Depleting Serotonin Levels

[trainman04]

good now that we are done arguing lets get to the serotonin issue. if you dont wanna help its fine but lets stay on topic...

So technically say I had defective SERT, defective MAO-A and MAO-B... Now the previous poster said if your SERT was broken then your other parts would break down the serotonin and take care of it and balance it?So say I have defective sert and defective MAO. Would Increasing MAO Fix the High Serotonin even tho my SERT would still be broken? Also Does GABA reduce serotonin? Because Progesterone orally in high dosages (100mg) increases Both MAO a/B and GABA a/b.


Also Can somebody tell me how serotonin works in the body like the journey from the start to the end? I know this much:
tryptophan hydroxylase enzymes convert tryptophan to 5-hydroxytryptophan with the help of oxygen, iron and THB as co-factors. Second, AAAD and PLP enzymes combine to convert 5-hydroxytryptophan to serotonin. Then what happens??

 

[sekio]

If you have defective MAO enzymes or SERT then increasing expression of them isn't going to help.

 

[Cotcha Yankinov]

IIRC, animal models attempting to model humans with short forms (who tend to hypoexpress SERT) showed that one of the main issues could be issues with serotonin receptor sensitivity rather than issues with excessive synaptic serotonin. These animals who were genetically altered to hypoexpress SERT seemed to have issues with serotonin receptor sensitivity because of elevated synaptic serotonin occurring during a developing state of the brain (receptors are homeostatically regulated different then).

I am far from convinced that decreasing serotonin is barking up the right tree, however, there are some medications that block and desensitize serotonin receptors. As an example, some drugs block 5-HT2A, 5-HT2C and 5-HT7 receptors, and this can seem to have an anti-depressant effect. Too much 5-HT2A/5-HT2C activation seems to be no good for depression, but its hard to tell what exactly is going on.

Sensitization and activation of 5-HT1A receptors seems critical for antidepressant response to typical antidepressant therapies, so don’t forsake the role that activation of serotonin receptors can play in antidepressant response.

Not that we have any idea what problems you are actually hoping to treat.

 

[sekio]

Too much 5-HT2A/5-HT2C activation seems to be no good for depression

Damn, I'll have to abort my clinical trial where I give major depressive patients 500ug of blotter acid twice a day.

 

[trainman04]

If you have defective MAO enzymes or SERT then increasing expression of them isn't going to help.

of course it will. if they are slow due to a mutation it will help.

 

[trainman04]

IIRC, animal models attempting to model humans with short forms (who tend to hypoexpress SERT) showed that one of the main issues could be issues with serotonin receptor sensitivity rather than issues with excessive synaptic serotonin. These animals who were genetically altered to hypoexpress SERT seemed to have issues with serotonin receptor sensitivity because of elevated synaptic serotonin occurring during a developing state of the brain (receptors are homeostatically regulated different then).

I am far from convinced that decreasing serotonin is barking up the right tree, however, there are some medications that block and desensitize serotonin receptors. As an example, some drugs block 5-HT2A, 5-HT2C and 5-HT7 receptors, and this can seem to have an anti-depressant effect. Too much 5-HT2A/5-HT2C activation seems to be no good for depression, but its hard to tell what exactly is going on.

Sensitization and activation of 5-HT1A receptors seems critical for antidepressant response to typical antidepressant therapies, so don’t forsake the role that activation of serotonin receptors can play in antidepressant response.

Not that we have any idea what problems you are actually hoping to treat.

Yeah I will find out ,If Increasing SERT wont work for me then I guess I have sensetive serotonin receptors, that would make more sense I guess. does that mean my SERT is too fast/expressed and that leads to sensetive serotonin receptors? or could the SERT be normal just the receptors are sensetive?

 

[LucidSDreamr]

can someone explain more about how sert regulates 5ht levels in the synapse? how is the direction of 5ht controlled by it?

so does 5ht get into the synapse from the cell through sert?

 

[Cotcha Yankinov]

Damn, I'll have to abort my clinical trial where I give major depressive patients 500ug of blotter acid twice a day.

Don’t abort it! Just sneak it into their coffee

For OP's sake I'll give a caveat here that while 5-HT2A/5-HT2C overexpression is noted in some depression patients, the causality isn't clear with regards to whether that is an unrelated coincidence or if the 5-HT2A overexpression is actually causing the issues. A selective 5-HT2A antagonist didn't work very well for major depression.

Psychedelic activation of 5-HT2A on the other hand, right on %)

 

[sekio]

SERT is a monoamine transporter that transports serotonin from the synapse back into the cell, it's how your nerve cells re-use serotonin rather than having to make it de novo every time. Once a cell is depolarized (signals) then it can release e.g. serotonin into the synapse and then after it's had time to bind and effect other cells, the

The whole "short"/"long" forms of SERT is actually a misnomer, it's actually short and/or long forms of the gene promoter for the serotonin transporter, one has 14 and one has 16 repeats, hence it doesn't describe a mutated/defective protien rather than just decreased or increased expression of whatever SERT protien your genes have. So it's more of a SNP in the regulatory part of SERT expression than anything else.

