TAAR1's role in the pharmacodynamic actions of Trace-Amines/Phenethylamine-Derivative

[Lightning-Nl]

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Background info

The Trace amine-associated receptor was discovered almost a decade ago, but it's been implicated in mediating effects of many stimulant, empathogenic, and hallucinogenic drugs. Most of which are Phenethylamine derivatives. Why is this? Most likely because the endogenous ligands for the TAAR is Phenethylamine and Amphetamine itself.

That's right internet. Amphetamine is actually produced within the body and is an endogenous ligand of the TAAR. Okay - it's technically not amphetamine. However, a derivative of Phenethylamine that is synthesized naturally within the human body has the same chemical formula as Amphetamine. N-Methylphenethylamine which is considered to be a structural isomer of amphetamine [source] has the same chemical formula as amphetamine - C9H13N.

However, many other trace-amines are ligands of the TAAR. All of those being... [Source] [Source] [Source]

• Phenethylamine
• N-Methylphenethylamine
• p-Tyramine
• Octopamine
• m-Tyramine
• Dopamine
• Tryptamine
• Histamine
• 5-Hydroxytryptamine (Serotonin)
• Norepinephrine

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The mechanism of the Trace amine-associated receptor

TAAR receptors are located in the presynaptic area of a neuron. It's found on every neuron associated with the monoamines "trace amines" - Dopamine, Norepinephrine, Epinephrine, Histamine, and Serotonin. TAAR1 is found only in Dopamine-related, Norepinephrine-related, Epinephrine-related, and possibly even Histamine-related neurons and systems. It's primary function is believed to be the opposite of an autoreceptor. It "measures" the amount of pre-synaptic neurotransmitters and reverses protein carrier function of the uptake cells if levels of agonizing ligands are agonizing TAAR in the presynaptic neuron (which is an indication of high levels of hormones).

The immediate result of TAAR agonism is the introduction of Adenyl Cyclase into the cell. This reacts immediately with Kinase proteins to induce the production of cAMP (Cyclic Adenosine Monophosphate). This is where things start to get really interesting.[Source] [Source] This results in an immediate interaction with the trace-amines in the pre, and postsynaptic neuron.

I searched far and wide, but this is the only study I could find on the proposed mechanism of how this induces the output of the trace-amines into the synapse. So, I can't claim any of this is fact. However, this (summary) is what the study proposed as a schematic.[Source]

Synaptic dopamine binds to the dopamine autoreceptor, which activates the DAT. Dopamine enters the presynaptic cells and binds to TAAR1, which increases adenylyl cyclase activity. This eventually allows for the translation of trace amines in the cytoplasm and activation of cyclic nucleotide-gated ion channels, which further activate TAAR1 and dump dopamine into the synapse. Through a series of phosphorylation events related to PKA and PKC, active TAAR1 inactivates DAT, preventing uptake of dopamine from the synapse. The presence of two presynaptic receptors with opposite abilities to regulate monoamine transporter function allows for regulation of the monoaminergic system.

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Relation to Amphetamine's MOA

Using Amphetamine as an example - I'll explain why this is incredibly important to the mechanism of action of drugs that effect this receptor.

Most drugs that could be agonists at TAAR can't gain access to it because it's located in the presynaptic cell. Amphetamine, however, gains access to TAAR through VMAT2. Amphetamine can enter the cell through direct diffusion of the cell membrane, or it can be carried directly into the cell by Vesicular Transporter and the Dopamine Transporter (DAT). By occupying these proteins - amphetamine acts as a competitive inhibitor of DAT and VMAT2 by "competing" with the endogenous ligands for binding affinity.

Once amphetamine gets inside of the cell - it binds with high affinity to the TAAR1 receptor. The half-maximal response that amphetamine induces upon this receptor is something like 6.5 if I remember correctly. Through activation of TAAR1, amphetamine allows the production of cAMP. This phosphorylates the Dopamine transporter which, upon phosphorylation, start to carry Dopamine out of the cell. Because amphetamine is exploiting one of the bodies natural ways of monitoring levels of the trace-amines - the body believes that levels of trace-amines in the post-synaptic neurons is dangerously low.

So it immediately dumps as much ligands as it can into the post-synaptic neuron. Normally, all of these chemicals would renter the post-synaptic neuron, but amphetamine inhibits reuptake, literally by occupying the vesicles where the endogenous ligands would be. Thus not allowing them into the cell and disallowing reuptake.

