A final explanation of the 5HT1A autoreceptors - Sonny OP

[brman]

A final explanation of the 5HT1A autoreceptors (Originally posted by Sonny).

Now that I have explained this 10 million times, I'm going to make it a sticky. Let me try the backwards approach. What is the main thing causing this problem?

It is inhibition of dopamine receptors in general, particularly in and around the Raphe nucleus. Which is a small cluster of nuclei found in the brain stem. It's main function is to release serotonin to the rest of the brain. SSSRI antidepressants are believed to act in these nuclei. They are not damaged, they are not desensitized, there is nothing wrong with dopamine binding, and it is more complicated than there just not being enough dopamine release into the synapse.

It is actually being inhibited. So it doesn't just release too little as a continual problem, when levels increase, they increase by lower a percentage. This is the basis for much of what people experience in different ways, due to differing genes. The main idea is the dopamine release is being inhibited. So those other dopamine receptors down the line aren't getting what they need.

Serotonin receptors inhibit dopamine. That is because they act as a method of regulation. The more serotonin that binds to the heteroreceptor, the more dopamine release is inhibited. This receptor accepts binding of different neurotransmitters in different places, which have different affects on it, including regulation of dopamine release.

So why is an excessive amount of serotonin in the synapse, binding to the heteroreceptor?

It is because the autoreceptor is releasing too much serotonin into the synapse. So we have to figure out why that is. The autoreceptor is regulated by the same neurotransmitter, in this case serotonin. So the amount of serotonin which binds to it, controls how much serotonin it releases. Serotonin is generally inhibitory. So the more activation of this receptor, the more it's release of serotonin is inhibited.

The main cause of PSSD is the receiving part of the autoreceptor being desensitized. So the normal amount of serotonin that was the right amount to do the job, now causes LESS activation of the receptor, and therefore it's inhibitory effect on serotonin release is INSUFFICIENT.

Our autoreceptors didn't go back to normal. They are stuck in that desensitized state. So the normal amount of serotonin which has always been there is not enough to do the job.

So in order to get the same amount of activation you had before, you must have MORE serotonin there than is normal. You have to compensate for that lack of sensitivity.

It's kind of like when a button on a remote wears out. The normal amount of pressure won't send the signal. You have to press harder to get it to work. In the same way, we have to press harder on the autoreceptor.

Agonism is not the same as reuptake inhibition. The former just means there is more there, but it is taken up normally. The latter means it is not taken up normally, and it builds up too quickly, too much.

So an antagonist on the autoreceptor is going to exacerbate the very problem you have. You can't press the button more softly. You need an agonist, to inhibit the release of the receptor the same amount it used to before you got PSSD.

Hopefully this is clear, and we can move on.

[maev]

Can we get some papers on this? There was some tremendous discussion back in the old forums. I would like to present them to my doctor.

[Micromegas]

Can we get some papers on this? There was some tremendous discussion back in the old forums. I would like to present them to my doctor.

This article has a video and illustrations on the topic: http://psychopharmacologyinstitute.com/ ... ion-ssris/

[pete]

So when serotonin receptors are desensitized, how it comes i react very sensitive to everything that boosts serotonin (5-htp, vitamin d, ssri)?
Shouldn't we are desensitzied to serotonin boosters with pssd or did i get anything wrong of the theory?

[Ghost]

So when serotonin receptors are desensitized, how it comes i react very sensitive to everything that boosts serotonin (5-htp, vitamin d, ssri)?
Shouldn't we are desensitzied to serotonin boosters with pssd or did i get anything wrong of the theory?

You likely respond quickly because you already have high levels of synaptic serotonin. By adding more...you are worsening an existing problem. SSRI's and 5-ht will both raise serotonin levels beyond the heightened levels that you already have. SSRI's block re-uptake of serotonin, and 5-htp is the precursor to serotonin.

[pete]

But if the receptors are desensitised i would need more than the normal recommended dose of 5-htp to get the same effect and not less, no matter how high the serotonin levels already are.

And why is sleep deprevation (which is supposed to raise serotonin as well) allevating pssd symptopms then? questions over questions...
http://www.pnas.org/content/111/29/10761.short

[Ghost]

But if the receptors are desensitised i would need more than the normal recommended dose of 5-htp to get the same effect and not less, no matter how high the serotonin levels already are.