The SERT promoter gene is not the only thing that determines SERT expression though, and certainly doesn't determine whether or not you'll have "too much" serotonin, it just means the half life in the brain is going to be slightly longer.

Keep in mind if this is a real genetic problem all the symptoms should be present from birth...

 

[Cotcha Yankinov]

can someone explain more about how sert regulates 5ht levels in the synapse? how is the direction of 5ht controlled by it?

so does 5ht get into the synapse from the cell through sert?

The bolded quote delineates how SERT operates in reverse facing conformation (e.g. with MDMA/serotonin releasing agents - where the SERT operates in reverse and pumps serotonin from the cytosol/inside the neuron, to out into the synapse).

Normally SERT takes in serotonin from the synapse and helps recycle serotonin, but its a bit dynamically regulated. For example, activation of a pre-synaptic autoreceptor like 5-HT1D can increase the amount of serotonin that SERT can transport.

As far as the direction, you may have more luck than I understand the symporter/sodium dependent bit. Another function of SERT related to the direction of 5-HT is to help terminate volume transmission, which serotonin and some other transmitters utilize.

Volume transmission is essentially where serotonin released at one terminal/varicosity can drift and travel a distance away to bind onto receptors elsewhere, rather than point-to-point communication where its traveling directly from a pre-synaptic terminal to a post-synaptic terminal directly across from it. If SERT did not exist, the serotonin could bounce around and travel quite some distance, binding and unbinding from different serotonin receptors a long way from where it was originally released.

 

[trainman04]

¨First, tryptophan hydroxylase enzymes convert tryptophan to 5-hydroxytryptophan with the help of oxygen, iron and THB as co-factors. Second, AAAD and PLP enzymes combine to convert 5-hydroxytryptophan to serotonin. Then Serotonin is stored in vesicles in the presynaptic terminal until a calcium signal induces the release of said vesicles. After being released into the synaptic cleft the seroronin acts on postsynaptic receptors. Thereafter it is either reuptaken into the presynaptic neuron by reuptake-enzymes or degraded.¨

what happens next? thats the end??

 

[Hodor]

¨First, tryptophan hydroxylase enzymes convert tryptophan to 5-hydroxytryptophan with the help of oxygen, iron and THB as co-factors. Second, AAAD and PLP enzymes combine to convert 5-hydroxytryptophan to serotonin. Then Serotonin is stored in vesicles in the presynaptic terminal until a calcium signal induces the release of said vesicles. After being released into the synaptic cleft the seroronin acts on postsynaptic receptors. Thereafter it is either reuptaken into the presynaptic neuron by reuptake-enzymes or degraded.¨

what happens next? thats the end??

The last sentence should be pretty self-explanatory. The serotonin is either reuptaken (so it can be released again at a later date) or degraded.

Anyway, are you aware that there are drugs that selectively block specific serotonin receptors? Suppressing the production of serotonin is generally a pretty bad idea, since serotonin regulates *a lot* of different things in your body. This is why modern antipsychotics target the 5HT2A and 5HT2C receptors (which, when overstimulated, cause feelings of anxiety/depression and even mania or psychosis), which might be more what you are looking for.

 

[trainman04]

The last sentence should be pretty self-explanatory. The serotonin is either reuptaken (so it can be released again at a later date) or degraded.

Anyway, are you aware that there are drugs that selectively block specific serotonin receptors? Suppressing the production of serotonin is generally a pretty bad idea, since serotonin regulates *a lot* of different things in your body. This is why modern antipsychotics target the 5HT2A and 5HT2C receptors (which, when overstimulated, cause feelings of anxiety/depression and even mania or psychosis), which might be more what you are looking for.

How and into what it is degraded?

are 5HT2A and 5HT2C the only receptors for anxiety? the other are not important? thats what your saying?

 

[doxylamine]

Serotonin is degraded (primarily) by Monoamine Oxidase A into 5-HIAL and then by Aldehyde Dehydrogenase into 5-HIAA.

There are other serotonin receptors that can be targeted for treating anxiety and depression. Primarily the 5-HT1A and IIRC the 5-HT7 receptors.

 

[trainman04]

ok heres another theory... is it possible I could have a broken/slow SERT + Sensetive serotonin receptors and LOW MAO - A activity? that should be rare and cause high serotonin right? or is there still something else in the brain that can break/reduce serotonin?

 

[Cotcha Yankinov]

There are multiple things that will compensate for chronically elevated synaptic serotonin. For starters, receptor downregulation and desensitization.

As Sekio has previously mentioned, things called pre-synaptic autoreceptors control the level of serotonin in the synapse as well - if the level of serotonin gets too high, the autoreceptors kick in and shut off serotonin cell firing and can also inhibit the ability of the vesicles containing serotonin to fuse with the cellular membrane and release serotonin into the synapse.

The enzyme that makes serotonin, tryptophan hydroxylase, is also dynamically regulated. Activation of autoreceptors decreases the expression of TPH and thus will act to homeostatically decrease serotonin release as well.

 

[trainman04]

There are multiple things that will compensate for chronically elevated synaptic serotonin. For starters, receptor downregulation and desensitization.

