Difference in glutamatergic receptor function

[Solipsis]

AFAIK all types of glutamatergic receptors are considered to be involved with neuroplasticity, mainly the ionotropic ones also LTP which seems to be important for learning / cognition.

But is it known what the difference is between function of NMDAr vs AMPA (or kainate for that matter)? If you take medications that influence either glutamate levels (or glu decarboxylase levels) like gabapentinoids, or ampakines or drugs that antagonize NMDAr... what are the implications for learning and mood?

For example if you take racetams to counter cognitive effects of dissociatives will you lose anti-depressant action?

I'm led to believe that cognitively speaking the brain can cope with sufficient action at any ionotropic glutamate receptors. Unfortunately it seems that the link is not yet understood between e.g. depression and neuroplasticity or neuroplasticity with other mental phenomenon that were not previously thought to be related.. a question would be: if you are messing with this, can you have your cake and eat it too?

Or if you take gabapentinoids blocking VDCCs and rebalancing GABA vs glutamate, and assume deleterious effects on cognition and perhaps other brain function (more long term perhaps) - including from dissociatives in the past... may racetams help and would overly enhanced or active glutamatergic action then be of any concern?
(My personal experience is that my mental condition - a form of ASD - is helped most by reduction in glutamatergic action, or increase in gabaergic action, though I never really had noticeable problems from nootropics)

AMPAkines or drugs that are said to enhance some pharmacological action... do they act not by increasing any neurotransmitter level, but by increasing the activation of receptors at a same neurotransmitter level as before? Otherwise I don't really understand enhancers, it sounds like a vague or broad term.

 

[serotonin2A]

One way that ligand gated ion channels terminate signaling is by changing conformation to a desensitized state, where the agonist is still bound but the channel is closed. AMPAkines work by destabilizing the desensitized conformation, so the channel flips back to a non-desensitized state after a short(er) period of time

AMPA and NMDA receptors both play a role in LTP, but they have completely different functions. LTP happens when NMDA receptor activation follows AMPA receptor activation. NMDA receptors are not active at resting membrane potentials due to magnesium blockade of the channel, but when AMPA depolarizes the membrane it dislodges the magnesium. (It is interesting that the binding site for Mg is near or may actually overlap the PCP binding site located inside the NMDA channel).

Ionotropic receptors and ion channels are usually heterogeneous because the subunits can come from multiple families. That may give you some leeway in terms of modifying ionotropic transmission for therapeutic purposes without nonspecifically impairing other functions of the channel. So in some situations it may be possible "to have your cake and eat it too" but that isn't universal. There are plenty of people who take Topimax et al and complain of cognitive deficits.

Modifying transmission allosterically is almost always preferable in terms of producing less side-effects. That is because the mechanism intrinsically has limited efficacy.

 

[Cotcha Yankinov]

Hey Serotonin, are you interested in any particular cognitive enhancers yourself? Not that you need them lol but I've been pondering trials of Piracetam/Aniracetam to help with some attention span issues.