What is the AMPA receptor, and what does it do?

[blase deviant]

Topic.

 

[toxide]

I too have trying to find answers to this for a LONG time. It seems like a very interesting but very unexplored region. I'm very interested in AMPA antagonists.

For instance there are spider/wasp toxins that block AMPA,polyamine site and to a MUCH lesser extent NMDA. There is some miniscule info on the fact that these are powerful immobilizing agents with good theraputic actions aswell. The immobilizing info mainly pertains to insects which is of absolutely no interest to me, but there may have been info on that relating to rats, I'm not sure tho.

They seem relatively safe and are simple to make with rather nontoxic materials as far as i know.

I would like to know much more about these and how they relate to traditional nmda AAs and dissociatives and so on...

 

[Dondante]

There are 3 types of ionotropic glutamate receptors: NMDA, AMPA, and kainate, named for the molecule that stimulates them. Activation of all of these receptor types produces EPSPs. Some gultamatergic synapses have only AMPA or NMDA, but most have both.

Other glutamate receptors are metabotropic, this consists of the mGluR family, which modify postsynaptic ion channels indirectly. Group II, mGluR2/3, are presynaptic receptors that have an inhibitory effect on AMPA. It was found that mGluR2/3 agonists blocked the 5-HT2A induced spontaneous EPSPs, while mGlu2/3 antagonists increased spontaneous EPSPs.

It's pretty clear that glutamate plays a key role in the action of hallucinogens. I don't know of any psychoactive drugs that have affinity for the AMPA receptor though. From Nichols' review paper on 5-HT2A - glutamate link:

Electrophysiological data first suggested that 5-HT2A
receptors amplify glutamate-induced EPSPs from apical
dendrites of pyramidal cells by increasing a persistent
sodium channel (Marek & Aghajanian, 1996a). These
effects appear to be mediated by release of glutamate,
induced by the stimulation of presynaptic 5-HT2A heteroreceptors,
and the subsequent activation of a-amino-3-
hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors
(Aghajanian & Marek, 1997, 1999b, 1999c; Marek et al.,
2000).

Also, from JPET 292:76–87, 2000 ...

The 5-HT-induced EPSCs are mediated via
AMPA/kainate receptors on layer V pyramidal cells because
they are completely blocked by the AMPA/kainate antagonist
LY293558 (Aghajanian and Marek, 1997).

Sorry, getting away from the original question there. Hope that helps.

Edit: More very interesting info about AMPA agonists:

Evidence for advantages of AMPA receptor antagonists over N-methyl-D-aspartate (NMDA) receptor antagonists for symptomatic treatment of neurological and psychiatric conditions, and for minimising neuronal loss occurring after acute neurological diseases, such as physical trauma, ischaemia or status epilepticus, have been shown in animal models. However, as yet AMPA receptor antagonists have not been shown to be effective in clinical trials. On the other hand, a limited number of clinical trials have been reported for AMPA receptor ligands that enhance glutamatergic neurotransmission by extending the ion channel opening time (positive allosteric modulators). These acute studies demonstrate enhanced memory capability in both young and aged humans, without any apparent serious adverse effects. The use of these allosteric modulators as antipsychotic drugs is also possible. However, the long term use of both direct agonists and positive allosteric modulators must be approached with considerable caution because of potential adverse effects.

Pharmacology of AMPA/Kainate Receptor Ligands and Their Therapeutic Potential in Neurological and Psychiatric Disorders. Lees, G.J. Drugs, Jan2000, Vol. 59 Issue 1, p33, 46p

Might as well add this interesting bit too (from the same article). AMPA antagonist were being tested for efficacy in reducing behavioral sensitization (post-withdrawl craving) to opiates, cocaine, and amphetamines. The regulation of the rewarding properties of these drugs seems to be related to a temporary increase in the responsiveness of dopaminergic neurons in the ventral tagmental area to AMPA transmission upon withdrawl:

In contrast, the acute hyperactivity
and stereotypy induced by apomorphine and cocaine
in rats are not altered by the competitive
AMPA antagonists, CNQX and NBQX,[374,392] but
are increased by GYKI-52466.[375] No behavioural
excitement is seen with NBQX or GYKI-52466
alone,[374,375] but it should be noted that in human
trials with GYKI-53773, euphoria was one adverse
effect noted.

 

[blase deviant]

Thanks.

Also, this isn't really advanced, but is aniracetam an AMPA agonist or antagonist?

 

[Oddeye]

Yup, Ampakines are apparently a very good coumpound. Should be the future stimulant, even better than modafanil.

 

[5-HT2]

The AMPA receptor is a tetrameric glutamate-gated cation channel that can be composed of homo- or heteromeric assemblies of four subunits (GluR1-4). Receptors that contain GluR2 are not calcium permeable. AMPA receptors are primarily expressed postsynaptically, and are widely expressed throughout the brain. GluR2-containing AMPA receptors are critical for normal basal synaptic transmission in cortical regions, and therefore must constitute the majority of postsynaptic AMPA receptors. Evidence gathered over the past decade or so strongly suggests that AMPA receptor trafficking is crucial for certain types of learning and memory. AMPA and kainate receptors can open at hyperpolarized (resting) potentials, whereas the NMDA receptor only becomes fully permeant once membrane depolarization removes divalent magnesium blockade of the channel. Thus, AMPA and kainate receptors provide the drive necessary to depolarize the postsynaptic membrane to the point where NMDA channels can make a major contribution to postsynaptic ion flux.

 

[Coolio]

Interesting... GYKI-52466 has an almost perfect manifestation of MDA within its 2,3-benzodiazepine structure.