Very nice find, Labrat. I should be able to grab that paper within a week, or maybe two.
I've only read anecdotal reports about ampakines so far. Could you explain anything about the pk/cognitive implications of activity at this receptor?
I just learned about glutamate receptors in a lecture yesterday. (Specifically, ionotropic - meaning the receptors themselves are ion channels). There are two kinds of ionotropic glutamate receptors: AMPA and NMDA. They're named that because of exogenous chemicals that are agonists for them; you can look them up, but they're actually not important).
are permeable to sodium and potassium. They respond very quickly to glutamate.NMDA receptors
are permeable to calcium. Glutamate has a higher
affinity for NMDA, but the actions of glutamate are delayed by a voltage-dependent magnesium block. Also, glycine or an analogue is required to open the NMDA channel.
Both channels "densensitize" - they close automatically after being exposed to glutamate and won't reopen until glutamate is taken away and re-introduced. This is probably to prevent overstimulation and excitotoxicity in case of glutamate excess. I won't go into the mechanism of denensitization, but one has been proposed.
In a normal dendrite (neuron input branch) where both AMPA and NMDA receptors are found:
1) Glutamate is released from a pre-synaptic neuron and binds to both
AMPA and NMDA receptors
2) In the post-synaptic neuron, AMPA receptors allow sodium and potassium cross the cell membrane, which depolarizes it (drives the resting voltage from negative up toward 0). The NMDA channel stays closed.
3) The depolarization triggers the release of magnesium from the NMDA receptor, and the NMDA opens.
4) Calcium enters the cell through the NMDA channel
5) Glutamate is taken up by the presynaptic neuron and glia, which causes glutamate to dissociate from the receptors (or other things can happen, like glycine uptake)
6) The AMPA and NMDA channels close
(If glutamate is in excess, the receptors will close anyway)
This all happens in under 10 ms
. It has to be fast, and the affinity of glutamate for the recepors is tuned so that small changes in concentration can happen rapidly.
The glutamergic signaling system is the fastest in the nervous system; in needs to be sensitive to high-frequency stimuli. The example our professor gave us was that a trained musician can tell the difference between a note at 350Hz and 351Hz - auditory processing requires sensory input and signal transduction that's extremely fast.
Calcium then triggers other functions in the post-synaptic cell. Under normal conditions, the concentration of calcium is nowhere near enough to be cytotoxic. But if the NMDA channel is kept open (with a toxin), then enough calcium enters and the cell dies.Ampakines
(positive allosteric modulators of the AMPA receptor) can A) increase glutamate affinity for AMPA B) prevent the AMPA channel from desensitizing and/or C) make the channel more permeable to ions Case (A) is actually not that interesting: the channel will just desensitize anyway, and it might activate at low physiological levels of glutamate, without pre-synaptic firing (too much "noise"). Case (B), reducing desensitization, and ©, increasing permeability, are much more interesting: the AMPA channel lets through more ions, which increases the strength of glutamergic transmission - and it can be switched on and off more rapidly (if all the other glutamate machinery is in place). Instead of having a refractory period, it becomes "multi-orgasmic." These are the kinds of ampakines that researchers are looking at; aniracetam and its derivatives seem to do (B): prevent desensitization of the AMPA channel.
Piracetam does not; its effects must be mediated through some other system.
The NMDA channel is a "fire when ready" receptor - it's sensitive to voltage changes (often caused by the AMPA receptor). For the NMDA channel, reducing desensitization can lead to too much calcium and excitotoxicity. But increasing its permeability to calcium is not so bad, as long as it still closes properly (which requires the presence of magnesium). Increased permeability to calcium means stronger response. (For calcium to reach toxic levels, the channel has to be open a long time -- too long to do any good.) It's likely that piracetam is a positive allosteric modulator of the NMDA receptor.
There are other factors that determine sensitivity of these channels, like additional membrane proteins, which are modified by more ligands.
Memantine is a voltage-dependent blocker of NMDA. It prevents calcium from entering the cell until a certain threshold is reached. Whether this is responsible for the cognitive effects is unclear. Dextromethorphan, ketamine and PCP are full NMDA blockers - not voltage-dependent.
There's an old thread about amphetamine tolerance being caused by too much intracellular calcium. I believe this to be false. Instead, I believe it's caused, at least in part, by the desensitization
of glutamate receptors. (Downregulation of dopamine and NE receptors probably contributes too).
Glutamergic transmission is important:
Simplified, dopamine, norepinephrine, and serotonin are responsible for mood and cognitive states
- alertness, reward, fear, attention, well-being. All the neurotransmitter systems are connected, but ultimately glutamate and GABA do the information processing; they're the ones that encode sensory inputs and thoughts (GABA directly modulates the effect of glutamate). Acetylcholine probably does both: sustains certain states (e.g. REM sleep) and
directly influences information encoding. But basically, the other systems affect how glutamate and GABA are going to behave. (This is the complicated part and basically the point of neuroscience: how chemical and electrical signals are encoded into thoughts and sustain consciousness).
A rational approach to "cognitive enhancement" requires knowing what cognition involves. What are we after: Increased short-term memory? Faster information processing? Faster recall? Enhanced long-term potentiation? Each one involves different circuits that involve multiple neurotransmitter systems.
Our professor mentioned cognitive enhancers, and I had a brief discussion with him about them (he noted that I seemed to know more about the field than him). Glutamate receptors are found throughout the CNS, so effects can be systemic. Furthermore, pharmaceutical companies have a very low success rate using them as drug targets. My professor was also skeptical about cognitive enhancers because the glutamate system is so fine-tuned: both fast and sensitive to changes in concentration. He also mentioned ethical concerns, but that was more of an aside. He's probably like a cognitive enhancer as much as anyone.
The lack of cognitive enhancers that modulate glutamate receptors (the ones that would really make a difference in cognition--not just attention, alertness, mood, etc) is based on a cost-benefit analysis.
Here's a good illustration of glutamergic synapse: