• N&PD Moderators: Skorpio | thegreenhand

muscimol binding

markosheehan

Bluelighter
Joined
Sep 17, 2016
Messages
238
Does muscimol behave as a agonist at all the subunits in GABAa receptors.

more specifically does it act at GABAa receptors containing the alpha 2 and 3 subunits.

I can not find data on this.

also which has the most anxiolytic potential out of the following : muscimol, THIP and tiagabine ?
 
I dont know exactly what they mean by non-specific but i interpret it as that it doesnt discriminate between different GABA-A receptor subtypes. Would help if i could read the articles theyre quoting.

The fact that muscimol is a non-specific GABA Areceptor agonist [38, 39], a substrate for the GABA-metabolizing enzyme, GABA transaminase [40], andmoreover a neurotoxin, makes the compound therapeuticallyless valuable. The 3-isoxazolol moiety of muscimol has,however, proved to be very efficient as a bioisostere for thecarboxyl group in GABA. Therefore, muscimol has beenextensively used as a lead structure in the search for potentand selective compounds acting at GABA A receptors asillustrated in Fig. (4)

http://www.eurekaselect.com/81523/article[38]
https://www.ncbi.nlm.nih.gov/pubmed/448364[39]
https://www.ncbi.nlm.nih.gov/pubmed/6274117
 
Last edited by a moderator:
well some people report muscimol not having much anxiolytic potential so it might not bind to gabaa receptors containing 2 and 3 subunits.

also it has very little anti convulsant potential which also might suggest it does not affect all the subunits so this confuses me.

does anyone have any experience or theoretical predictions for which has the most anxiolytic potential.?
 
Muscimol binds at the orthosteric site, the GABA recognition site at GABAa receptors of the canonical types, and also as an agonist at GABAa-Rho receptors which are primarily located in the retina of the eye, composed of entirely Rho-type GABAa subunits, these assemble into functional receptors, also sometimes called GABAc receptors, which are insensitive to the prototypical GABAa antagonist/inverse agonists bicucculine and picrotoxin.

Does it affect GABA transaminase?

Also, with most reports about muscimol, it is almost certainly coming from Amanita muscaria,so it can't really be compared to pure muscimol, especially given that there seems to be an iinitial proglutamatergic stage after fly agaric ingestion, presumaably from residual ibotenic acid, given the frequent reports of an initial phase of myoclonus and twitching. Unless of course this is a consequence of muscimol displacing GABA at GABAa receptors.

What is the intrinsic activity at GABAaRs for muscimol and for GABA itself.?
 
Wouldn't the IA of GABA at GABAAR be 100%, by definition?
 
I was meaning the difference in IA between GABA and muscimol, relatively speaking, wondering if the muscular twitching and clonus etc. are related to NMDAr-mediated agonism caused by residual ibotenic acid, (assuming one isn't dumb enough to try eating fly agaric fresh without knowing how to cook it properly for use as a table mushroom rather than a spice (I.e boil twice, throwing away the water each time, before cooking in whatever way one wants to serve them, to leach out the active or toxic principles, allowing it to be served as food, kind of like what is needed to allow Amanita rubescens (Blusher) to be eaten, uncooked, or improperly cooked, it is toxic, containing a haemolytic toxin, but it can be leached out by boiling twice with changes of water. Same is done by some folk for false morels (Gyromitra spp) although those just shouldn't be eaten at all, giving off monomethyl hydrazine either in vivo or off-gassing it during boiling, sometimes killing the cook whilst those eating it have suffered no ill effects. The Amanita species, those two are good enough, but false morels just shouldn't be consumed at all, I wouldn't, and I'm pretty adventurous when it comes to wild fungi)

But is ibotenic acid stable enough to survive the slow drying at low, low oven temperatures in trace quantities? I know its not stable to heat or drying, but HOW unstable is it? It does cross the BBB does it not? via an active transport mechanism IIRC. Undesirable at best. So it'd be good to know how well it survives the curing process.

