Cellular mechanism of Hallucinogens 'Solved'

[BilZ0r]

It's been known for a long time that hallucinogens (5-HT2A receptor agonists) enhanced excitatory transmission into cortex, but no one has been able to find out how, that is to say, where is the excitation coming from. Early experiments reported that no increase in cell firing could be found in the cortex due to 5-HT2A Receptor agonists, so it seemed that hallucinogens didn't enhance the way the cortex excited itself.

Then it was shown the if you destroyed the animals thalamus, the hyperexcitation was reduced. This lead people to assume that hallucinogens enhanced thalamocortical traffic. However some stuff published last year showed that if you selectively knock out the 5-HT2A receptor in the cortex only, hallucinogens don't work in animals anymore.

A paper published on the 29th of May, has answered the seeming paradox that hallucinogens increase excitatory transmission to the cortex, that this excitation is generated in the cortex, but doesn't increase cortical cell firing.

It was shown, in a very thorough, and methodologically advanced suite of experiments, that hallucinogens massively increase the firing of a very small population of cells in the cortex. These cells presumably must potently act on neighbouring neurons to produce the excitation.

Mechanism of the 5-hydroxytryptamine 2A receptor-mediated facilitation of synaptic activity in prefrontal cortex
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0700436104
Jean-Claude Béïque, Mays Imad, Ljiljana Mladenovic, Jay A. Gingrich, and Rodrigo Andrade

Abstract:
http://www.pnas.org/cgi/content/abs...INDEX=0&sortspec=relevance&resourcetype=HWCIT

 

[hussness]

Anyone have a copy of this that they wouldn't mind sending me? Pm me for the address.

 

[nuke]

Also nifty and recent:

Functional Selectivity of Hallucinogenic Phenethylamine and Phenylisopropylamine Derivatives at Human 5-Hydroxytryptamine (5-HT)2A and 5-HT2C Receptors.
Moya PR, Berg KA, Gutiérrez-Hernandez MA, Sáez-Briones P, Reyes-Parada M, Cassels BK, Clarke WP.

Department of Pharmacology-7764, University of Texas Health Science Center, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. [email protected].

2,5-Dimethoxy-4-substituted phenylisopropylamines and phenethylamines are 5-hydroxytryptamine (serotonin) (5-HT)(2A/2C) agonists. The former are partial to full agonists, whereas the latter are partial to weak agonists. However, most data come from studies analyzing phospholipase C (PLC)-mediated responses, although additional effectors [e.g., phospholipase A(2) (PLA(2))] are associated with these receptors. We compared two homologous series of phenylisopropylamines and phenethylamines measuring both PLA(2) and PLC responses in Chinese hamster ovary-K1 cells expressing human 5-HT(2A) or 5-HT(2C) receptors. In addition, we assayed both groups of compounds as head shake inducers in rats. At the 5-HT(2C) receptor, most compounds were partial agonists for both pathways. Relative efficacy of some phenylisopropylamines was higher for both responses compared with their phenethylamine counterparts, whereas for others, no differences were found. At the 5-HT(2A) receptor, most compounds behaved as partial agonists, but unlike findings at 5-HT(2C) receptors, all phenylisopropylamines were more efficacious than their phenethylamine counterparts. 2,5-Dimethoxyphenylisopropylamine activated only the PLC pathway at both receptor subtypes, 2,5-dimethoxyphenethylamine was selective for PLC at the 5-HT(2C) receptor, and 2,5-dimethoxy-4-nitrophenethylamine was PLA(2)-specific at the 5-HT(2A) receptor. For both receptors, the rank order of efficacy of compounds differed depending upon which response was measured. The phenylisopropylamines were strong head shake inducers, whereas their phenethylamine congeners were not, in agreement with in vitro results and the involvement of 5-HT(2A) receptors in the head shake response. Our results support the concept of functional selectivity and indicate that subtle changes in ligand structure can result in significant differences in the cellular signaling profile.

So most of the 2c-x family are partial agonists, whereas the DOx family are full agonists for 5HT2A, and they're all partial agonists at 5HT2C.

 

[BilZ0r]

Just in case anyone wanted to read the full version of the article:
http://www.ilikethings.net/5-HT2Asolved.pdf

Re: that paper cited above, I don't trust anything looking at second messenger systems went the receptor is expressed in a hetrologous system. Too often I've seen weird coupling mechanisms in expression systems. Heck, even in long term primary cell culture, receptors start doing things you can't make them do in a real system.

 

[kidamnesiac]

so from my gleaning the intro and conclusions, it looks like what they are saying is that activating the 5-HT system causes a sort of multiplier effect via the glutamic pathways. in essence, it is not nearly as simple as the serotonin sites are responsible for this, rather, there is some sort of network multiplier, sum-is-greater-than-parts effect.
am I on track or just reiterating what is already known and missing the point of this article. It seems they are still missing exactly what is causing the majority of the cause for the excitation that was previously believed the be the retrograde messenger.
perhaps a summation of the major new knowledge created could be generated by one of you more neurochemically competent peoples.

 

[BilZ0r]

In essence it's saying that 5-HT2A receptor agonists cause the increase in glutamate release (excitation), by massively directly activating (depolarizing) a small population of neurons in the cortex. That is to say, that 5-HT2A receptors on about 1/3 of cortical neurons can some action which directly depolarizes neurons.

 

[time traveler]

Thanks a lot Blizor....... now next time i go tripping im going to get all paranoid about my cortex melting ......

 

[IGNVS]

i dont know much about neurochemistry but isnt that good when brain cells get excited? is the depolarization bad in excess? what does this new information tell us about psychedelics (what new information can we infer). in what ways does this change the way chemists will design psychedelics in the future?

 

[bigmac74]

Here's my answers to your questions...

i dont know much about neurochemistry but isnt that good when brain cells get excited?

Depends, good/bad are subjective words, it highly depends on the situation.

is the depolarization bad in excess?

It can be.

what does this new information tell us about psychedelics (what new information can we infer). in what ways does this change the way chemists will design psychedelics in the future?

I didn't read the study, so my judgements are based on what has been posted in this thread, but i'm guessing that it tells us nothing about structure activity relationships, so psychedelics will continue to be developed in the same way as they are at the moment.

 

[BilZ0r]

Brain cell excitation is neither good nore bad, it's like asking is an engine running at high revs or low revs good; it depends on whether you need high revs or not.


Excess anything is bad; that's kinda the definition of excess. And this case is exactly the same. Excess is bad; however, it is unlikely that this level of excitation is excess.

Well probably the most interesting thing this paper tells us, from the users point of view; is that if they are right, and this depolarization is how hallucinogens work; the high doses of opioids will directly stop hallucinations, as they directly stopped the depolarization (I have never mixed high doses of either, so I can't comment).

 

[MattPsy]

^ Ha, funny you mention that, I had some 4-AcO-DMT last night, with a high-ish dose of Codeine.
The 4-AcO-DMT was definitely working while the opiate high was too, but when the opiate started to wear off it got a fair lot stronger (minor patterning transitioned to full color pictures in the floor, flowing color, tracers everywhere, etc) !

 

[BristolRob]

I don't think this paper solves anything, it's just another interesting addition - I heard from a little Birdie that Dave Nichols was actually surprised it got past review - something about all the emphasis being on Gq proteins when Gi proteins are more impt for the action of hallucinogens - I've got to admit, I'm not too hot on this signalling cascade stuff so I don't know who's right