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While Amphetamine agonizes TAAR, it can only agonize receptors that it's able to gain access to. While amphetamine can gain access to Dopamine and Norepinephrine related neurons with ease - it's affinity for such an action at the SERT is minuscule in comparison - it does exist however. Amphetamine is able to diffuse into Serotonergic neurons and influence the SERT in the same way it does with VMAT2 (TAAR1 agonism). Amphetamine, however, does not inhibit the SERT to the same extent as the DAT and NET. Amphetamine enters the Serotonergic vesicles with the same ease as the Dopamine, and Norepinephrine containing vesicles (as far as I'm aware).

This makes Amphetamine's ability to influence Serotonin to the extent of Methamphetamine, very small. Why is this? Amphetamine lacks formidable binding affinity to the TAAR subtype located in 5HT-related cells. Amphetamine can only influence Sertonergic neurons that have TAAR1 expressed.

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Relation to Methamphetamine

Methamphetamine has all the same actions as Amphetamine (so what was stated above) but with much higher affinity for Serotonergic neurons and sertonergic action. Methamphetamine is able to competitively inhibit SERT function as well as agonize TAAR1 in Serotonergic neurons much more readily than Amphetamine.

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Well that about sums things up. Any input on this information would be appreciated. I'm interested in hearing thoughts, reservations and revelations based on this fascinating information. As always - thanks for your time. I hope you enjoyed the information!

SwampFox

 

[ebola?]

It "measures" the amount of pre-synaptic neurotransmitters and reverses protein carrier function of the uptake cells if levels of agonizing ligands are agonizing TAAR in the presynaptic neuron (which is an indication of high levels of hormones).

This is essentially right, but the wording confused me a bit. Do you mean that agonism at TAAR induces monoaminergic efflux? That sounds correct to me.

However, a derivative of Phenethylamine that is synthesized naturally within the human body has the same chemical formula as Amphetamine. N-Methylphenethylamine which is considered to be a structural isomer of amphetamine [source]

No, n-methylphenethylamine is argued to be exogenous by that source you cite. I thought that PEA itself was thought to be the most key endogenous ligand for TARR1.

Synaptic dopamine binds to the dopamine autoreceptor, which activates the DAT. Dopamine enters the presynaptic cells and binds to TAAR1, which increases adenylyl cyclase activity. This eventually allows for the translation of trace amines in the cytoplasm and activation of cyclic nucleotide-gated ion channels, which further activate TAAR1 and dump dopamine into the synapse. Through a series of phosphorylation events related to PKA and PKC, active TAAR1 inactivates DAT, preventing uptake of dopamine from the synapse. The presence of two presynaptic receptors with opposite abilities to regulate monoamine transporter function allows for regulation of the monoaminergic system.

Ah, interesting. so here we have a more complex set of mechanisms by which the brain maintains homeostasis of synaptic monoamines. Now, I wonder what the effects of monoaminergic agonism (both at receptors and transporters) might be on genetic transcription of TARR1.

Most drugs that could be agonists at TAAR can't gain access to it because it's located in the presynaptic cell.

Actually, it's currently unclear whether TAAR1 resides primarily intracellularly.

Because amphetamine is exploiting one of the bodies natural ways of monitoring levels of the trace-amines - the body believes that levels of trace-amines in the post-synaptic neurons is dangerously low.

So it immediately dumps as much ligands as it can into the post-synaptic neuron.

Actually, it is currently unclear how important activity at TAAR1 is in explaining amphetamine's effects.

While Amphetamine agonizes TAAR, it can only agonize receptors that it's able to gain access to. While amphetamine can gain access to Dopamine and Norepinephrine related neurons with ease - it's affinity for such an action at the SERT is minuscule in comparison - it does exist however. Amphetamine is able to diffuse into Serotonergic neurons and influence the SERT in the same way it does with VMAT2 (TAAR1 agonism)

It's actually unclear that TAAR1 agonism induces transporter reversal or inhibits transporter activity for SERT. Also, amp further affects VMAT2 more directly.

ebola

 

[Lightning-Nl]

No, n-methylphenethylamine is argued to be exogenous by that source you cite. I thought that PEA itself was thought to be the most key endogenous ligand for TARR1.

I've never come across that information. I'm not saying you're wrong, however, many of the studies list N-methylphenethylamine as an endogenous trace-amine. Maybe the precursor to it comes from external sources? And then it gets metabolized into NMPEA? Either way, I'm going by information that I know.

