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N,N-DMT is an endogenous sigma receptor regulator

5-HT2

5-HT2

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The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator

Dominique Fontanilla(1), Molly Johannessen(2), Abdol R. Hajipour(3), Nicholas V. Cozzi(1), Meyer B. Jackson(2), Arnold E. Ruoho(1)*

The sigma-1 receptor is widely distributed in the central nervous system and periphery. Originally mischaracterized as an opioid receptor, the sigma-1 receptor binds a vast number of synthetic compounds but does not bind opioid peptides; it is currently considered an orphan receptor. The sigma-1 receptor pharmacophore includes an alkylamine core, also found in the endogenous compound N,N-dimethyltryptamine (DMT). DMT acts as a hallucinogen, but its receptor target has been unclear. DMT bound to sigma-1 receptors and inhibited voltage-gated sodium ion (Na+) channels in both native cardiac myocytes and heterologous cells that express sigma-1 receptors. DMT induced hypermobility in wild-type mice but not in sigma-1 receptor knockout mice. These biochemical, physiological, and behavioral experiments indicate that DMT is an endogenous agonist for the sigma-1 receptor.

1 Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
2 Department of Physiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
3 Pharmaceutical Research Laboratory, Department of Chemistry, Isfahan University of Technology, Isfahan 84156, IR Iran.

* To whom correspondence should be addressed. E-mail: [email protected]

from Science Magazine
 
5-HT2 said:
The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator

Dominique Fontanilla(1), Molly Johannessen(2), Abdol R. Hajipour(3), Nicholas V. Cozzi(1), Meyer B. Jackson(2), Arnold E. Ruoho(1)*

The sigma-1 receptor is widely distributed in the central nervous system and periphery. Originally mischaracterized as an opioid receptor, the sigma-1 receptor binds a vast number of synthetic compounds but does not bind opioid peptides; it is currently considered an orphan receptor. The sigma-1 receptor pharmacophore includes an alkylamine core, also found in the endogenous compound N,N-dimethyltryptamine (DMT). DMT acts as a hallucinogen, but its receptor target has been unclear. DMT bound to sigma-1 receptors and inhibited voltage-gated sodium ion (Na+) channels in both native cardiac myocytes and heterologous cells that express sigma-1 receptors. DMT induced hypermobility in wild-type mice but not in sigma-1 receptor knockout mice. These biochemical, physiological, and behavioral experiments indicate that DMT is an endogenous agonist for the sigma-1 receptor.

1 Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
2 Department of Physiology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
3 Pharmaceutical Research Laboratory, Department of Chemistry, Isfahan University of Technology, Isfahan 84156, IR Iran.

* To whom correspondence should be addressed. E-mail: [email protected]

from Science Magazine
Click to expand...

yes, the UW is vastly underrated.

Maybe this will spark some profesisonal interest in DMT studies again, since sigma receptor seems to be the hot mental illness receptor of the month.
 
Link to a PDF of the article:

http://www.neurophys.wisc.edu/~cozz...r regulator. Science 323, 934-937 (2009).pdf


sigma1pharmacophoremu1.png
 
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Curious- in subjective terms, and also concerning the smoking of exogenous DMT, what does this mean for us? Could this explain the 'anti-depressant' and anxiolytic effect that DMT use can produce?
 
"DMT has been hypothesized to act through an unknown “hallucinogen” receptor."

This is a quote from the paper, which is referring to an article published in 1981. The sigma receptor hypothesis is interesting, but the fact that they choose not to mention DMT's known 5-HT1A/2A binding profile is strange to say the least. It has been known for a good 20 years that that DMT binds to 5-HT1A/2A, the same receptors bound by psilocin/psilocybin.

What do you all think about the sigma receptor hypothesis? Perhaps the TAAR or sigma receptors play a role in function of endogenous DMT, if there is such a thing.
 
Dondante said:
"DMT has been hypothesized to act through an unknown “hallucinogen” receptor."

This is a quote from the paper, which is referring to an article published in 1981. The sigma receptor hypothesis is interesting, but the fact that they choose not to mention DMT's known 5-HT1A/2A binding profile is strange to say the least. It has been known for a good 20 years that that DMT binds to 5-HT1A/2A, the same receptors bound by psilocin/psilocybin.

What do you all think about the sigma receptor hypothesis? Perhaps the TAAR or sigma receptors play a role in function of endogenous DMT, if there is such a thing.
Click to expand...

