What the Christ is TAAR, and what does it do?

[nuke]

I'm curious now because of this study:

Trace Amine-Associated Receptor 1 Displays Species-Dependent Stereoselectivity for Isomers of Methamphetamine, Amphetamine, and Para-Hydroxyamphetamine
E. A. Reese, J. R. Bunzow, S. Arttamangkul, M. S. Sonders, and D. K. Grandy

Department of Physiology and Pharmacology (E.A.R., J.R.B., D.K.G.) and Vollum Institute (S.A.), Oregon Health & Science University, Portland, Oregon; and Center for Molecular Recognition, Columbia University, New York, New York (M.S.S.)


The synthetic amines methamphetamine (METH), amphetamine (AMPH), and their metabolite para-hydroxyamphetamine (POHA) are chemically and structurally related to the catecholamine neurotransmitters and a small group of endogenous biogenic amines collectively referred to as the trace amines (TAs). Recently, it was reported that METH, AMPH, POHA, and the TAs para-tyramine (TYR) and -phenylethylamine (PEA) stimulate cAMP production in human embryonic kidney (HEK)-293 cells expressing rat trace amine-associated receptor 1 (rTAAR1). The discovery that METH and AMPH activate the rTAAR1 motivated us to study the effect of these drugs on the mouse TAAR1 (mTAAR1) and a human-rat chimera (hrChTAAR1). Furthermore, because S-(+)-isomers of METH and AMPH are reported to be more potent and efficacious in vivo than R-(–), we determined the enantiomeric selectivity of all three species of TAAR1. In response to METH, AMPH, or POHA exposure, the accumulation of cAMP by HEK-293 cells stably expressing different species of TAAR1 was concentration- and isomer-dependent. EC50 values for S-(+)-METH were 0.89, 0.92, and 4.44 µM for rTAAR1, mTAAR1, and h-rChTAAR1, respectively. PEA was a potent and full agonist at each species of TAAR1, whereas TYR was a full agonist for the rodent TAAR1s but was a partial agonist at h-rChTAAR1. Interestingly, both isomers of METH were full agonists at mTAAR1 and h-rChTAAR1, whereas both were partial agonists at rTAAR1. Taken together, these in vitro results suggest that, in vivo, TAAR1 could be a novel mediator of the effects of these drugs.

http://jpet.aspetjournals.org/cgi/content/abstract/321/1/178

Toward deciphering the code to aminergic G protein-coupled receptor drug design.
Tan ES, Groban ES, Jacobson MP, Scanlan TS.

Chemistry and Chemical Biology Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA.

The trace amine-associated receptor 1 (TAAR(1)) is a biogenic amine G protein-coupled receptor (GPCR) that is potently activated by 3-iodothyronamine (1, T(1)AM) in vitro. Compound 1 is an endogenous derivative of the thyroid hormone thyroxine which rapidly induces hypothermia, anergia, and bradycardia when administered to mice. To explore the role of TAAR(1) in mediating the effects of 1, we rationally designed and synthesized rat TAAR(1) superagonists and lead antagonists using the rotamer toggle switch model of aminergic GPCR activation. The functional activity of a ligand is proposed to be correlated to its probable interactions with the rotamer switch residues; agonists allow the rotamer switch residues to toggle to their active conformation, whereas antagonists interfere with this conformational transition. These agonist and antagonist design principles provide a conceptual model for understanding the relationship between the molecular structure of a drug and its pharmacological properties.

http://www.ncbi.nlm.nih.gov/pubmed/18420141

Trace amine-associated receptor 1 modulates dopaminergic activity.
Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, Bettler B, Wettstein JG, Borroni E, Moreau JL, Hoener MC.

Pharmaceuticals Division, Central Nervous System Research, Department PRDNP5 CH, Bldg. 70/331, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland.

The recent identification of the trace amine-associated receptor (TAAR)1 provides an opportunity to dissociate the effects of trace amines on the dopamine transporter from receptor-mediated effects. To separate both effects on a physiological level, a Taar1 knockout mouse line was generated. Taar1 knockout mice display increased sensitivity to amphetamine as revealed by enhanced amphetamine-triggered increases in locomotor activity and augmented striatal release of dopamine compared with wild-type animals. Under baseline conditions, locomotion and extracellular striatal dopamine levels were similar between Taar1 knockout and wild-type mice. Electrophysiological recordings revealed an elevated spontaneous firing rate of dopaminergic neurons in the ventral tegmental area of Taar1 knock-out mice. The endogenous TAAR1 agonist p-tyramine specifically decreased the spike frequency of these neurons in wild-type but not in Taar1 knockout mice, consistent with the prominent expression of Taar1 in the ventral tegmental area. Taken together, the data reveal TAAR1 as regulator of dopaminergic neurotransmission.

http://www.ncbi.nlm.nih.gov/pubmed/18083911

Trace amine-associated receptors and their ligands.
Zucchi R, Chiellini G, Scanlan TS, Grandy DK.