(I do mine by taking the caps only, scooping away the gills, which give off a ton of water during the drying, which can make the caps soggy and nasty, and besides, IMO its a good thing to return the gills to potential sites of growth for new mushroom spots, They are rubbish to me, so might as well help return them to nature and help spawn other patches to harvest in the future. And then drying them on the minimum sustainable gas flame in the oven, overnight until they are dry enough to snap if one tries to bend the caps, and ideally, retaining a bright golden orange colour to the cap surface, overnight at least, propping the door of the oven open with a knife handle or whatever else come to hand so as to allow the water to escape.

I would call it my favourite of all fungi, for its many, many uses, as medicine, as recreational intoxicant, as endurance-booster, tonic, and once cured and dried, it goes in every red meat dish I ever cook, I would never even think of making chile con carne without fly agaric for example, and every time I make steak, I use a spice blend based on fly agaric, szechuan pepper, pink peppercorns and peppery boletus (Chalciporus piperatus, a parasite of fly agaric when the Amanita chooses silver birch as host, never seen the peppery boletes under pine, which A.muscaria sometimes grows with as mycorrhizal partner), along with a host of other spices.

So I end up using quite a lot of fly agaric for one reason or another, it'd be nice to know that as little ibotenic acid as possible would survive the curing process. (annually would be whatever can fit in a couple of those large bin liners intended for outside trash, as I've some really prolific spots that produce so many its difficult to cure them all given I've only one oven plus one small autoclave, and I'll pick a year's supply when they are fruiting, and go through the lot, or almost all of them until the next harvest comes along. AFAIK round here at least, I'm the only one who will touch them, I've had people stop me, and try to warn me that I'd be poisoning myself, as all the guidebooks call them poisonous, but thats only fresh, uncooked, they have a lot of value IMO when correctly processed.

What I'm wondering is if the initial neuromuscular phase of fly agaric intoxication is due to glutamatergic agonistic activity or due to muscimol having a lower intrinsic activity but higher affinity than GABA, leading to contined GABAa agonist activity at the orthosteric site but at a lower overall level than in the absence of muscimol, in-vivo, causing myoclonus but not full blown seizure or anxiogenic effects.

As for the mention of muscimol as neurotoxic, can anyone support that muscimol itself, rather than ibotenic acid, is neurotoxic? and if so, in what way?
 
Last edited:
Limpet, can you not just get pure synthetic muscimol and see if that induces the twitching?
 
I've never tried, I could probably make it if I were inclined, I wouldn't mind doing a synthesis of thiomuscimol sometime, but *I* don't get the twitching, I've never noticed it at least, and I am a somewhat enthusiastic consumer of the mushroom, but its commonly reported that there is an initial muscle jerking phase prior to the deep coma-like sleep and vivid oneirogenic effects, where fly agaric is the source. But I myself haven't noticed any 'off' effects with it, so I can't really compare the two, if the natural source doesn't produce such a side effect in me personally. I've had both those growing under pine, and under silver birch, without any ill effects. I do take a 10mg dose of hyoscine/scopolamine butylbromide to prevent any muscarinic cholinergic crap due to trace levels of muscarine, but even so, I haven't noticed anything akin to this often spoken of first phase of onset myself, and as such, even with synthetic muscimol or thiomuscimol, I cannot compare it to the natural source to see if it eliminates the side effect, given that I, personally, do not experience the side effect in question, rather, it is one often experienced by those who use the mushroom.
 
could it be due to GABAc receptors?
They seem to behave opposite to GABAa receptors. agonists at GABAc receptors cause stimulation and are anxiogenic. I personally would stay away from muscimol due to this.
 
The mushroom has always shown sedative-catatonic to anxiolytic effects in vivo personally. Avoid fly agaric? fuck that! I can't convince people what they are missing out on because of their personal toxic effects, personally I cannot even conjure up the picture of a food without A.muscaria in beef or lamb in either. Hell you'd have a tough time convincing me to EAT beef not spiced with A.muscaria. I'd be tempted to slap someone who even spoke of the possibility! blasphemy and heresy of the worst kind! I should kill you just for THINKING about a beef steak with no fly agaric spice blend sprinkled over it! I should nail you to a cross, set you on fire, and walk away laughing, if it were not such atrocious abomination that nobody sane would think to eat such food!
 
Top