D2 Receptors

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Jul 16 08 12:29 AM

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I'm positive agonizing D2 receptors produces visuals.

Ketamine, Salvinorin A, PCP, LSD, several phenethylamines (mescaline, PEA itself, and possibly all phenethylamines and amphetamines) bind to D2. The psychedelics also bind to 5-HT2A.

However, the effects of Ketamine, Salvinorin A, and PCP include visual effects, not just euphoria. D2 is a psychedelic receptor. That's how THC causes visuals, and how Phenethylamine causes small visuals, because PEA binds to D2.

Kappa Opioid activation causes D2 upregulation. Salvinorin A activates both, which means it potentiates itself.

http://keykappa.blogspot.com/
http://jn.physiology.org/content/85/3/1153.full

When both Cannabinoid receptors are activated PEA is released and D2 is upregulated. I haven't found out which one does which yet, but THC activates both.

Even more interesting is the fact that 5-HT2A agonization upregulates the production of the precursor for anandamide (which activates both cannabinoid receptors and upregulates and activates D2 receptors).

From wikipedia (the source of all correct knowledge, lol jk):


The 5-HT2A receptor is known primarily to couple to the Gαq signal transduction pathway. Upon receptor stimulation with agonist, Gαq and β-γ subunits dissociate to initiate downstream effector pathways. Gαq stimulates phospholipase C (PLC) activity, which subsequently promotes the release of diacylglycerol (DAG) and inositol triphosphate (IP3), which in turn stimulate protein kinase C (PKC) activity and Ca2+ release.[20]
There are many additional signal cascade components that include the formation of arachidonic acid through PLA2 activity, activation of phospholipase D, Rho/Rho kinase, and ERK pathway activation initiated by agonist stimulation of the receptor.


I'm not certain yet, but it's possible that 5-HT2A activation causes visuals by activating D2 receptors and enhancing their effect through many other mechanisms.



If that's not true, then at the very least D2 is another hallucinogenic receptor. 


The main difference between 5-HT2A and D2 receptors is that D2 causes NMDA antagonism (or a similar effect but without blocking the receptor itself) in the same cell it's on. This causes dissociative effects, which are why THC and Phenethylamine both produce a slightly dissociated state.


According to that scientific article, Kappa Opioid receptors block the effects of the glutamatergic system in the NAc (the dopamine system), and also upregulate D2 receptors. This shows its role as an anti-addiction receptor because it downregulates the AMPA receptors on the dopamine cells while upregulating the dopamine receptors on the cell. This reduces the strength of the connection, which is what cures the compulsive part of addiction. It also resensitizes you to dopamine.


http://onlinelibrary.wiley.com/doi/10.1002/syn.20647/abstract;jsessionid=9353035533B2B8CE1393A28594465856.d01t02?systemMessage=Wiley+Online+Library+will+be+disrupted+4+June+from+10-12+BST+for+monthly+maintenance


Will finish this post later

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toastus

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Jul 16 08 6:11 AM

Interesting thread with back and forth banter: http://www.bluelight.ru/vb/archive/index.php/t-494408.html

Research leads me to conclude that:

D2 is at the very least an additional hallucinogenic receptor, if not the only hallucinogenic receptor. It causes dissociative hallucinogenic states (blocks NMDA's effect, causes visuals through an unknown mechanism). 5-HT2A increases the production of anandamide through its signal cascade, which, when combined with other signals, would lead to increased activation of D2 receptors. Since 5-HT2A agonists also enhance your intelligence, I figured the mechanism for that would be enhanced glutamate activity. I think it's in one of those articles I posted, but either way I found evidence that 5-HT2A actually does enhance the activity of both AMPA and NMDA receptors.

Kappa Opioid Receptor's main function is to shut down dopamine neurons by releasing GABA, and to upregulate D2. The shutting down of dopamine neurons causes the characteristic dysphoria of dynorphin, Salvinorin A, DXM, etc.

