DMT and sigma-1 receptor activity

[crOOk]

Not sure if this is common knowledge already, but I found it interesting with the mystery that both this drug and the receptor are.

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

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.


[/I]Source: Fontanilla D, Johannessen M, Hajipour AR, Cozzi NV, Jackson MB, Ruoho AE. [I KNOW you smoked some of that shit!!][/I]
Department of Pharmacology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA.
Science. 2009 Feb 13;323(5916):934-7.

When the endogenous hallucinogenic trace amine N,N-dimethyltryptamine meets the sigma-1 receptor.

N,N-dimethyltryptamine (DMT) is a hallucinogen found endogenously in human brain that is commonly recognized to target the 5-hydroxytryptamine 2A receptor or the trace amine-associated receptor to exert its psychedelic effect. DMT has been recently shown to bind sigma-1 receptors, which are ligand-regulated molecular chaperones whose function includes inhibiting various voltage-sensitive ion channels. Thus, it is possible that the psychedelic action of DMT might be mediated in part through sigma-1 receptors. Here, we present a hypothetical signaling scheme that might be triggered by the binding of DMT to sigma-1 receptors.
[/I]Source: Su TP, Hayashi T, Vaupel DB.
Cellular Pathobiology Section, Cellular Neurobiology Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD 21224, USA. [email protected]
Sci Signal. 2009 Mar 10;2(61)e12.

I have the articles ofc for those interested. Drop me a line.

 

[sekio]

Other "magical" drugs target the sigma receptors too, like cocaine, DXM, noscapine (a component of opium) and Ketamine.

 

[crOOk]

Other "magical" drugs target the sigma receptors too, like cocaine, DXM, noscapine (a component of opium) and Ketamine.

Ye, we all had a feeling it's there to get us high eh? Noscapine is anything but magical though from my experience... :D

 

[Mudeltakappa]

A lot of tricyclics and SSRIs bind to Sigma-1 as well. Some with fairly high affinity I believe.
There's one tricyclic anti-depressant, opipramol, that acts primarily as a sigma-1 agonist. It doesn't have any signifigant monoamine reuptake affinity, though I think it does have the typical tricyclic profile of antiserotonergic, antidopaminergic, antihistaminic, and antichollinergic activity.

I haven't seen the full text of the DMT study but I remember someone saying its affinity was actually pretty low.

Noscapine is anything but magical though from my experience... :D

What is it like? I've read that it has some DXM-type effects, which is interesting if true.

 

[atara]

DMT's affinity for sigma-1 is quite low, but its affinity for various transporters is quite high, and so the concentration of DMT varies throughout the brain. If DMT is an endogenous sigma ligand, it wouldn't be too surprising to find that it is released from synaptic vesicles in regions where sigma receptors are located, increasing the local concentration enough to activate the receptor.

 

[crOOk]

DMT's affinity for sigma-1 is quite low, but its affinity for various transporters is quite high, and so the concentration of DMT varies throughout the brain. If DMT is an endogenous sigma ligand, it wouldn't be too surprising to find that it is released from synaptic vesicles in regions where sigma receptors are located, increasing the local concentration enough to activate the receptor.

lol I just wrote the exact same thing into the other thread on this topic. This one can be deleted btw.. i wouldnt even have understood what you said back then, but these days im impressed by your flexible thinking skills, i dont think this had in any way been suggested back then had it?

id be happy to know anyone aside from my physiology prof (who is absolutely awe-inspiring, the only person ive ever viewed as a rolemodel, the only lecturer who actually seems enthusiastic about our communication and shows full support at all times that goes past most of my expectations) who does not only have a very good understanding of neurochemistry (preferably much better than me), but also has an unsatisfiable thirst for knowledge, a flexible brain that doesnt know limitations and doesnt focus on what blocks the road when there are tunnels, doesnt treat knowledge as a status symbol or something you can otherwise possess.
i guess its always been like that without me knowing it, at least i have an idea where to find a real social niche now (eventually... at least i hope so). unfortunately with studying medicine the constant occupation with and striving towards finding the truth is showing higher social costs than ever before. A lot of people who I don't even talk to seem to develope an intense resentment for me when they witness me gain the narcisstic supply from authorities that they so desperately strive for with hours and hours of hard "work" (studying). Mommy's and daddy's approval seems to be the number one theme in most medicine students' biographies (at least here in Germany) and that's exactly what I feared and why I delayed my decision for a full 8 years, god awful intellectual narcissm that is not reflected upon and lived out to the fullest. I on the other hand finally start having some fun in life after 28 years, after fucking 13 years of pure boredom and intellectual degeneration in school which took the fun out of both learning and creative processes (quite an achievement, thank you german school system!), after years of 9 to 5 slavery hell I finally am enjoying what I do and now have to keep myself rfom diving in to deep into questions that spark my interest instead of burdening myself with pure extrinsically motivated studying to receive some kind of indirect fulfilment through how i score compared to other folks, well i finally enjoy what im doing and all i and all I get is jealousy and resentment at a higher than ever social cost while simultaneously feeling the comfort of a social niche that i havent yet gained access to lol. Ironic isn't it? Enough with the rant though, feel free to delete this thread

 

[crOOk]

btw atara, here's link to the thread. you might enjoy hearing that your assumptions seem to have been confirmed in every last aspect. :D I haven't completely made sense of the claim that it is transported into neurons by SERT since I've heard anecdotal evidence that single SSRI administration can considerably boost dmt's effects though... intracellularly vmat2 stores dmt in vesicles it seems btw. but youll find the information in the other thread (unless you are already up-to-date which seems more than likely). i am still learning at a rapid rate since im only in my 3rd semester and had been out of school for yrs before that and therefore not all my statements will live up to the scientific standard youre used to, but at least i finally am able to acquire every last bit of information i need to at least temporarily understand every sentence in every publication, no matter how complex it may be. kudos to my prof for producing that level of comfort in me while moving through a field that is still new territory. he recently wrote an article about dmt btw without knowing anything of the mystery surrounding it, nor about the size the santo daime religion has gained within the last two decades, but still called it a healer of "broken hearts" and the sigma receptor a "chaperone for the heart and soul". :D that got published 3 damn days after i again isolated dmt (after an retrospectively idiotic 4 year break from it caused by my infamous lab accident, see lame-ass vice article in hamiltons column) which was also when i first started realizing the enormous effect this lecturer has on my motivational developement. seems like massive hyperspacially induced synchronicity to me.

godamn ill start to turn manic again if i dont sleep properly. i swear im gone now.

 

[crOOk]

lol i didnt even post the link to the other thread, its basically a proper version of this shit lol,
http://www.bluelight.ru/vb/threads/410139-DMT-Sigma-Receptor-Ligand?p=10174099#post10174099

sorry bout the sudden hypomanic outburst, feels almost like mania could be creeping up, especially looking at the structure and lack of direction up there sigh... i havent slept for more than 3-4h the past few days and appetite has been suppressed. its not directly drug induced, im in fact more sober than id usually be past midnight. since im not ruining a good thread though, ill just leave it there lol.

 

[eatcod]

i for one enjoyed the read!