Ah, interesting. so here we have a more complex set of mechanisms by which the brain maintains homeostasis of synaptic monoamines. Now, I wonder what the effects of monoaminergic agonism (both at receptors and transporters) might be on genetic transcription of TARR1.

There was way more information in that study then what I wrote as the summary. You should really check it out. It's quite fascinating.

Actually, it's currently unclear whether TAAR1 resides primarily intracellularly. Actually, it is currently unclear how important activity at TAAR1 is in explaining amphetamine's effects. It's actually unclear that TAAR1 agonism induces transporter reversal or inhibits transporter activity for SERT. Also, amp further affects VMAT2 more directly.

ebola

Actually, there's no evidence suggesting one way or another if TAAR1 resides outside of cells. What we do know is what I've stated in this thread. What we know as fact right now is that TAAR1 receptors are found within the presynaptic cell. Actually, it's totally clear how important Amphetamine's effects on TAAR are. All you have to do is read the studies I provided. Amphetamine mimics Phenethylamine at the receptor and induces the exact same reaction as Phenethylamine at the TAAR.

I already explained how important TAAR is for monoaminergic regulation. I don't see why you think that Amphetamine's TAAR1 agonism couldn't be the key factor behind Amphetamine's such strong stimulant actions - especially since TAAR1 agonism is responsible for some inhibition of DAT, and the outflow of trace-amines into the synapse.

Actually, I stated in the thread that Amphetamine does no reverse transporters at the SERT. It only has affinity for some Serotonin Uptake vesicles - and it's only action there is inhibition of Serotonin reuptake.

 

[ebola?]

Actually, there's no evidence suggesting one way or another if TAAR1 resides outside of cells. What we do know is what I've stated in this thread. What we know as fact right now is that TAAR1 receptors are found within the presynaptic cell.

The question is of how close the receptor lies to the membrane, not whether it's inside or outside of the cell. Pre and postsynaptic cells are both quite responsive to synaptic ligands; think of chemotransmission not as a water pistol being shot but more like a bucket of soluble dye being dumped into a swimming pool.

All you have to do is read the studies I provided.

I did, and they indicated that no conclusion has been arrived at as to whether the TAAR1 receptor resides in the membrane or not.

I've never come across that information. I'm not saying you're wrong, however, many of the studies list N-methylphenethylamine as an endogenous trace-amine. Maybe the precursor to it comes from external sources? And then it gets metabolized into NMPEA? Either way, I'm going by information that I know.

I came across that information in the very source you linked! Besides, though epinephrine is also n-methylated, i don't know if it is plausible that other endogenous trace amines are as well.

I already explained how important TAAR is for monoaminergic regulation. I don't see why you think that Amphetamine's TAAR1 agonism couldn't be the key factor behind Amphetamine's such strong stimulant actions - especially since TAAR1 agonism is responsible for some inhibition of DAT, and the outflow of trace-amines into the synapse.

That's not what I claimed. Rather, again, I said that no consensus has yet been arrived at.

It only has affinity for some Serotonin Uptake vesicles

No, amphetamine doesn't have affinity for 5ht-containing vesicles.

ebola

 

[sekio]

many of the studies list N-methylphenethylamine as an endogenous trace-amine. Maybe the precursor to it comes from external sources? And then it gets metabolized into NMPEA? Either way, I'm going by information that I know.

Given the close similarity of many of the amines, I'd expect a small amount of enzymatic N-methylation of anything resembling a phenethylamine.

I don't see why you think that Amphetamine's TAAR1 agonism couldn't be the key factor behind Amphetamine's such strong stimulant actions - especially since TAAR1 agonism is responsible for some inhibition of DAT, and the outflow of trace-amines into the synapse.

Indeed, it seems TAAR does certainly play a mediating role in at least the release of dopamine and other monoamines.[1][2] However I don't think it's responsible for the entirety of amphetamine's action. In fact, studies with TAAR knockout mice suggest that presence of TAAR1 actually reduces sensitivity to amphetamine's stimulating effects. (knockout mice have a higher sensitivity to amphetamine).

Taar1 Knockout Mice Display Elevated Sensitivity to Amphetamine. The effect of d-amphetamine on the locomotor function of Taar1–/– and Taar1+/+ littermates was compared (Fig. 3). A dose of 1 mg/kg d-amphetamine caused a significant increase in locomotor activity in Taar1–/– animals (P < 0.05), but not in wild-type siblings, whereas no difference was observed in vehicle-treated animals (Fig. 3a). A higher dose of d-amphetamine (2.5 mg/kg i.p.) significantly increased locomotor activity also in wild-type animals (P < 0.05), but the effect was substantially stronger in Taar1–/– animals than in wild-type littermates (P < 0.05) (Fig. 3b).