As Sekio has previously mentioned, things called pre-synaptic autoreceptors control the level of serotonin in the synapse as well - if the level of serotonin gets too high, the autoreceptors kick in and shut off serotonin cell firing and can also inhibit the ability of the vesicles containing serotonin to fuse with the cellular membrane and release serotonin into the synapse.

The enzyme that makes serotonin, tryptophan hydroxylase, is also dynamically regulated. Activation of autoreceptors decreases the expression of TPH and thus will act to homeostatically decrease serotonin release as well.

rs1049353 TT = The T allele of rs1049353 may cause lower receptor numbers and less activation. With this variation, the receptors also don't become significantly less sensitive when activated - i.e. you don't build up tolerance.

What if high serotonin is normal for my brain due to the mutations so the autoreceptors dont recognize it as high and dont do anything? I dont know im just clutching at straws.

But im so sure my problem is serotonin I would bet my life on it. I wish there was a way to prove it.

I remember when I took 5-htp 500mg... Oh my god I felt sick... my stomach .. dizzy... sweating... this was before I found out serotonin was my problem. the typical dosages are 300mg-500mg according to Examine.. So why did I feel sick when I took that normal dosage? All I could do was be in my bed and wait it out I couldnt eat and it lasted like 3 days the bad feeling I got from 5-htp.

I threw the 5-htp away first day I got it and since then I know I dont have low serotonin and many other occurences has happend after I took 5-htp that has lead me to belive I have high serotonin. I have high hopes In Increasing SERT.

 

[Cotcha Yankinov]

But im so sure my problem is serotonin I would bet my life on it. I wish there was a way to prove it.

I remember when I took 5-htp 500mg... Oh my god I felt sick... my stomach .. dizzy... sweating... this was before I found out serotonin was my problem. the typical dosages are 300mg-500mg according to Examine.. So why did I feel sick when I took that normal dosage? All I could do was be in my bed and wait it out I couldnt eat and it lasted like 3 days the bad feeling I got from 5-htp.

I threw the 5-htp away first day I got it and since then I know I dont have low serotonin and many other occurences has happend after I took 5-htp that has lead me to belive I have high serotonin. I have high hopes In Increasing SERT.

... I would not say that 500mg is a normal dose lol. That's pretty high, and some people are just sensitive to it. It can increase serotonin in the periphery (5-HTP doesn't cross the BBB and does not increase serotonin in the brain very well at all) and serotonin in the periphery can do a great job of causing nausea.

See for example chemotherapuetic mediated release of serotonin from enterochromaffin cells, these serotonergic cells in the gut can release serotonin into the periphery and stimulate nausea. So all the symptoms you mention can have entirely to do with acutely too much serotonin in the periphery.

.. No need to jump to "I too much serotonin in my brain" here.

Look, I've seen a lot of people tunnel vision on different things as the source of their issues. If its not one thing like serotonin, its another. But it never does them any good, and is very likely never the real source of their problems. I know you are absolutely convinced that serotonin is your problem, but the degree of which you are convinced of that has no bearing on how true it is.

Some people are absolutely convinced Elvis is still alive, or whatever. But they don't have any evidence for it, and I don't believe you have any actual evidence that "high serotonin" is your problem either - its simply a fixated belief that you're going to be better off without if you can learn to let go of it and go get real professional help.

 

[Hodor]

are 5HT2A and 5HT2C the only receptors for anxiety? the other are not important? thats what your saying?

If we’re only talking about serotonin receptors, then yes, 5HT2A and 5HT2C are the main culprits where over-activation can lead to mental illness. There‘s also 5HT1A, where over-activation can give you mania and under-activation can cause depression and anxiety. „Abilify“ is an antipsychotic that blocks 5HT2A and activates 5HT1A part-way, potentially hitting two birds with one stone.

5HT7 is a major suspect for another anxiety-inducing serotonin receptor, but most modern antipsychotics block it anyway already. Activation of 5HT3 is known to cause nausea and apparently also anxiety, but again, it is already blocked by a number of antipsychotics currently on the market (although higher selectivity for this receptor might be a goal for future drug candidates).

Basically, pharma companies have come up with far more advanced ways of dealing with serotonin receptors than just decreasing overall serotonin production.

 

[trainman04]

If we’re only talking about serotonin receptors, then yes, 5HT2A and 5HT2C are the main culprits where over-activation can lead to mental illness. There‘s also 5HT1A, where over-activation can give you mania and under-activation can cause depression and anxiety. „Abilify“ is an antipsychotic that blocks 5HT2A and activates 5HT1A part-way, potentially hitting two birds with one stone.

5HT7 is a major suspect for another anxiety-inducing serotonin receptor, but most modern antipsychotics block it anyway already. Activation of 5HT3 is known to cause nausea and apparently also anxiety, but again, it is already blocked by a number of antipsychotics currently on the market (although higher selectivity for this receptor might be a goal for future drug candidates).

Basically, pharma companies have come up with far more advanced ways of dealing with serotonin receptors than just decreasing overall serotonin production.

so something like Mirtazapine would be good in my case? blocks 5HT2A,5HT2C and 5ht3 but not 5-ht7 or 5HT1A ....