Where does the glutamate go? (DXM/NMDA antagonist question)

[mecaib]

Hello,

The title pretty much sums up my question.

If one of the primary neuroprotective effects of NMDA antagonists is to prevent glutamic acid-aided excitoxity in the brain, then what happens to all the glutamate in the mean time? Is it sitting there, waiting to taken back up by the NMDA receptors? Does it go anywhere? Is it possible that NMDA antagonists, by delaying the reuptake of glutamic acid, actually cause a dangerous rebound effect because the glutamate had nowhere else to go?

I would appreciate a response. A link to some research findings would be even better. Thanks in advance~

edit: Ok, I found out that Glutamate Transporters ferry the excess glutamate away from extracellular space, where it can build up and become toxic under certain conditions. It would appear that adenosine triphosphate, oxygen, and proper blood flow facilitate this action.

My question about a possible rebound effect still stands. Could temporary antagonism of NMDA receptor activity result in an accumulation of glutamate because the glutamate transporters cannot work fast enough?

Also, Is it possible that NMDA antagonism, over time, might actually result in a more efficient glutamate transportation system because the glutamate is not always being taken in by the NMDA receptors and it has to go somewhere?

 

[The Monkey Mantra]

Receptors don't take anything up. They're more like doorbells that the glutamate rings than they are "holes" it goes into to enter the cell. Anyone else have the energy to set this guy straight? I'm in a major hurry!

 

[Sturnam]

well, glutamate would be stored in the presynaptic vesicles, and an NMDA antagonist would simply prevent these vesicles from being released. And as long as there is no shortage of glutamate, then the body doesn't need to synthesize more. The body has very efficient feedback loops so that chemicals don't build up to dangerously high levels.

so to answer your question, no.

 

[Hammilton]

well, glutamate would be stored in the presynaptic vesicles, and an NMDA antagonist would simply prevent these vesicles from being released.

This isn't true.

An antagonist does not block reuptake or release, it blocks binding to receptors.

I suggest taking a look at a generic receptor to get an idea for how the whole process works.

 

[mecaib]

Well I feel very silly 8) I obviously need a better understanding of basic neuropharmacology.

<..> And as long as there is no shortage of glutamate, then the body doesn't need to synthesize more. The body has very efficient feedback loops so that chemicals don't build up to dangerously high levels.

Your statement may be true for young, healthy individuals. But according to literature on the subject, this is not true for people suffering brain injury, stroke and/or certain diseases such as Alzheimer's and Parkinson's. As for Alzheimer's patients, excess levels of glutamate are probably present long before symptoms of failing mental acuity manifest.

At any rate, you guys helped to answer my questions and put my mind at ease about what I thought could be a potentially overlooked problem with NMDA antagonists. I'm beginning to feel that dextromethorphan in particular is a relatively safe compound, and may work similar to Memantine to delay the effects of neurological decline associated with Alzheimer's. My grandfather had the disease, and with more and more people becoming ill with it all the time, it seems like an eventuality for me as well. I know the subject is more complicated than glutamate toxicity, but I would like to do everything I can to keep the disease from taking me before I can die some other way. I don't know about you guys, but mental failure scares the shit out of me

 

[Sturnam]

This isn't true.

An antagonist does not block reuptake or release, it blocks binding to receptors.

I suggest taking a look at a generic receptor to get an idea for how the whole process works.

sorry, I just skipped those steps inbetween. i just assumed that the OP knew them already.

^ as for mecaib, I've heard (very offhand) that doing crossword puzzles helps prevent Alzheimer's. But aside from that, I think just staying mentally active especially as you hit 50+ helps prevent Alzheimer's, or at least slow it a little. But especially if you're young, I wouldn't worry about it now.

oh, and this kind of understanding takes a while. honestly, I think a basic understanding of molecular cell biology would be the place to begin. start off with the basic cells of the body before you move onto complex neurobiology. i tried to jump in and start learning all the neurobiology and psychopharmacology but it wasn't until recently when I got a better understanding of simple biology that i've finally started to understand all of this.

 

[overstoned]

The glutamate goes to AMPA receptors.