This makes Amphetamine's ability to influence Serotonin to the extent of Methamphetamine, very small. Why is this? Amphetamine lacks a capable molecular formula to enter Serotonergic neurons to a formidable extent.

Amphetamine is actually really good at crossing cell walls, it's just that it lacks significant affinity for serotonin transport protiens.

[1] Trace Amine-Associated Receptor 1 Is a Modulator of the Dopamine Transporter, Zhihua Xie and Gregory M. Miller, doi: 10.1124/jpet.106.117382 JPET April 2007 vol. 321 no. 1 128-136
[2] Modulation of Monoamine Transporters by Common Biogenic Amines via Trace Amine-Associated Receptor 1 and Monoamine Autoreceptors in Human Embryonic Kidney 293 Cells and Brain, Synaptosomes Zhihua Xie, Susan V. Westmoreland and Gregory M. Miller, doi: 10.1124/jpet.107.135079 JPET May 2008 vol. 325 no. 2 629-640
[3] Trace Amine-Associated Receptor 1 Modulates Dopaminergic Activity, Lothar Lindemann, et al., doi: 10.1124/jpet.107.132647 JPET March 2008 vol. 324 no. 3 948-956

 

[Lightning-Nl]

No, amphetamine doesn't have affinity for 5ht-containing vesicles.

Quite the opposite actually. Amphetamine has all the same effects on the SERT as it does on NET an DAT. The difference is - Amphetamine is unable to influence an effect on Serotonin containing vesicles that don't have a TAAR1 receptor. (As Sekio said, it has only minuscule affinity for SERT proteins )

Also, NMPEA is produced naturally inside the human body by phenylethanolamine N-methyltransferase. With Phenethylamine itself acting as the substrate.

I would have given you studies, but I'm on a mobile device. Studies can be provided upon request, however, all the information above was easily accessible via Google

 

[sekio]

Quite the opposite actually. Amphetamine has all the same effects on the SERT as it does on NET an DAT.

Really? The EC50 of serotonin release for amphetamine is very high compared to DA/NE release. Amphetamine is 100-1000x better at releasing DA and NE than serotonin.
(EC50, nM)[ref]
NET: 7.07 ± 0.95
DAT: 24.8 ± 3.5
SERT: 1,765 ± 94

BTW, being on a cellphone is a lame excuse not to post pubmed citartions.

 

[Lightning-Nl]

Really? The EC50 of serotonin release for amphetamine is very high compared to DA/NE release. Amphetamine is 100-1000x better at releasing DA and NE than serotonin.
(EC50, nM)[ref]
NET: 7.07 ± 0.95
DAT: 24.8 ± 3.5
SERT: 1,765 ± 94

BTW, being on a cellphone is a lame excuse not to post pubmed citartions.

I suspect you didn't read my post entirely. Amphetamine has all the same actions at the SERT. It has no where near the same inhibition affinity on the SERT as on DAT or NET, and it appears that the only cells that Amphetamine can influence Serotonergic effects on are the ones that possess TAAR receptors.

 

[Lightning-Nl]

BTW, being on a cellphone is a lame excuse not to post pubmed citartions.

Not if you have a shitty cell phone. Anyways, here's the studies on NMPEA proving what I said.

http://link.springer.com/article/10.1007/BF00505743
http://www.sciencedirect.com/science/article/pii/S0163725809002174 (Doesn't really talk about NMPEA specifically, but rather encompasses all trace-amines)

Here is the proof that Amphetamine has direct effects on Serotonergic neurons and cells.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005101/ (I apologies for the length of this study. I very much suggest you read all of it however. It provides a very clean, full picture of TAAR and it's subtypes and how they affect the body. If you're only interested about the Sertoninergic information - skip to the paragraph "TAAR1 is expressed in brain monoaminergic systems". It talks about Serotonin and the effects that TAAR has in relation to Serotonin)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2830119/ (Pretty much the same idea as the one above. However, it's an actual study recommending the nomenclature of TAAR - but it explains in depth, it's function and while it encompasses all monoaminergic systems - it has some specific information on Serotonin)

 

[ebola?]

