5ht2a receptor myth?

[Infectedstyle]

I have a specific question that's been on my mind for a little while.

It has been established in most of psychedelic scientific literature (that i know of) that the 5ht2a receptor pathways are crucial in psychedelic effects.

From what i understand it is vital for Cerebrum and Cerebellum interaction. 5ht2a exceeds a lot of it's effects in the bridge of Varolius. It is also the main excitatory receptor subtype among the GPCRs for serotonin.

Now the "myth" i'm talking about is that 5ht2a activity is absolutely crucial for psychedelic hallucinations. AFAIK the only basis for this claim is that is has been tested on labaratory rats. In rats where 5ht2a receptors are removed and drugs are administered they do not show the "tell-tale" signs for being under the influence of a psychedelic.

I forgot what these signs are but i thought they consist (again AFAIK) of motor function and disorientation. Since the cerebellum is mostly used for motor function and the rat has no way of saying it is hallucinating like crazy isn't is so that this receptor plays a role in motor function. And these tests say nothing about actual hallucinations?

Sorry if i seem ignorant, cuz i really am ignorant. It's just that i want to be absolutely sure of the facts and don't get stuck at some point because my knowledge is of limited understanding and some of the things i thought i knew are simply not true.

 

[benzyme]

rats are rather poor models for testing psychedelics. they have no gag-reflex (a somatic/visceral response common with serotonergics), and complex sensory processing is quite different in humans.

there was that one video from 1958, where they administered a cat LSD..

 

[Vodsel]

...plus researchers give them more than heroic doses... according to this paper,

Mice were intraperitoneally injected with the hallucinogens DOI (2 mg/kg) and LSD (0.24 mg/kg), or vehicle.

0.24 mg/kg equals 16mg of LSD for a person weighing 70 kgs. Around a hundred times the usual dose.

Take a human, lock him up in a lab setting, hold him tight and inject into his gut 16 mg of LSD. Then measure somatic response. Would that response be representative of what's going on when someone drops 100-200 mics?

 

[Infundibulum]

I have a specific question that's been on my mind for a little while.

It has been established in most of psychedelic scientific literature (that i know of) that the 5ht2a receptor pathways are crucial in psychedelic effects.

From what i understand it is vital for Cerebrum and Cerebellum interaction. 5ht2a exceeds a lot of it's effects in the bridge of Varolius. It is also the main excitatory receptor subtype among the GPCRs for serotonin.

Now the "myth" i'm talking about is that 5ht2a activity is absolutely crucial for psychedelic hallucinations. AFAIK the only basis for this claim is that is has been tested on labaratory rats. In rats where 5ht2a receptors are removed and drugs are administered they do not show the "tell-tale" signs for being under the influence of a psychedelic.

I forgot what these signs are but i thought they consist (again AFAIK) of motor function and disorientation. Since the cerebellum is mostly used for motor function and the rat has no way of saying it is hallucinating like crazy isn't is so that this receptor plays a role in motor function. And these tests say nothing about actual hallucinations?

Sorry if i seem ignorant, cuz i really am ignorant. It's just that i want to be absolutely sure of the facts and don't get stuck at some point because my knowledge is of limited understanding and some of the things i thought i knew are simply not true.

The type of experiment you'd want to do to demonstrate the extend to which the 5HT 2A receptor is the main psychedelic receptor in humans, you'd need to go into pharmacological inhibitions. That means, you'd have to administer a very specific 5HT 2A receptor antagonist prior to a psychedelic being taken, then see what happens when said psychedelic is taken. No study comes to my mind that does such an experiment, but on the other hand I haven't searched at all. Your question is very interesting and I will do some searching, time permitting.

 

[AlbertKLloyd]

Now the "myth" i'm talking about is that 5ht2a activity is absolutely crucial for psychedelic hallucinations. AFAIK the only basis for this claim is that is has been tested on labaratory rats.

Serotonin-glutamate complex implicated in hallucinogenic action

Okay all you pharmacology geeks, a new study linking schizophrenia and psychedelic action to novel serotonin and glutamate receptor interactions was reported on...

www.dosenation.com

NMDA and 5ht2a

Neuropsychopharmacology. 2005 Nov 2;
Hallucinogen-Induced UP States in the Brain Slice of Rat Prefrontal Cortex: Role of Glutamate Spillover and NR2B-NMDA Receptors.

Lambe EK, Aghajanian GK.

Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.