D1's main function is to cause euphoria, but when activated it also signals NMDA receptors to activate, which decrease the dopamine receptors on the cell (does it also increase AMPA, or are there no AMPAs on dopamine cells?)

D2's main function is to block the NMDA signal on the dopamine neurons so the "habit" can go away (downregulating AMPA? or are there only Dopamine receptors on dopamine neurons?), but it also causes visuals. It also upregulates D1 receptors (restoring the normal sensitivity of dopamine neurons?).

No idea about D3 and 4 yet. haha

Mu Opioid receptor releases dopamine and inhibits GABA release in dopamine neurons, which leads to increased addictiveness (more NMDA signaling in dopamine neurons means increased signal strength (habit), but also means decreased number of dopamine receptors (tolerance)).

CB1 and CB2 are analogous to Mu opioid and Kappa Opioid receptors but without bad effects (for the most part; I may be wrong lol). One would release phenethylamine while the other would upregulate D2 receptors. D2 stimulation would produce visuals and dissociation (the dissociation would be from NMDA effect blockage, which would fix D1 receptor levels and AMPA levels). Phenethylamine also causes euphoria by increasing the outflow of dopamine into the synapse.

According to this: http://www.ncbi.nlm.nih.gov/pubmed/18160635 Dopamine neurons do have AMPAs as well as NMDA, glutamate, and dopamine receptors, so that part of my theory still stands.



This means THC works by upregulating D2 and releasing Phenethylamine. Phenethylamine releases dopamine which binds to D1 and other receptors. D1 on its own would cause D1 to downregulate. But PEA also binds to D2, which causes visuals and dissociation (potentiated by the other effect of THC). The dissociation, from intercepting the NMDA signal (not directly blocking it, but affecting the signal downstream), causes the dopamine receptors to reset (but also downregulates D2, haha).

Salvia would work through a similar mechanism, (KOR upregulates D2, D2 causes visuals and dissociation) but while causing dysphoria instead of euphoria (caused by KOR releasing GABA into Dopamine neurons). Its mechanism greatly increases the visuals over THC, though, which is a plus.


LSD is known to have a two-stage effect: first of 5-HT2A receptor stimulation, and second of D2 receptor stimulation. I'm guessing this has to do with a metabolite (which might explain why it lasts for so long compared to other molecules? not so sure about that though). The effects are mental and stimulating at first, then relaxing and (according to theory, but haven't verified this part yet) dissociating. Some reports indicate that mental stimulants (activating the glutamate system like the initial 5-HT2A phase does) destroy the relaxing spiritual phase of LSD, which would mean they block the dissociating NMDA inhibition. This gives evidence for and against the theory of D2 being the core hallucinogenic receptor, with 5-HT2A activating it. It's a nice theory, but I just want the truth.

Mescaline binds to both 5-HT2A and to D2. It would have both effects from both receptors.

Tryptamines bind only to 5-HT2A, but they also bind to D1 (which doesn't cause hallucinogenic effects, but euphoria! hahaha).

So the theory is that D2 causes the enhanced spiritual effects (visuals, ineffable experiences, seeing God, enhanced perception of music, etc.) and dissociation by blocking NMDA's effect, and 5-HT2A merely activates D2 while enhancing it through engaging the glutamate system to enhance intelligence. Hopefully we can verify or disprove this theory.


This all shows that Ketamine/ Methoxetamine are the perfect anti-addiction aids. They activate KORs to upregulate D2, activate Mu Opioid to prevent the dysphoria from KOR and to add in some euphoria from dopamine release, activate D2 to upregulate D1 (also causing fun visuals) which blocks NMDA's upregulation of AMPA (causing the "habit" to go away). They enhance this effect through directly antagonizing NMDA as well. All of these effects combine to completely reverse addiction while blocking tolerance and withdrawal symptoms at the same time, and providing euphoria and psychedelia as well. This is better than a pure NMDA antagonist (which helps, but not as much). Methoxetamine is less toxic (and more legal) than ketamine, which makes it PERFECT for anti-addiction (both to prevent it before it happens and to reverse it after it happens). It might not be as 100% effective as ibogaine, but it's certainly a LOT more enjoyable and a lot more repeatable.