It is indeed remarkable that they did not mention the 5-HT2A binding properties of DMT, even though they must know about them. I'm guessing they did this in order to maximize the "discovery" spin on their story. There is strong evidence that 5-HT2A receptor activation is necessary for the hallucinogenic effects of all tryptamine and phenethylamine hallucinogens. However, this does not exclude a potentially important modulatory role for sigma receptor activation. Perhaps it is this modulation that imparts the out-of-body immersiveness of the experience.
 
If you look at what other compounds are sigma agonists it seems more like sigma receptors modulate mood.
 
Beenhead said:
I emailed the editor and told them of the error with 5ht2a and what not!
Click to expand...

There's no way they were unaware of this fact. They'll be catching some flack in the next issue or two of Science, I can guarantee that much. ;)
 
LOL, I don't think they didn't know it binds to HT2a. I think they purposely focused on this sigma receptor to make it seem like a totally new advance in knowledge.

If they had cashed it out like...well this drug predominantly binds to HT2a (we all know this) but also slightly binds to this random receptor...well then they seem less cool than they actually are!

Alright HT2a for pioneering the speculation! More of ya'll that know whats up please speculate what functional role sigma receptor activation might play especially in regards to the unique antidepressant type effects that DMT exhibits.
 
I immediately questioned why there wasn't at least a simple reference to DMT having serotonin receptor activity in the paper. The last half of the abstract doesn't seem to be very well written in this respect, ie, "DMT acts as a hallucinogen, but its receptor target has been unclear." I personally would not say the target is unclear but rather something such as "Although DMT has been shown to be capable of activating 5-HTRs, its unique psychoactive profile leads one to speculate that it may have action at other targets."

I wouldn't say they focused only on the sigma receptor because they wanted to "make their work seem cooler" though. The most important conclusion the paper comes to (as I, an unbiased observer, reads it) is that DMT is the likely endogenous regulator of sigma receptors in vivo. Although I don't think they directly show this despite their firm conclusion that it is indeed the case. DMT certainly has detectable activity at the sigma-1R, but whether it is the true endogenous agonist is not shown definitively (unless I missed something and just need to read it again...).

The paper would have received a great strengthening if they postulated in 1-2 paragraphs how 5-HTR activity and sigma-1R activity could work in concert to produce the pharmacology of DMT. It is especially important to recognize the difference between administering a molecule exogenously versus endogenously when the exogenous administration produces effects that one does not expect to see from endogenous release. That is, if our body/brain is indeed using DMT on a regular basis, then why do you not hallucinate all the time?

Well my answer is that the exogenous DMT administration allows it to act much more non-specifically than it does when released endogenously. It is important to remember that neurons do things in ordered fashions and are unlikely to release DMT en masse when it has possible side activity at nearby 5-HTRs. Thus DMT release is probably a very controlled process to prevent undesirable action at the 5-HTRs, assuming its primary function is in fact to regulate sigma-1R activity.

Just my 2 cents... I would have liked to be able to review a paper like this and see what the PI had to say about my & some of the other similar comments posted here. =P
 
I don't understand the sigma pharmacophore posted. I don't understand how it takes into account for methamphetamine. DMT fits, I guess, but what about DXM?

Or PCP?

Or Hydrastinine? Or is it hydrastine that I'm thinking of? They're related, but the latter fits

edit: interestingly, it was hydrastinine that was the reason for the original patent of MDMA, IIRC.
 
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Yeah cocaine doesn't fit directly, it has an extra methylene group. I'm still a bit uncertain of their results. You might be able to pick up some issues if you read it a few times with an absurdly careful eye & adequate education on the subject... maybe...

Science occasionally will put out a paper that has some flaws but gets the publication nod because it is such an important subject. It's part of the business... that's not to take anything away from the researchers though, this stuff is no easy task.
 
Well, I don't know, with cocaine, the obviously important functional groups are the phenyl ring and the tertiary amine, appropriately located.

I should take a look with chembio3d and see if they have similar configurations.

I suspect theyre different enough- otherwise haloperidol would inhibit the reuptake of DA. Though being a DA antagonist would negate that. Any idea if haloperidol does have affinity for DAT?
 
Hm my post didn't work earlier. Anyways I guess if you consider the amine to be drawn into the overall structure a little, it can make itself look more like the phenpropylamine backbone.
 
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