Quite the opposite actually. Amphetamine has all the same effects on the SERT as it does on NET an DAT. The difference is - Amphetamine is unable to influence an effect on Serotonin containing vesicles that don't have a TAAR1 receptor. (As Sekio said, it has only minuscule affinity for SERT proteins )

Perhaps you missed my larger point, that having affinity for a vesicle (which doesn't really make sense, as vesicular membranes don't except ligands for binding as receptors do) is a distinct thing from having affinity for a transporter.

http://link.springer.com/article/10.1007/BF00505743

This article argues that phenethylamine has a low affinity for phenylethanolamine N-methyltransferase.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3005101/ (I apologies for the length of this study. I very much suggest you read all of it however. It provides a very clean, full picture of TAAR and it's subtypes and how they affect the body. If you're only interested about the Sertoninergic information - skip to the paragraph "TAAR1 is expressed in brain monoaminergic systems". It talks about Serotonin and the effects that TAAR has in relation to Serotonin)

While I will concede that amphetamine might induce 5ht efflux indirectly via TAAR1 agonism, it also appears to be the case that binding to transporters is crucial for increased TAAR1 activity. Again, given amphetamine's poor affinity for SERT, these effects should prove relatively minor.

ebola

 

[Hammilton]

If TAAR is expressed in a location where the ligand can't access it, and it can only be accessed by being transported, then the lack of SERT affinity starts to seem much more important. Since that seems to be the case, it would seem that amphetamine does not have the same effect on serotonergic neurons as DA/ NA-ergic ones, don't you think? You need to consider all the facts to make informed statements.

 

[ebola?]

Yeah, that was essentially the point I was trying to make, though diffusion into serotonergic neurons expressing TAAR1 sans facilitation via binding at SERT likely occurs to some minute extent, and a tad moreso with meth.

ebola

 

[Lightning-Nl]

If TAAR is expressed in a location where the ligand can't access it, and it can only be accessed by being transported, then the lack of SERT affinity starts to seem much more important. Since that seems to be the case, it would seem that amphetamine does not have the same effect on serotonergic neurons as DA/ NA-ergic ones, don't you think? You need to consider all the facts to make informed statements.

I never said that Amphetamine had the same "effects" on the SERT as the others. If I had said that - that would have been incorrect. However, Amphetamine does in fact, have all of the same actions at the SERT as as it does at the DAT and NET. It's affinities for action there, however, are pale in comparison to it's affinities for the DAT/NET.

Yeah, that was essentially the point I was trying to make, though diffusion into serotonergic neurons expressing TAAR1 sans facilitation via binding at SERT likely occurs to some minute extent, and a tad moreso with meth.

ebola

Exactly. Amphetamine is still, very easily, able to enter Serotonergic cells via diffusing through the membrane. It's just unable to competitively inhibit the transporter proteins to the same extent that it does at the DAT/NET.

 

[Hammilton]

I don't think it's very easy. Cell walls are tough. Possible reason why meth has stronger serotonergic action, it's just better able to make it through.

 

[Geaux Tigers!]

Interesting thread! Really enjoyed reading the theoretical science behind TAAR1. I learned a lot about how amphetamine and pharmacology work from reading this thread. Very enjoyable. So, if its not SwampFox's mechanism that explains amphetamine's psychostimulation-- then what is? And, please explain it in a "complicated" way if that makes sense lol.

 

[Lightning-Nl]

Quite the opposite actually. Amphetamine has all the same effects on the SERT as it does on NET an DAT.

Really? The EC50 of serotonin release for amphetamine is very high compared to DA/NE release. Amphetamine is 100-1000x better at releasing DA and NE than serotonin.
(EC50, nM)[ref]
NET: 7.07 ± 0.95
DAT: 24.8 ± 3.5
SERT: 1,765 ± 94

BTW, being on a cellphone is a lame excuse not to post pubmed citartions.

I suspect you didn't read my post entirely. Amphetamine has all the same actions at the SERT. It has no where near the same inhibition affinity on the SERT as on DAT or NET, and it appears that the only cells that Amphetamine can influence Serotonergic effects on are the ones that possess TAAR receptors.

Just retread this.

Wow I feel like a dumbass. You're right sekio - I did say effects and I meant that too. But when I read your post I realize that I had not properly explained what I believed the mechanism was.

I honestly read my post so I could read it as I wanted it to be. Fascinating. And concerning - because it makes me wonder just how often I do that. But anyways. I apologies for that because that was just plain stupid.

Maybe I should have someone proofread my posts? \:

 

[Lightning-Nl]

^^
EDIT: eh... Yeah. This was mainly my unstable mood talking. So pretty much ignore this. Although my original point I do agree with.