This also explains a lot of the effects of schizophrenia. It could easily be caused by upregulated dynorphin from excess stress, which would constantly upregulate and activate the D2 hallucinogenic receptor while keeping the dopaminergic neurons suppressed causing dysphoria. This doesn't explain everything, as there is likely an anticholinergic effect at play, but it does play its part.

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toastus

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Jul 17 08 1:01 AM

Thanks :)

Also I just realized: Several reports have said that 5-MeO-DMT and LSD both cause you to view familiar things as if they were new, in a new light, as if seeing them for the first time.

This is totally from D2 agonization. It downregulates brain pathways so they start fresh. Familiarity with things would break down (just like addiction). This doesn't mean you forget about it, but you lose your tolerance to its novelty. Sweeeet!

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69ron

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Jul 19 08 3:59 AM

5-MeO-DMT and LSD definitely have that effect of making things look new. I didn't know this was D2 agonizm causing this. I thought it was 5-HT1A agonizm causing this effect. Both 5-MeO-DMT and LSD are very potent 5-HT1A agonists. Are you sure it’s D2 doing this?

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toastus

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Jul 25 08 7:28 AM

Yes, I'm sure. SWIM has recently been testing out some memantine samples, which aren't a 5-HT1A agonist but are a D2 agonist. DXM is not a D2 agonist. Memantine produces a feeling of childlike wonder; it connects you with how you innocently viewed the world as a child. You don't take anything for granted anymore, you feel it all. You feel that curiosity and that "spark of life" that you remember from long ago but no longer feel. Honestly, SWIM believes it's the best feeling in the entire world and he values it MUCH more than the ineffable psychedelic experiences. To him it feels like infinite satisfaction without addiction, much more so than the non-addicting "euphoria" of phenethylamine. This produces satisfaction without addiction, not just euphoria without addiction. That's the true holy grail. :)

DXM doesn't produce this "childlike wonder" effect. LSD has been said to produce this effect too; it's also a D2 agonist (during the second phase of the trip). I'm sure ketamine and methoxetamine produce this as well.

Memantine also causes beautiful visuals. They are exactly like your eidetic imagery, but intensified into actual visuals. So what you've been thinking about or doing all day is what your visuals will be about (more so than with other psychedelics). This can only be explained by D2 agonism, much like ketamine's visuals.

I'm thinking the 5-HT receptor activity of many psychedelics is the cause of the "expanded mind" effect. I'm not sure of this, but it's my theory.

Speaking of that, does anyone know something that expands the mind but without visuals or anything that interferes with daily life? It could be incredibly useful as a nootropic.

Does cinnamaldehyde hordenone do that? It would go great with Tryptamine, lol

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69ron

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Jul 25 08 7:09 PM

A small safe dose of the toxin strychnine (50-100 mg of nux vomica seeds) is the only nootropic other than the psychedelic ones that I know of that actually works. I’ve heard of others, but know little about them. They may work even better. I just don’t know.

Strychnine works by increasing the brains ability to gather information from all the senses. It has no effect on D2.

I have never heard of memantine until I read this thread. Besides its effect on D2, it also affects 5-HT3, a serotonin site that is not affected by LSD. I wonder if it will potentiate the effects of LSD?

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#7 [url]

Jul 25 08 8:37 PM


Speaking of that, does anyone know something that expands the mind but without visuals or anything that interferes with daily life? It could be incredibly useful as a nootropic.

-toastus

There is a plant called mouse eared hawkweed (Hieracium pilosella) that grows as a weed in much of N. America and Europe. It is said that smoking the leaves of this plant produces psychedelic effects but without visuals. The only problem with this plant is that it's generally unknown and very few people have tried it so it could actually do nothing.

