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Taking glycine with an NMDA antagonist

C

CrimpJiggler

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Glycine is a ligand for chloride channels in the CNS, similar to GABA. Conversely though, glycine is a co-agonist for the NMDA receptor, when glutamate binds to the NMDA receptor, it needs glycine to bind at the same time for the receptor to be activated. As a result, too much glycine causes excitotoxicity. If one was to take an NMDA antagonist, along with a high dose of glycine, then one would get the inhibitory effects of the glycine, without activating NMDA receptors. I wonder what the effects would be.
 
If one was to take an NMDA antagonist, along with a high dose of glycine, then one would get the inhibitory effects of the glycine, without activating NMDA receptors
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except glycine which normally exists as a charged zwitterion has trouble crossing the BBB

also consider gelatine is almost entirely polyglycine; that would mean ingesting jello would lead to psychoactive f/x ...
 
sekio: Ah right. I wonder if an ester would make it across the BBB. Not sure if it'd be dealkylated once it did reach the CNS though.

Ho-Chi-Minh: Its an inhibitory neurotransmitter when it binds to the glycine receptor. Its excitatory when it binds to the NMDA receptor.
 
Its an inhibitory neurotransmitter when it binds to the glycine receptor. Its excitatory when it binds to the NMDA receptor.
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This is a bit confusing, as the glycine binding site is an area on glutaminergic receptors, including nmda receptors. In the case of NMDA receptors, two glutamate or aspartate molecules must binde to glutaminergic sites, and glycine must bind to the glycine site for the voltage gated channel to open effectively. Where does glycine exhibit inhibitory effects and why?

ebola
 
No expert, but it would appear that George Eby had remarkable success in treating his depression with magnesium glycinate (glycinate being a combination of glycine and lysine) i think. He attributed the antidepressant properties of this supplement largely to its NMDA antagonizing effects. Thus it would seem plausible that one could significantly increase intake of glycine without causing excessive stimulation of glutamate receptors.
 
ebola? said:
This is a bit confusing, as the glycine binding site is an area on glutaminergic receptors, including nmda receptors. In the case of NMDA receptors, two glutamate or aspartate molecules must binde to glutaminergic sites, and glycine must bind to the glycine site for the voltage gated channel to open effectively. Where does glycine exhibit inhibitory effects and why?

ebola
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Inhibitory glycine receptors are different receptors altogether, they have nothing to do with NMDA receptors. They are located on neurons in the CNS, mainly in the spinal cord. In NMDA receptors, glycine is an allosteric modulator but in glycine receptors, its the primary ligand. NMDA receptors are ligand (not voltage) gated cation channels which, when activated, let an influx of sodium, potassium and calcium ions (calcium ion influx being what triggers NMDA excitotoxicity). This cation channel can only open up when glycine binds to the allosteric site at the same time as glutamate binding to the receptors primary site. Glycine receptors on the other hand are chloride channels that open up when a molecule of glycine binds to them. The opening of cation channels is excitatory (because the inside of neurons is negatively charged, while the outside is positively charged, so when cations flow into the neuron, it becomes less negatively charged and is thus, depolarised), whereas the opening of anion (such as chloride) channels is inhibitory because it makes the inside of the neuron more negatively charged than usual so it becomes hyperpolarised (and thus, harder to depolarise by excitatory receptors).

You referred to the glutamate receptor as a voltage gated ion channel. If I'm not mistaken, the term voltage gated channel is reserved for ion channels that are opened only by changes in the resting membrane potential so that excludes glutamate receptor since its opened by a ligand. For example, voltage gated sodium channels let an influx of Na+ ions into the cell when it becomes depolarised, this way that depolarisation gets transmitted to the rest of the neuron in a chain reaction. Voltage gated potassium channels let K+ ions out of the cell in order to bring the depolarised neuron back to its resting potential. Interesting fact: local anasthetics paralyse and numb the body by completely clogging up voltage gated sodium channels, so if a particular area of a neuron gets depolarised by say a glutamate receptor, that depolarisation (which is known as an action potential I think) can't get transmitted to the rest of the neuron. I think curare (the stuff that Amazonian indians put on their blowdarts to paralyse animals) is primarily a sodium channel blocker.
 
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Isn't strychnine/brucine a GlyR antagonist, causing convulsions etc and its "stimulatory" effects at lower doses?

