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Working with the Muscarinic receptors and their potential

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Feb 17 09 5:10 AM

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So SWIM for a few months now has been looking into the Muscarinic receptors as SWIM has been fascinated with their potential for helping Parkinson's patients and also for the odd effects from the Datura + Cramp Bark combination.

Something wasn't adding up for the longest time so SWIM went looking for answers. SWIM is still looking into it further but feels they should at least report what they have found out so far.
The reason SWIM is rehashing all this again is because SWIM thought the Muscarinic receptors had to deal soley with acetylcholine levels, but SWIM has been potentially viewing this situation wrong.

Scopolamine and other chemicals from datura affect the Muscarinic receptors. They (chemicals from datura) are antagonists of the muscarinic receptors.

Scopolamine receptor targets:
http://www.drugbank.ca/drugs/DB00747#targets

Not only that, but antagonizing M2 and M3 receptors upregulate the receptors (with atropine)
http://molpharm.aspetjournals.org/content/44/5/940.short

So datura is naturally increasing M2 and M3 receptors and antagonizing them.

Then comes the interesting bit. The synergy between two receptors..... M1 / M2 and D1 / D2 respectively!!
http://www.ncbi.nlm.nih.gov/pubmed/9264077

Note that in the article they state the Dopamine and Muscarinic receptors act in a synergistic fashion when it comes to dopamine, but separate when it comes to other systems (such as cholinergic systems)

So with the trail so far, we see that datura will upregulate M2, antagonize M2, and now there is a synergy between M2 and D2 receptors. D2 being the receptor that Toastus has stated / claimed is responsible for hallucinations.

Some missing pieces of the puzzle:

1) Does antagonizing or agonizing M2 increase D2 receptor activity?
2) 69Ron mention serotonin receptors play a role in this a well, do they? and / or does it affect D2 receptors?

(Claim about 69Ron talking about serotonin playing a role in the combination http://herbs.maxforum.org/2010/09/03/cramp-bark-datura-inoxia-closed-eye-visuals/page2/#post30 )


Conclusion:

SWIM is speculating that the Datura + Cramp Bark combo may creating the hallucinations in such fashion as described above. SWIM needs to look into it more though.


That is it for now.

Pce,
ElusiveMind

P.S. SWIM would like to thank Medievil from Longecity with this further insight into Muscarinic receptors

P.P.S @ alyssum, So SWIM may have been half right on the reason to use Galantamine to help SWIY's persistent problems from their abuse of diphenhydramine. But the reason it would work isn't because of the increase of Acetylcholine directly, but because they agonize Alpha7-Nicotinic and Muscarinic receptors downstream. SWIM will try to come to a better conclusion why this would work when more information presents itself. Example, the reason some hospitals use Physostigmine to treat datura poisoning is because it increases acetlycholine levels, which indirectly affect nicotinic and muscarinic receptors downstream.

Links to some of SWIM's digging:
1) http://www.longecity.org/forum/topic/52893-m5-muscarinic-receptors-are-needed-for-slow-activation-of-dopamine-neurons-and-for-rewarding-brain-stimulation/
2) http://www.mindandmuscle.net/forum/37675-dopaminergic-muscarinic-system-interactions
3) http://www.ncbi.nlm.nih.gov/pubmed/9264077



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#1 [url]

Mar 17 09 4:27 AM

So SWIM has been incredibly busy of late but will update this thread with some new information and the general direction SWIM is going with this research.

Research of Scopoletin so far:

  • Has in vivo AChE inhibitory effects increased Ach 170% and 300% with scopoletin and its glucoside scopolin respectively above basal levels. At the same amount, the positive control galantamine increased basal levels to about the same.
    • Acetylcholinesterase Inhibitory Activity of Scopolin and Scopoletin Discovered by Virtual Screening of Natural Products

  • Scopoletin has a bell curve dose dependant effects similar to galanthamine. (4 um and 1um maximum concentrations respectively). The nAChR antagonist mecamylamine abolished the effects of both scopoletin and galantamine. So while scopoletin has been shown to have AChE inhibitor and mild MAOI effects, the majority may come from it being a nAChR agonist.
    • Effects of the coumarin scopoletin on learning and memory, on release of acetylcholine from brain synaptosomes and on long-term potentiation in hippocampus

