2 ligand can be selective for DA, SE or NE- obviously there must be some selectivity.