Introducing: The trace amine receptor

[ChuangTzu]

I came across a few abstracts the other day which mentioned a family of receptors, the trace-amine-associated receptors (TAR/TAAR). I didn't find anything when I searched the forums so I thought I'd summarize what little I could find about them. Here's what I've dug up so far:

Primate TA1 receptors are direct targets of trace amines, amphetamine, and MDMA:

The trace amines tyramine and {beta}-phenylethylamine (PEA) and the monoamine transporter substrates (±)-amphetamine and (±)-MDMA stimulated cAMP accumulation in rhTA1-expressing cell lines, as measured by a cAMP response element-luciferase assay. Cocaine did not stimulate cAMP accumulation in rhTA1 cells, but it blocked [3H]PEA transport mediated by the dopamine transporter. Cotransfection with the human dopamine transporter enhanced PEA-, amphetamine-, and MDMA-mediated rhTA1 receptor activation, but it diminished tyramine activation of rhTA1. Because TA1 (EGFP-rhTA1 chimera) was largely intracellular, conceivably the dopamine transporter can facilitate access of specific agonists to intracellular TA1. rhTA1 mRNA expression was detected in rhesus monkey substantia nigra, implying that TA1 may be colocalized with the dopamine transporter in dopamine neurons. In summary, primate TA1 receptors are direct targets of trace amines, amphetamine, and MDMA. These receptors could also be indirect targets of amphetamine, MDMA, and cocaine through modification of monoamine transporter function.

The trace amine receptor 4 gene is not associated with schizophrenia in a sample linked to chromosome 6q23.
[No abstract available]

TRAR4 may or may not be associated with schizophrenia:

Recent study of linkage disequilibrium mapping showed one of the trace amine receptor (TRAR) genes, TRAR4, was associated with schizophrenia. We conducted a replication study of TRAR4 with schizophrenia in Japanese patients. We used two large independent sets of samples in a first-set analysis (cases=405, controls=401) and second-set analysis (cases=503, controls=440). In the first-set analysis, one Marker (Marker5) showed a significant association, but this significance was not seen in the second-set analysis. Our results indicate that TRAR4 may not play a major role in Japanese schizophrenia patients, and that it is important to examine the possibility of false positives in genetic association analysis.

TAR may be involved in the efficacy of L-dopa in treatment of Parkinson's disease:

In this article, we discuss evidence that suggests that dopamine produced from L-dopa has a larger number of actions compared with dopamine receptor agonists. In addition to stimulating D1- and D2-like dopamine receptors, dopamine might also activate adrenoceptors, novel dopamine sites, the dopamine transporter and trace amine receptors, all of which might contribute to the superior effect of L-dopa in Parkinson's disease.

An anxiolytic role for DMT:

The recent discovery of a G-protein-coupled, human trace amine receptor has triggered a reappraisal of the role of compounds present in limited concentrations in biological systems. Interestingly enough, DMT and other psychoactive tryptamine hallucinogens elicit a robust response at the trace amine receptor. While it is currently accepted that serotonin 5-HT(2A) receptors play a pivotal role in the activity of hallucinogenic/psychedelic compounds, we propose that the effects induced by exogenous DMT administration, especially at low doses, are due in part to activity at the trace amine receptor. Furthermore, we suggest that endogenous DMT interacts with the TA receptor to produce a calm and relaxed mental state, which may suppress, rather than promote, symptoms of psychosis. This hypothesis may help explain the inconsistency in the early analysis of endogenous DMT in humans. Finally, we propose that amphetamine action at the TA receptor may contribute to the calming effects of amphetamine and related drugs, especially at low doses.

Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor:

An extensive pharmacological survey revealed that psychostimulant and hallucinogenic amphetamines, numerous ergoline derivatives, adrenergic ligands, and 3-methylated metabolites of the catecholamine neurotransmitters are also good agonists at the rat trace amine receptor 1 (rTAR1). These results suggest that the trace amines and catecholamine metabolites may serve as the endogenous ligands of a novel intercellular signaling system found widely throughout the vertebrate brain and periphery. Furthermore, the discovery that amphetamines, including 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy"), are potent rTAR1 agonists suggests that the effects of these widely used drugs may be mediated in part by this receptor as well as their previously characterized targets, the neurotransmitter transporter proteins.

So it looks like these receptors are targeted by at least: tyramine, octopamine, DMT, amphetamine, MDMA, PEA, hallucinogenic amphetamines, ergoline derivatives, tryptamine, etc. And they may be involved in everything from mental illness, Parkinson's disease, migraine headaches, and the mind-altering effects of hallucinogens.

I found the last two articles particularly interesting. Does anyone have anything else, articles/insights?

If anyone gets fulltext of any of the above or related articles, I'd love a copy :D

 

[fastandbulbous]

The comment on the action of low doses of DMT at the TAR goes some way towards my own observation that low doses had an opiate-like effect; of course it would be possible to confuse an anxiolytic effect with that of an opiate.

Up until this point, I'd only really read about the role of the TAR in the actions of chocolate (PEA found in chocolate to be precise). You live & learn!


PS - I can even see, in my mind's eye, the basic structural requirement for activity at this receptor (more later when I've had a bit play with a drawing program!)

 

[BilZ0r]

^ It's hard to know how potent DMT is at the TAR.. the paper which did the big screening of tryptamines and PEAs at the TAR didn't do full binding studies on most of the ligands. They just showed that DMT is an agonist at 1uM.... its Ki at the 5-HT2A is in the 200-400nM range....

I think right now, the TAR (TR1) is about as unknown as the GHB receptor... actually it's worse.. there are no selective ligands, no antagonists at all, no immunocytochemistry, no in situ hybridization...

 

[yaesutom]

Well my friend that came in town with schizophrenia for 1 year+ after hitting my bowl of DMT, is *STILL* normal.. no psychosis, no schizoanything, no voices.. its been at least a couple months after he left town now and last time we talked on teh phone (recently) he mentioned how even now back at home there's still no voices or anything because of that hit of DMT. Just thougth i'd add..

http://www.bluelight.ru/vb/showthread.php?t=218481&highlight=dmt

 

[nanobrain]

TARS are back in fashion, as predicted. SMAs?