  • A study showing that Scopoletin does affect nAChR. The effects of scopoletin and galanthamine were blocked by the nAChR antagonist mecamylamine, showing the involvement of nAChRs for scopoletin. It also appears to help promote neural plasticity in the hippocampus.
    • The Coumarin Scopoletin Potentiates Acetylcholine Release From Synaptosomes, Amplifies Hippocampal Longterm Potentiation And Ameliorates Anticholinergic- And Age-Impaired Memory

  • The results indicate that its antidepressant-like effect is dependent on the serotonergic (5-HT2A receptors), noradrenergic (α1- and α2-adrenoceptors) and dopaminergic (dopamine D1 and D2 receptors) systems. (Very weak maoi like properties, only shown in rats and no human studies done yet)
    • Antidepressant-like effect of scopoletin, a coumarin isolated from Polygala sabulosa (Polygalaceae) in mice: Evidence for the involvement of monoaminergic systems

The sub bulletins are the article titles that SWIM found the information from. As SWIMMERs can see, there is a multitude of actions going on from weak MAOI properties, AChE inhibitory properties, and more surprisingly that scopoletin seems to act on some sub-units of nACh receptors.

Interestingly, galantamine also has properties similar to scopoletin. SWIM is going to investigate further which sub-units may be affected by deducing what the antagonists affected and using galantamine as a comparison.

SWIM was wanting to try a small dose of galantamine in combination with a safe dose of datura to see if there are were any effects similar to the cramp bark + datura combination but can't get a hold of any galantamine. This may be tested at a later date with the materials if possible.

Where all this is going:

SWIM has been looking at the current chain of events and receptors that each individual substance affects and the neurotransmitters that are affected. Levels of dopamine, acetylcholine, and possibly other neurotransmitters seem to be what may be causing these hallucinations.

SWIM is currently compiling data on neurotransmitter levels in wake, NREM (non-REM sleep), and REM sleep patterns to built comparison model against my compiled list of areas and neurotransmitters affect by this combination.

SWIM has a theory that this combination may be acting in a similar way that possibly dreaming occurs. Again, all theory and just the direction this study is going so far. SWIM mention this possibility a while ago in another thread.

Reason for comparison is because like sleep, this combination changes some of the core transmitter levels that are similar to sleep. SWIM is looking into it more to see how similar or even if they are or are not similar.

May things may come to play with this but its a study over time and will take some time. SWIM will update this thread when new material presents itself.

Questions from last time:

SWIM still hasn't found any answer for question one as hasn't looked into it too much. The other reason is that


muscarinic receptors modulate DA efflux in the brain in a dynamic manner in which the brain region, the specific muscarinic receptors, the tone of the cholinergic system, and the particular neuronal elements involved represent critical contributing factors.


    • Dopamine–acetylcholine interactions in the brain studied by in vivo microdialysis
This is why SWIM has been compiling copious amounts of data lately; it's all affected in a dynamic manner...



As for question two, SWIM found that it was actually hyoscyamine that may have anti-serotonin effects as it is used for problems related to the gastrointestinal tract.
SWIM so far though hasn't found any scholarly/academic information confirming the anti-serotonin effects but is still looking.

Closing:

Well that's it for now folks. SWIM will update this thread when new information comes to light or is smothered by false connections.

If any SWIMMER has anything to add, please do!

Thanks for reading.

Pce,
ElusiveMind

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toastus

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#2 [url]

May 25 09 10:18 PM

This is suddenly interesting to me. I have a weird pulsing ability to understand something like this; at first I'm disinterested but suddenly it all makes sense. lol

What we should do is investigate the total actions of each muscarinic receptor. The best way to do this is bioassay of specific muscarinic agonists and comparing that with scientific literature. Are there any muscarinic agonists that only agonize one muscarinic receptor type? Muscarine? Arecoline? Etc.

Just like Alpha-7 is one of the most important nicotinic receptors, there is probably a very important muscarinic receptor.

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#3 [url]

May 26 09 6:35 AM


This is suddenly interesting to me. I have a weird pulsing ability to understand something like this; at first I'm disinterested but suddenly it all makes sense. lol

Hahaha. Yes, SWIM thinks the big long posts also might have been a turn off for some. But... meh.Anyways, the one problem with bioassaying  "specific" muscarinic receptors is that there aren't really an chemicals that SWIM knows of that target only 1 sub-set of muscarinic receptor. And when SWIM says they don't know of any, SWIM has looked EXTENSIVELY for something that only targets 1 or even 2 that is easy enough to get their hands on.
Bottom line, doesn't look good going down that route. That is why SWIM has been doing more theory first and research. It will only get SWIM so far but it looks better than trying for an individual receptor.