Psychedelic hallucinogens (eg LSD or DOI) induce disturbances of mood, perception, and cognition through stimulation of serotonin 5-HT(2A) receptors. While these drugs are not proconvulsant, they have been shown by microdialysis to increase extracellular glutamate in the prefrontal cortex. Electrophysiological studies in the rat prefrontal slice have shown that both LSD and DOI enhance a prolonged, late wave of glutamate release onto layer V pyramidal neurons after an electrical stimulus. Here, we hypothesize that the network activity underlying this UP state involves glutamate spillover from excitatory synapses. To test this hypothesis, we raised the viscosity of the extracellular solution by adding the inert macromolecule dextran ( approximately 1 mM) that is known to retard glutamate overflow into the extrasynaptic space. Dextran suppressed the UP state or late excitatory postsynaptic current (EPSC), but neither the fast EPSC, the traditional polysynaptic EPSC, nor a synaptic form of 5-HT(2A)-mediated transmission (serotonin-induced spontaneous EPSCs). Consistent with the previous work showing that extrasynaptic glutamate transmission in adult depends on NR2B-containing NMDA receptors, we found that NR2B-selective antagonists, ifenprodil and Ro25-6981, also suppressed the late EPSCs. The effect of psychedelic hallucinogens on UP states could be partially mimicked by inhibiting glutamate uptake but only after blocking inhibitory group II metabotropic glutamate receptors. This difference suggests that hallucinogens increase glutamate spillover in a phasic manner unlike glutamate uptake inhibitors. Increases in glutamate spillover have been suggested to recruit synapses not directly in the pathway activated by the electrical stimulus. Such recruitment could account for certain cognitive, affective, and sensory perturbations generated by psychedelic hallucinogens.Neuropsychopharmacology advance online publication, 2 November 2005; doi:10.1038/sj.npp.1300944.

There is a lot of evidence for this, harmala alkaloids potentiate psychedelics and have been showed to affect glutamate, in fact a huge number of things that potentiate psychedelics affect glutamate.

I forgot what these signs are but i thought they consist (again AFAIK) of motor function and disorientation. Since the cerebellum is mostly used for motor function and the rat has no way of saying it is hallucinating like crazy isn't is so that this receptor plays a role in motor function. And these tests say nothing about actual hallucinations?

it often has to do with behavior more than anything else. Mice and rats when under the influence of psychedelics tend to not hide or act afraid of anything, they sort of seem "one with the universe" but then evidence suggests that affecting the perfection of self is something psychedelics do.

Some of the scientists working on this have invented new and potent hallucinogens or psychedelics by working backwards from the enzymes and receptors.

 

[Infectedstyle]

Vodsel's link is a good example of what i mean. Not sure what they tried to accomplish in these tests.. What did they try to accomplish?

Here i read that taking away the mGluR2 pathway (AFAIK the 5ht2a normally triggers this pathway) abolishes "head-twitching" normally observed in LSD administered rats.

" Head-twitch behavioral response, expression of c-fos, which is induced by all 5-HT2AR agonists, and expression of egr-2, which is hallucinogen-specific, were determined in wild type and mGluR2-KO mice. "

Not sure if i understand this part. Never heared the terms c-fos and egr-2 before. I supposed mGluR2-"KnockOut" means an inactive mGlu receptor? But then i don't understand why they later give the rats a mGluR2 antagonist..
Don't understand why they say egr-2 is hallucinogen-specific either.

When the rats are given an mGluR2 antagonist it seems that EGR2 gene expression is lowered or something. EGR2 being involved a lot periphical nervous system activities (once again, motor functions). It comes as no suprise that head-twitching is simultaneously abolished in this case.

Once again saying nothing about hallucinations. But i theorize that had they given the poor cat an mGluR2 antagonist before they spoonfed him a giant dose of LSD the cat woulden't be twitching it's muscles as much.. And possibly could be enjoying his trip a lot better. Suggesting mGluR2 has nothing to do with anything except motor functions. Which is probably a big misunderstanding of mine.

Any thoughts or criticism? Sometimes i'm not sure if i'm on the right track or if i'm just starting to believe my own bullshit.

 

[benzyme]

But i theorize that had they given the poor cat an mGluR2 antagonist before they spoonfed him a giant dose of LSD the cat woulden't be twitching it's muscles as much..

an ACh antagonist (ex. benztropine mesylate) would be more direct and effective.

 

[AlbertKLloyd]

Promise of mGluR2/3 activators in psychiatry

P Jeffrey Conn1 and Carrie K Jones1

1Vanderbilt Program in Drug Discovery, Department of Pharmacology, Vanderbilt Medical Center, Nashville, TN, USA

that might be worth checking out... evidently the mGluR2 receptor plays a role in more than just muscle twitches

 

[Infectedstyle]

This talk makes excellent use of recent findings. Especially at about 20 minutes in when he starts talking about the Thalamus it gets really really interesting. He gives a basic model of how psychedelics affect the brain. His model is the basis of my understanding at this point. He states himself it is a gross reductionist view of what is actually happening but it is very insightful and mindblowing nontheless.

David Nichols - Psychedelic Science

I'm also interested in the NMDA connection in psychedelics. Having personally overdosed on a NMDA agonist which did NOT feel very good. I felt a slight correlation between NMDA's bodily effects and mushroom's bodyload and "aural" hallucinations.

I'll make sure i'll read your post later today AlbertKLloyd but evidently the more i learn the less i understand.
So don't count on me to spurr much more of a discussion here. Thanks for your informative responses once again. I love to be able to talk to you guys. Makes me feel kind of privileged

Hope we can keep talking and exchanging ideas

 

[Infectedstyle]

But i theorize that had they given the poor cat an mGluR2 antagonist before they spoonfed him a giant dose of LSD the cat woulden't be twitching it's muscles as much..

an ACh antagonist (ex. benztropine mesylate) would be more direct and effective.

I guess it is so. I'm very unfamiliair with ACh pathways and effects. Tho i know Galantamine is useful in remembering dreams and treating mild alzheimer's disease.