I need to pay more attention to my posts

 

[Seppi]

I'm sure swampfox knows who I am - I made an account literally just to reply to this thread.



N-methylphenethylamine is endogenous and produced by Phenylethanolamine N-methyltransferase with PEA as a (high affinity) substrate (i.e., a nontrivial amount is produced, similar to PEA and dopamine with AADC). The fairly complete metabolic pathway for phenethylaminergic trace amines is here: https://en.wikipedia.org/wiki/Phenylethanolamine_N-methyltransferase
The sources I used to make it are listed in the associated image page, but just to link them here: https://www.ncbi.nlm.nih.gov/pubmed/15860375?dopt=Abstract and https://www.ncbi.nlm.nih.gov/pubmed/19948186?dopt=Abstract

I'll also point out that this article - http://link.springer.com/article/10.1007/BF00505743 - calls "PEA" phenylethANOLamine (no clue why), not phenethylamine. PEA has comparable affinity at PNMT to norepi. Humans also have both NMT and PNMT - both enzymes act on PEA.


Rat indices - like Ki and EC50 don't translate well to humans, unless expressing rhTAAR1 (an engineered hybrid), as rTAAR1 and hTAAR1 have a divergent genetic sequence. (ref - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236098/ )


Amphetamine produces significant activity in serotonin neurons co-localized with TAAR1 - its effects on SERT are weaker than DAT or NET, but the reason for this hasn't been conclusively determined yet. Simply due to the fact that amphetamine can induce serotonin syndrome in overdose, it's evident that its effects on serotonin are not as weak as they are in rats; probably worth stating that there are other notable pharmacodynamic differences between humans and rats besides TAAR1 as well. Its activity in serotonin neurons is otherwise analogous to dopamine and norepi, since it is a substrate for all three membrane transporters and VMAT2 (plus a few non-neuronal transporters). See the image in https://en.wikipedia.org/wiki/Amphetamine#Pharmacodynamics for reference.

If you have questions about the compound, feel free to post them here: https://en.wikipedia.org/wiki/Talk:Amphetamine

 

[Seppi]

Forgot to add, the evidence that TAAR1 is presynaptic and located inside the membrane is summarized in this review: https://www.ncbi.nlm.nih.gov/pubmed/21073468

 

[Lightning-Nl]

I'm sure swampfox knows who I am - I made an account literally just to reply to this thread.



N-methylphenethylamine is endogenous and produced by Phenylethanolamine N-methyltransferase with PEA as a (high affinity) substrate (i.e., a nontrivial amount is produced, similar to PEA and dopamine with AADC). The fairly complete metabolic pathway for phenethylaminergic trace amines is here: https://en.wikipedia.org/wiki/Phenylethanolamine_N-methyltransferase
The sources I used to make it are listed in the associated image page, but just to link them here: https://www.ncbi.nlm.nih.gov/pubmed/15860375?dopt=Abstract and https://www.ncbi.nlm.nih.gov/pubmed/19948186?dopt=Abstract

I'll also point out that this article - http://link.springer.com/article/10.1007/BF00505743 - calls "PEA" phenylethANOLamine (no clue why), not phenethylamine. PEA has comparable affinity at PNMT to norepi. Humans also have both NMT and PNMT - both enzymes act on PEA.


Rat indices - like Ki and EC50 don't translate well to humans, unless expressing rhTAAR1 (an engineered hybrid), as rTAAR1 and hTAAR1 have a divergent genetic sequence. (ref - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236098/ )


Amphetamine produces significant activity in serotonin neurons co-localized with TAAR1 - its effects on SERT are weaker than DAT or NET, but the reason for this hasn't been conclusively determined yet. Simply due to the fact that amphetamine can induce serotonin syndrome in overdose, it's evident that its effects on serotonin are not as weak as they are in rats; probably worth stating that there are other notable pharmacodynamic differences between humans and rats besides TAAR1 as well. Its activity in serotonin neurons is otherwise analogous to dopamine and norepi, since it is a substrate for all three membrane transporters and VMAT2 (plus a few non-neuronal transporters). See the image in https://en.wikipedia.org/wiki/Amphetamine#Pharmacodynamics for reference.

If you have questions about the compound, feel free to post them here: https://en.wikipedia.org/wiki/Talk:Amphetamine

This is what I needed. Thanks Seppi ;P It's appreciated and it's the message I've been trying to get across