OH!! One thing SWIM just thought about it comparing scopolamine's and hyoscyamine's affinity for DIFFERENT muscarinic sub-units!! That would help solve the mystery on the different effects of the two, since they both affect the same sub-units, but have different overall effects (one moreso sedating, one moreso stimulating).
DAMN! This could help solve the "most important" receptor problem too. As noted by 69Ron, the effects of the two in the combination were different... but from my research they affect the same sub-units... but SWIM never looked into their individual affinity's for their respective sub-units!!

SWIM has been doing some tests with 3 year old Datura stromm. seeds.... not the best for testing purposes but still active. SWIM has also been trying Cramp Bark tincture 1:3 ration by itself too and has been logging those effects too.
SWIM will post these results once enough tests have been done to obtain a "general" effect overview for the individual substances at their respective doses and combined.

Pce,
ElusiveMind

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toastus

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#4 [url]

Jul 22 09 4:39 AM

I've been noticing that taking a couple seeds of datura stramonium causes light euphoria, stimulation, psychedelic effects via 5-HT2A, and the obvious anticholinergia. Muscarinic receptors block dopamine, right? So a mild muscarinic anticholinergia should be euphoric, right?

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#5 [url]

Jul 22 09 1:31 PM

Are we researching on how dautra works or the muscarinic receptors in general? If we are maybe we could look at arecoline that works on the muscarinic receptors.
.

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#6 [url]

Jul 23 09 5:26 AM

I've been noticing that taking a couple seeds of datura stramonium causes light euphoria, stimulation, psychedelic effects via 5-HT2A, and the obvious anticholinergia. Muscarinic receptors block dopamine, right? So a mild muscarinic anticholinergia should be euphoric, right?

-toastus


Don't think the psychedelic effects are achieved via 5-ht2a (as my research shows otherwise so far). The euphoric feeling has to do with the fluctuation of dopamine in different areas in the brain. Of course, to get to a great euphoria with datura alone causes great agony if one has every experienced a true datura trip. SWIM will hopefully post their comparison between sleep states and Datura intoxication soon. Been very busy with other things and have little time to work on this project :/

@uglybuddy6

It was to get a better understanding of both honestly... and the interaction between the Datura + Cramp Bark experiments. Datura was the most accessible material for this experiment and has quite a history in both human experiences and scientific studies.

Arecoline could be another great avenue to search. SWIM never really considered it right away as they don't have easy access to the materials needed for experiments, but will take a look at it through literature to get a better understanding of its interactions on the Muscarinic system.

-Update-

As said in earlier post, SWIM has been compiling data on scopolamine's and hyoscyamine's affinity for different Muscarinic sub-units. Also still compiling effects from Datura + Cramp Bark experiments and results so far are a LOT more pleasing than a full blown datura trip.

Pce,
ElusiveMind


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#7 [url]

Sep 23 11 1:28 AM

I see no one has admitted to taking a stupid high dose of it yet.

I extracted some leaves with alcohol... basically the other half of what I was extracting was ayahuasca. I'd been incredibly careless in making a ridiculously strong extract using alcohol, that I nearly dehydrated just off the DMT. After acute effects of tryptamines had passed, I left my camp and walked off somewhere. It was probably not 5 minutes until I went to turn around, but I have very little memory between sunset and midnight. Oh and I had somehow left my camp without shoes or pants, so I'd cut up my legs pretty bad wandering around for hours. It started raining lightly, I could tell from the tolling of the clocktower in nearby iquitos it was midnight. I took shelter under some trees, which to me was an office building like from that show "the office" which had lost power but the management wouldn't let the cast go home. The soundtrack in my head included the endlessly whispering voices of the characters. The visuals were of silhouettes, shadows dancing in impossible ways. My imagination did not understand how dangerous a distraction it had become as I wandered captivated, hypnotized.. Zombie is a good word.

I finally found my camp just before dawn

Datura is also quite carcinogenic. I could not read the next day because my eyes would not focus. Carcinogenicity manifests itself as this effect on the eyes.

I finally noticed I could get a similar yet very mild form of the datura visuals with nicotine. Looks like squiggles or lines fighting colors, and then the lines set up a scene and put on their hypnotizing show when you pay attention to them. Easy to see with eyes unfocussed.

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vnc

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#8 [url]

Sep 24 11 12:52 AM

Carcinogenicity manifests itself as this effect on the eyes. 

I hope your trolling with this sentence....

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