Either way I don't think playing with GlyR is a good plan!
 
sekio: Yeah strychnine is a potent GlyR antagonist. Picrotoxin is a potent GABA antagonist and causes convulsions at low doses too.
 
ebola? said:
This is a bit confusing, as the glycine binding site is an area on glutaminergic receptors, including nmda receptors. In the case of NMDA receptors, two glutamate or aspartate molecules must binde to glutaminergic sites, and glycine must bind to the glycine site for the voltage gated channel to open effectively. Where does glycine exhibit inhibitory effects and why?

ebola
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You're actually right here, its both ligand gated and voltage gated due to the Mg2+ ion jammed in there.
 
Good point.
...
Sheesh. The structure of the NMDA receptor provides weak evidence against intelligent design (suggesting instead completely nuts design).

ebola
 
ebola? said:
Good point.
...
Sheesh. The structure of the NMDA receptor provides weak evidence against intelligent design (suggesting instead completely nuts design).

ebola
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Just wait till you do some reading on synaptic vs extrasynaptic NMDAR, I swear it seems like extrasynaptic are just there to trigger apoptosis.
 
Epsilon Alpha said:
You're actually right here, its both ligand gated and voltage gated due to the Mg2+ ion jammed in there.
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Errr the requirement for a divalent cation co-ligand doesn't make it a voltage gated channel, it still doesn't open due to changes in membrane potential as far as I know. Maybe I'm misunderstanding you though.
 
Thanks for the clarification EA, I didn't realize NMDA had voltage dependence as well. You should read that report though, unless I'm misunderstanding something their data argues that NMDA voltage dependence is independent of magnesium.
 
endotropic said:
Thanks for the clarification EA, I didn't realize NMDA had voltage dependence as well. You should read that report though, unless I'm misunderstanding something their data argues that NMDA voltage dependence is independent of magnesium.
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I was actually surprised at that myself, that's the first I've heard of magnesium not being a key element of NMDA function. Man, there has been some interesting research on the Glu receptors in recent years
 
As for glycine receptors, (strychnine-sensitive GlyRs, that is, not the glycine binding site on the NMDAr complex), these seem primarily expressed in the spinal cord, and it seems potent selective agonists, such as gelsemine do pretty much what one would expect the inverse of strychnine to do. Namely decrease muscle tension, exert an anxiolytic effect, and decrease reflexes, IIRC gelsemine has some analgesic properties also. Although not something to fuck about with, even the 5 and 10c homeopathic preparations from stock synthetic gelsemine retained sufficient concentration to agonise glycine receptors.

Been contemplating trying it actually, for the intractable spasms I get in my iffy leg. Although too much, and its pretty toxic stuff.
 
actually I've been doing a few experiments with glycine, glutamate and racetams with NMDA antagonists.
Predosing with glycine and glutamate seems to "open up" receptors - maybe making more of them available to be antagonised.
Thus on a sensible MXE regime, say, one could get up to as much as 50% more bang for the buck. This is after weeks of tolerance.
Initially I was interested in an antidote to MXE overdose, which I had once and was very scary for all around me.
The best "antidote" I have found to NMDA antagonists is Oxiracetam.
 
Glycine (trimethylglycine) , taurine , zinc ,d-serine,magnesium are all co-factors or mild substrates of the NMDA receptor. Calcium and B12 to an extent too... Zinc, taurine, and magnesium will cause problems if theres a deficiency . If you're a vegan taking a few grams of taurine before a dissociative may suprise you.

I know d-serine is the most potent of those listed. Trimethylglycine being the next (causes VERY noticable inhbitory effects for me, much sedation and higher doses psychedelic effects just like noopept if similar if not same mechanism of action as TMG, albeit weaker) 3000 mgs of TMG would probally be way too much.

I have not experimented with d-serine yet , but am most curious about that one... Seems there are no vitamin/supplement companies selling that one because its probably a little too potent for the general public...

Theres no reason why having more precursors and minerals available for ion-gating wouldn't HELP with the effects of NMDA antagonists.

For example, a zinc defiency will DEFINITELY cause lowered effects of dissociatives... A analogy would be low brain/blood calcium causing less potent inhibition of calcium ion channels.

Anyone taken d-serine?
 
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