The following rant is about only a theory... not set in stone.
I spent a lot of today researching KCC2, a transporter in the brain. This subject has pretty much been blowing my mind. I've known for a long time now that GABA, the major inhibitory neurotransmitter, is said to have excitatory actions instead in young brains, but I never really knew why until now. It's because GABA(A) receptors actually are excitatory receptors, but they're constantly modulated throughout the brain by KCC2 which causes their effect to become inhibitory instead. A slow rise in KCC2 is what causes the change to happen with age, and evidence that this is all the case can be seen in rare circumstances like where GABA is localized in vasopressin neurons; it's one of the only places without KCC2 also being present, and GABA has an excitatory action there. Disruptions in this setup have been implicated in neurological disorders particularly those related to injury or disease, but there's also some evidence that KCC2 is not functioning at full capacity in schizophrenia. That's what really brings me here.
I read that 5-HT2A receptors have been shown to upregulate KCC2 in motor neurons. I'm so annoyed that they tested it there and nowhere else! Here's where the story starts to get maybe a little too romantic, though, but I can't help thinking about it. When I hear that a receptor upregulates something, my first suspicion is that it somehow lowers its activity during the main reaction to its activation. My thought in this case then would be that 5-HT2A receptors in that area are actually inhibiting the activity of KCC2. This is something you would probably want to avoid doing on a larger scale, but in isolated areas through this kind of thing it could be safe, similarly to how widespread dopamine can cause lots of serious side effects by the time you start hallucinating from it, but if it's released entirely in the hippocampus you'll get pretty much just hallucinations and the effect can be used much more safely. The idea as far as motor neurons are concerned if my theory so far is correct, I would guess anyway, would be that activation of 5-HT2A suppresses the inhibitory actions of local GABA and therefore facilitates the activity of things that GABA would normally block, like dopamine receptors, and at higher doses could possibly even make the GABA excitatory. But here's where I have to make another leap of faith. What I wonder is, if 5-HT2A can suppress KCC2 in motor neurons, can it do it in the prefrontal cortex?
I admit, I'm always on the look for new explanations of how this system in the prefrontal cortex works, but I do think this is a pretty neat idea. Studies seem to show that 5-HT2A receptors are not directly involved in the development of schizophrenia, but that 5-HT2A inverse agonists can act as antipsychotics to help with the symptoms. They have been found to do this through the recepter heterodimer in the prefrontal cortex that inversely links 5-HT2A and metabotropic glutamate receptor 2 (mGluR2), and mGluR2 agonists have correspondingly been shown to be active as antipsychotics as well. So my first thought is of course that anything that lowered 5-HT2A activity would induce the activity of KCC2 if it worked that way, and if it was linked up in the prefrontal cortex as well then activation of mGluR2 could logically have the same effect. This interests me because of how I believe I can tie it in to the way oxytocin works in the prefrontal cortex. It induces the release of endocannabinoids which activate presynaptic CB1 receptors to inhibit local glutamate release, which leads to lowered activation of mGluR2. I've mentioned this before recently, it's how I believe cannabinoids and sexual practices like kundalini get there overlap with psychedelics. This lowered glutamate is known to cause anti-anxiety effects in healthy amounts, and this is likely at least in part because of its mGluR2 inhibition because 5-HT2A agonists can do the same. Psychedelics usually cause mainly euphoria in low to moderate doses, but the chances of things get much stranger increase dramatically the higher you dose.
The way I see it, in this theory that could be related to how little inhibitory activity of GABA people are comfortable with. It's the same kind of thing that makes some people freak out on weed while others don't; some people find that lower GABA can be rewarding by means of enhancing dopamine activity and the like while others just get anxious from it. So when you lower KCC2 activity, it's the same as blocking the regular inhibitory activity. The intense and cosmic alterations in perception that can come with psychedelics and sexual euphoria could then in this way come about from disinhibition of systems like dopamine, allowing there receptors to be more active than normal. And quite intriguingly to me, there have been some mGluR2 antagonists which were said to effect the activity of dopamine receptors in a manner resembling this.
And, of course... there's no proof, as I said. But wouldn't it be awesome? I just think the thing about how GABA switches from inhibitory to excitatory is so cool, if this theory is true it would be like those states of mind completely reconfigure your mind temporarily, which would be totally believable....
Sigh. Life is beautiful.
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