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5-HT2A antagonist block the Glutamate increase induced by NMDA recptor antagonists

BilZ0r

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The article which has most recently peaked by interest is Ceglia et al., 2004, which you can find the abstract of here and the PDF here (214k).

The interaction between NMDA receptors and 5-HT2A receptors is one I find very interesting, and I'm still hoping my supervisor is going to let me have a look at it for my thesis. It's allready been shown that on a single cell level, 5-HT2A receptor agonists interact with NMDA receptors and antagonise them, quite potently and effecaciously, and this has been suggested as how classical hallucinogens act (Arvanov et al., 1999a; 1999b. When I wrote The Neuropharmacology Of Hallucinogens V2 for erowid, I kinda attacked that work, because basically "come on, ketamine doesn't feel like LSD does it?". To support that view, I say " if hallucinogens worked solely by inhibiting the NMDA receptor in some fashion, one would expect hallucinogens to generalize to NMDA-receptor antagonists in drug discrimination experiments, but only few do, and to a very small extent (Jones et al., 1998; West et al., 2000). Furthermore, if the NMDA-receptor inhibition theory was the complete explanation of hallucinogen action, it seems surprising that mGluR2/3 agonists, which inhibit 5-HT2A receptor-mediated glutamate release in vitro, also inhibit behavioral aspects of hallucinogens such as head shakes (Klodzinska et al., 2002) and drug-induced stimulus control (Winter et al., 2004)."

But if I was honest with myself, Jones et al, he had rats and monkeys train to descriminate PCP from saline. He gave them LSD and he got up to 60% responding (rats), and 1 out of 4 monkeys showed completely responding. West et al shows completely blockade of PCP responding, but he never truely tests what LSD will do on its own.

So theres some obvious interplay going on here, one way or the other.
So the paper at hand, Ceglia et al., 2004. Basically, they give the COMPETITIVE NMDA receptor antagonists CPP, to rats either IP, or via microdialysis (directly into the brain) to the medial prefrontal cortex (mPFC).

CPP increased glutamate (glu) by 200-230% respectively, and this increase probably represented increased neuronal activity as it was blocked by tetrodoxin (which blocks action potentials).

Then they gave the 5-HT2A antagonist M100,907, subcutaneously or via microdialysis, and it caused a complete reversal to base line of the released glutamate.

And what makes this interesting, is that they recorded the serotonin (5-HT) release in the mPFC, and they saw that it was increased (140%).

So one could make a quick conclusion here if you were lazy. NMDA antagonists cause an increased in 5-HT release, which acts on 5-HT2A receptors to increase cortical glutamate. Just like how classical hallucinogens are supposed to act...

There's some problems with this study. The 5-HT release doesn't match with the glutamate release, as far as dose goes. CPP at 20mg/kg IP or at 100µM microdialysis, produces the maximum glu release, (30µM CPP induces no glu release). But 10mg/kg CPP produces maximum 5-HT release, and 20mg/kg produces no 5-HT release. Similarly, 30µM CPP produces maximum 5-HT release, and 100µM actaully produces a decrease in 5-HT release.

I don't know what to make of it, but I think I'm willing to forget about the dose descrepancy, and it could be a technical thing.

BUT, competitive antagonists don't tend to generalize to non-competative antagonists (ketamine/pcp)... and non-competative antagonists stimulus control isn't blocked by 5-HT2A antagonists, even though they induce glutamate release as well...

So it would seem that the glutamate release induced by NMDA antagonists isn't responsible for their interoceptive cues

*pant pant pant*....
 
Well the pathway you suggest doesnt soundto illogical. The brain is something we try to understand. But the more we know, the less we exactly understand.
 
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