You could also try something that doesn't quite expand the mind but that increases focus. I have found good old catnip to do that for me. It kind of shuts up the excess chatter in the back of my mind and really lets me think clearly. A strong tea works but smoking it works a great deal better. Or you could try adderal if ur into that kind of thing.

If you don't mind me asking, how did you procure this memantine.

All hail King Neptune and his water breathers!!!! maayyonaaaze!

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#8 [url]

Jul 25 08 8:45 PM

@ Ron
 
Isn't the 5-HT3 site responsible for nausea caused by certain psychedelics? So, Memantine is a 5-HT3 antagonists or agonist?
 
If it's an antagonist, Lemon essential oil as discussed in that category could be used with the LSD.
 
Pce,
ElusiveMind

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#9 [url]

Jul 25 08 9:49 PM

D2 agonism in the area postrema will cause nausea too.  I know, AFOAF once tried snorting some apomorphine HCL thinking "its a dopamine agonist it should be great".  NOT!   Also, neuropletics, D2 blockers are great anti-emetics and much much cheaper than FDA approved 5-HT3 antagonists, like ondansetron. 

Memantine inhibits steady-state 5-HT3 receptor responses with an IC50 of 2.3 μM.  But I would not use memantine in combination with anything.  It has too long a half life and combining with stimulants like amphetamine can dramatically increase its dissociative effects (when used in doses greater than 20mg).

I would stick with lemon oil or ginger extract (the right kind of course).

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#10 [url]

Jul 25 08 9:57 PM


"Speaking of that, does anyone know something that expands the mind but without visuals or anything that interferes with daily life? It could be incredibly useful as a nootropic.


-toastus"

 

I have been reading up on Convolvulus pluricaulis from India. It has anti-anxiety and procognitive effects and its phytochemistry is very interesting (novel alkaloids (some tropine), essential oils, and flavonoids.  Check out this paper:

 

Review on ethnomedicinal uses and phytopharmacology of memory boosting herb Convolvulus pluricaulis. Australian Journal of Medical Herbalism 2010 22(1): 19-.

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toastus

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Jul 26 08 12:53 AM

Memantine is a 5-HT3 antagonist, it eliminates nausea.

SWIM got memantine from a friend, that's all.

That Shankhpushpi vine looks interesting. Do you know where I can get seeds for it?

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69ron

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Jul 26 08 8:28 AM

Isn't the 5-HT3 site responsible for nausea caused by certain psychedelics? So, Memantine is a 5-HT3 antagonists or agonist?

-elusivemind

Yes a 5-HT3 agonist will cause nausea. This is the reason bufotenine taken orally causes nausea. Memantine is an antagonist of 5-HT3 like lemon oil. Lemon oil completely blocks the nausea from oral bufotenine.

What’s more interesting to me is that memantine is a D2 agonist like LSD. I am wondering if this action will potentiate LSD in some way.

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toastus

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Aug 9 08 5:00 PM

Check out this study:
http://www.ncbi.nlm.nih.gov/pubmed/11378162

CB1 activation upregulates D2 and D1 receptors.

This study elaborates on that, showing that there are also more complex interactions:
http://www.benthamscience.com/cdtcnsnd/sample/cnsnddt8-6/0003Z.pdf

THC releases Phenethylamine at some point along the line. Phenethylamine binds to dopamine receptors, and also releases dopamine into the synapse. If THC releases Phenethylamine and also upregulates the receptors that PEA binds to, it would massively increase its activity. The effects would be the effect of D1 (euphoria) and D2 (psychedelic visuals and thoughts, dissociation).


In a series of behavioral experiments, Palazzo et al. demonstrated that NMDA, an ionotropic glutamate receptor, and the metabotropic glutamate receptors (mGluRs) work in concert with CB1 to induce analgesia in mice, although the mechanism underlying this effect is unclear. Together, these findings suggest that CB1 influences neuronal excitability by a variety of mechanisms, and these effects are relevant to perception and behavior.

