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Discussion Starter · #1 ·
Correct me if I'm overthinking this one, but an nmda receptor antagonist, specifically memantine, would increase the effects of glutamate, causing the brain fog that people experience? If the glutamate cannot get to the receptor because it's cockblocked by memantine, it'll either reuptake or degrade through MAO, OR will it kill brain cells, in a suicide way, which I'm figuring is what happens with MSG. Now the killer, literally. If the glutamate can't get to the receptor, won't your brain excrete even more glutamate? To maintain homeostasis of course. Even if this doesn't match up with the literature you have read, it makes sense in terms of homeostasis. I'm not informing anyone, I'm wishing to collaborate. SWIM finally bought some memantine and it's shipping atm
 

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Discussion Starter · #2 ·
I figured NMDA receptors controlled glutamate, mistakenly. Now I think I understand that activation of an NMDAR through NMDA opens the calcium ion channel to allow glutamate to enter wherever it's meant to go?
 

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Nardil Gangster
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It's complicated so someone correct me if I'm wrong. Memantine is a voltage-dependent uncompetitive NMDAr antagonist. The term uncompetitive has a very specific meaning in pharmacology and is not the same as non-competitive. For an uncompetitive antagonist to work requires binding of a separate agonist to occur. In this case, Memantine will not bind anywhere on the NMDA receptor until glutamate has locked into place in its receptor. When that happens, Memantine gains a much stronger affinity to find its binding domain, which is an allosteric domain (apart from glutamate's site) located within the NMDA complex's ion channel. In fact, the higher the concentration of glutamate the greater Memantine's binding inside the channel. So in effect, greater glutamate binding causes greater Memantine binding and subsequent increased blockage of ionic currents in and out of the neuron.

So Memantine doesn't kill glutamate or (I think) change concentrations of it. It just has a positive glutamate receptor activation dependent binding affinity.

Importantly, excessively high levels of calcium ion influx through the channel are the "killing of braincells" I think you were alluding to. So Memantine could theoretically be neuroprotective by modulating the channel and preventing too much calcium influx caused by glutamate binding. Of significance here though is that Memantine does not block the actual glutamate receptor. And Memantine's binding in the channel is very plastic and subject to removal through a couple of mechanisms. This is relevant to maintaining the functionality of the glutamate receptors.

The complete story is a jillion times more complex than this but I can't type any more. Hopefully what I wrote isn't completely opaque and wrong.
 

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Discussion Starter · #4 ·
So to summarize, memantine overrides glutamate using a different binding spot on the same receptor, preventing the gate from opening allowing an influx of harmful calcium ions. I've read that magnesium and zinc do something along those lines that memantine does. I guess this is a question pertaining to neurology in general; What happens to the molecules (memantine and glutamate) once their job is done? Knowing this could improve brain function and speed.
 

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Nardil Gangster
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I think magnesium2+ is probably the native ligand for the "Memantine receptor" and performs a function similar to Memantine within the channel, but Memantine displaces it due to a higher affinity for the receptor; it's there that its particular chemical properties are able to act.

Once Memantine gets removed from its receptor, its likely fate is to be metabolized by kidney enzymes in repeated cycles until it all gets transformed in the kidney into three biologically inert metabolites which are excreted in the urine.

Glutamate is such an important neurotransmitter / amino acid that it never gets wasted. There are transporters located on presynaptic neurons that recycle a small amount as well as much greater efficiency transporters located on nearby glial cells which take-up and retransport about 90% of the initial glutamate back to the original cell where it gets repackaged into synaptic vesicles for subsequent firing. A small amount of the synaptic glutamate gets used in the Kreb's cycle. Interestingly, Glutamate is used to make GABA.
 
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