The only side that's desensitized is the pre-synaptic side. Most of the PSSD problems come from there being too much serotonin on the post-synaptic side. Adding 5htp will release more serotonin from the pre-synaptic side, and therefore there will be more on the post synaptic side. You'd need more 5htp to activate the desensitized auto-receptor on the pre-synaptic side, yes, but a big part of this is the excess serotonin on the post-synaptic side.

And why is sleep deprevation (which is supposed to raise serotonin as well) allevating pssd symptopms then? questions over questions...
http://www.pnas.org/content/111/29/10761.short

There is a thread about this somewhere on the old forum...ah-ha!



SLeep deprivation and the link to finding a cure

PSSD collaborative research :: Forums :: Treatments and experimentation

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SLeep deprivation and the link to finding a cure

Post az89 on Fri May 09, 2014 5:12 pm

I've posted about it before, sleep deprivation >95% of time completely cures all of my symptoms (I's 9:11am right now, havn't slept and i can experience again), and also makes me feel how i used too before anti depressants (I only realise how bad my normal state of lack of excitement anhedonia is while in this sleep deprived state). Look into what happens to the receptors during sleep deprivation and you can find the mechanism for why we are the way we are now. Which then means you can target it with specific agonists/antagonists.

forgive me for the horrible punctuation and coherence but i really cbf reading thru it as my concentration is severely lacking right now.


nvm okiy gaiz it's really simple, i turn into geniouz mode with no sleeperinos

5ht (serotonin levels) is increased in the brain stem (Dorsal raphe nuclei) from sleep deprivation. This is where the 5ht1a autoreceptors are. Binding/Activating these particular receptors inhibits 5ht release in the other parts of the brain (WE WANT THIS). SSRI's also increase 5ht levels in the brain stem dramatically, so high that they eventually desensitise our 5ht1a autoreceptors... (This is what is considered the "therapeutic benefit" and why there is some weeks delay before it happens when you first start taking them, AKA this fucking HELL we are IN!!!!). For some reason our 5ht1a autoreceptors are permanently desensitized/down regulated through an unknown mechanism, after all this is what SSRI's target, and i have no idea why because there is a dramatic increase in happyness and emotion as soon as the complete opposite occurs!!! - Fuck their retarded studies!!! I think this receptor determines whether or not we are happy OR sad, because i can basically feel both now, depends what is bothering me... IT JUST MEANS YOUR NORMAL. For depressed people with horrible things going on in their lives, it makes sense to drain out this receptor, and make it non responsive, they basically become numb to the pain. I was never depressed before SSRI's so i don't care if this receptor returns to normal function, it means i'll be normal again. Perhaps this is why they target this receptor desensitization, BUT I'D LIKE TO POINT OUT TO THE STUDIES THAT being numb and forgetting about your pain IS NOT THE SAME THING as not being depressed.

Points to consider:
-If SSRI's can increase 5ht in the brain stem, would a realllly low dosage of them be able to help??? Remember high serotonin levels in the brain are bad - but in the brain stem it is good. 5ht1a autoreceptor activation inhibits serotonin release in most of the brain! - Probably won't work because they will still activate all the serotonin in the brain
-Can anyone successfully obtain a 5ht1a autoreceptor agonist??
-If the outcome of 5ht1a autoreceptor activation means serotonin inhibition in most of the brain, then a heavily carb restricted diet can help as it basically makes it so you have really low serotonin levels.
-Carbs bloat the shit out of me, i feel more normal without them... ever since SSRI's i bloat and have a lot of gas, there are a lot of serotonin receptors in the gut, would make sense that i have high serotonin levels

Disclaimer : Could be wrong Smile

Only 5ht1a autoreceptor agonist i could find was Idazoxan - http://www.sciencedirect.com/science/ar ... 4096131323
Also that drug has been studied for desire/sexual dysfunction and found to be of help at least in rat studies. http://onlinelibrary.wiley.com/doi/10.1 ... 5367.x/pdf


Sources: http://www.readcube.com/articles/10.1016/S0893-133X(97)00025-0
and me.

[pete]

Thank you Ghost. Nice informations.

[MostlyLurks]

Yeah, thanks Ghost! I finally picked up on the fact that the sleeplessness produced by the huperzine A and choline is what you want. Is this related to why I only get brain zaps when I'm tired anymore? When I was on the SSRI I could get them any time, especially when I was changing doses, but now (four years after quitting) I only get them when I'm really, really tired.

Also, thanks Sonny, for the original stickied post. Great stuff, man.

[Sonny]

You're quite welcome, MostlyLurks. Glad I could help.