- Wikipedia

D2 activation would block NMDA's effect (not at the receptor, but downstream. This is backed up by other studies showing that NMDA agonists don't behave in a competitive manner with the receptor when D2 is activated; they all bind, so D2's effect is not directly at the receptor). This would produce dissociation and would prevent excitotoxicity. The overall effect would be very close to that of Ketamine! Ketamine's NMDA effect is strongly amplified though, because NMDA is inhibited by the drug itself instead of downstream. This points to THC being a natural dissociative psychedelic like Ketamine.

So far my understanding of it is that THC activates CB1 and CB2. CB1 upregulates D1 and D2 receptors, while CB2 releases tons of Phenethylamine. Phenethylamine binds to D1 and D2, producing euphoria and dissociative psychedelic effects, respectively.

Also, in one of the studies it showed that the pain relieving effects of THC are from its NMDA antagonistic effects. Note: THC doesn't directly antagonize NMDA receptors. A downstream effect of THC is that NMDA's effect is blocked. I forget which study it is though... lol

Interesting how the Phenethylamine and D2 systems are intertwined with practically every psychoactive there is: Opiates, 5-HT2A Psychedelics, Dissociative Psychedelics (Ketamine/Methoxetamine, Memantine, Cannabinoids, Salvinorins), Entactogens (phenethylamine, MDMA, cannabinoids), the Cannabinoid system, and the Endorphin/ Dynorphin system.

An interesting implication of this is that claiming that THC causes memory deficits is like claiming Ketamine causes memory deficits. This is true, but only while it is in the person's system. Coming down from Ketamine, the person regains their memory because the NMDA system is coming back online. The NMDA system isn't damaged over time, so memory isn't impaired after the effects have worn off. Therefore THC only inhibits memory while it is in the person's system. Afterwards it has no inhibiting effects on memory. And even then the effects aren't that dramatic. The NMDA effects of cannabis never reach that of Ketamine, so you'd never go through the "K-Hole" of cannabis (where you lose almost all memory and identification of the self). So it only has mild memory-inhibiting effects of very short duration.

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#15 [url]

Aug 9 08 6:55 PM

Wonderful work toastus! Slow and steady work is producing intriguing and amazing finds in my opinion.

Got a question for you. Not sure how best to word this but would you think the "Greening out" effect of smoking too much cannabis has to do with the NMDA effect that you talk about? Or is something else responsible you think?

Great work again,
ElusiveMind

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toastus

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Aug 10 08 1:00 AM

What do you mean by the "Greening out" effect? Passing out from too much cannabis?
I was going to say no, that it might be a mix of that and cannabis's other sedating chemicals, but...
Yes, as far as I know it is the NMDA effects that cause you to pass out, lol.

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#17 [url]

Aug 10 08 5:59 PM

I wouldn't call it passing out. I guess you do eventually pass out, but this stage seems extremely similar to ketamine to SWIM. The person looses almost all contact (feeling) with their body, everything is slow, feels extremely dissociated and dizzy. Zoned out to the MAX. To SWIM, that feels like a good dose of K without going into a K hole.

So that's why I was thinking it could have to do with the NMDA effects rather than just some sedating chemicals (even though im sure they have some part in that too).

Just a thought,
ElusiveMind

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toastus

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Sep 14 08 8:16 PM

WHOA CHECK THIS OUT
http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2005.03485.x/abstract;jsessionid=D3CAE296602629F9B73315787D911303.d01t01
5-HT2A causes dopamine neurons in the VTA to fire! I WAS RIGHT, the visual component works through dopamine and is connected to D2! I think part of 5-HT2A's effect is to cause dopamine release and D2 upregulation, which will cause visuals. It modulates this with many other effects, but this is what causes visuals! WHOOOOO, this is exciting information! :D

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