Dipartimento di Scienze dell'Uomo e dell'Ambiente, University of Pisa, Pisa, Italy. [email protected]

Classical biogenic amines (adrenaline, noradrenaline, dopamine, serotonin and histamine) interact with specific families of G protein-coupled receptors (GPCRs). The term 'trace amines' is used when referring to p-tyramine, beta-phenylethylamine, tryptamine and octopamine, compounds that are present in mammalian tissues at very low (nanomolar) concentrations. The pharmacological effects of trace amines are usually attributed to their interference with the aminergic pathways, but in 2001 a new gene was identified, that codes for a GPCR responding to p-tyramine and beta-phenylethylamine but not to classical biogenic amines. Several closely related genes were subsequently identified and designated as the trace amine-associated receptors (TAARs). Pharmacological investigations in vitro show that many TAAR subtypes may not respond to p-tyramine, beta-phenylethylamine, tryptamine or octopamine, suggesting the existence of additional endogenous ligands. A novel endogenous thyroid hormone derivative, 3-iodothyronamine, has been found to interact with TAAR1 and possibly other TAAR subtypes. In vivo, micromolar concentrations of 3-iodothyronamine determine functional effects which are opposite to those produced on a longer time scale by thyroid hormones, including reduction in body temperature and decrease in cardiac contractility. Expression of all TAAR subtypes except TAAR1 has been reported in mouse olfactory epithelium, and several volatile amines were shown to interact with specific TAAR subtypes. In addition, there is evidence that TAAR1 is targeted by amphetamines and other psychotropic agents, while genetic linkage studies show a significant association between the TAAR gene family locus and susceptibility to schizophrenia or bipolar affective disorder.

http://www.ncbi.nlm.nih.gov/pubmed/17088868

Sounds like a new target for stimulant drugs, and also perhaps antipsychotics.

 

[nuke]

Oh, and here's another neat one, which should also be of interest to the people from the phenethylamine thread:

Beta-phenylethylamine alters monoamine transporter function via trace amine-associated receptor 1: implication for modulatory roles of trace amines in brain.
Xie Z, Miller GM.

New England Primate Research Center, Harvard Medical School, One Pine Hill Drive, Southborough, MA 01772, USA.

Brain monoamines include common biogenic amines (dopamine, norepinephrine, and serotonin) and trace amines [beta-phenylethylamine (beta-PEA), tyramine, tryptamine, and octopamine]. Common biogenic amines are well established as neurotransmitters, but the roles and functional importance of trace amines remain elusive. Here, we re-evaluated the interaction of trace amines with trace amine-associated receptor 1 (TAAR1) and investigated effects of beta-PEA on monoamine transporter function and influence of monoamine autoreceptors on TAAR1 signaling. We confirmed that TAAR1 was activated by trace amines and demonstrated that TAAR1 activation by beta-PEA significantly inhibited uptake and induced efflux of [3H]dopamine, [3H]norepinephrine, and [3H]serotonin in transfected cells. In brain synaptosomes, beta-PEA significantly inhibited uptake and induced efflux of [3H]dopamine and [3H]serotonin in striatal and [3H]norepinephrine in thalamic synaptosomes of rhesus monkeys and wild-type mice, but it lacked the same effects in synaptosomes of TAAR1 knockout mice. The effect of beta-PEA on efflux was blocked by transporter inhibitors in either the transfected cells or wild-type mouse synaptosomes. We also demonstrated that TAAR1 signaling was not affected by monoamine autoreceptors at exposure to trace amines that we show to have poor binding affinity for the autoreceptors relative to common biogenic amines. These results reveal that beta-PEA alters monoamine transporter function via interacting with TAAR1 but not monoamine autoreceptors. The functional profile of beta-PEA may reveal a common mechanism by which trace amines exert modulatory effects on monoamine transporters in brain.

So, yes, PEA should act similar to amphetamine if it does not get munched upon by MAO-B, at least from the perspective of TAAR, and that perhaps TAAR is at least partially responsible for the efflux of monoamines by certain amphetamines.

 

[vecktor]

TAARs also seem to be important for sensing of pheromones in some mammals too.
what they do in humans is a bit of an unknown.

 

[Riemann Zeta]

It's the magical mystery receptor--step right this way. Interestingly, it is a real ligand-whore, with affinity for a number of phenethylamines, amphetamines, tryptamines and even ergoloids. I think it is cool that it binds my favorite chemicals: (d)-amphetamine, DMT and LSD with relatively high affinity. As it is a target of amphetamines, most researchers have the unfortunate knee-jerk response, "it must cause schizophrenia, so we need to antagonize it."

One of the most interesting papers that I have read about it, however, claims that it might underlie the calmative effect of low-doses of amphetamine, as well as endogenous/low-dose DMT:

Jacob MS & Presti DE (2005). Endogenous psychoactive tryptamines reconsidered: an anxiolytic role for dimethyltryptamine. Med Hypotheses. 64: 930-7.

Abstract:

The presence of the potent hallucinogenic psychoactive chemical N,N-dimethyltryptamine (DMT) in the human body has puzzled scientists for decades. Endogenous DMT was investigated in the 1960s and 1970s and it was proposed that DMT was involved in psychosis and schizophrenia. This hypothesis developed from comparisons of the blood and urine of schizophrenic and control subjects. However, much of this research proved inconclusive and conventional thinking has since held that trace levels of DMT, and other endogenous psychoactive tryptamines, are insignificant metabolic byproducts. 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.

 

[yaesutom]

I've always loved low doses of DMT, very calming but made my brain sharper / speedier quite like amph..

 

[jspun]

Anything new about this receptor and its mechanism of action for amphetamines. Wonder if cocaine or ritalin have any affinity for this receptor.

 

[Limpet_Chicken]

Yes yaesutom! my first thoughts, recently after getting hold of a gram of good quality mhrb DMT, was 'wow! nootropic!), very very soothing and calming, yet at the same time, sharpened my thought processes, after 70-80mg of DMT, vaporised and taken in a couple of hits, I was content to just lie back and relax, the equivalent level, to the extent the two can be compared, of psilocybin would have had the hairs on the back of my neck standing up and be a bit of a white knuckle ride.

I'd be game for trying a selective TAAR agonist ligand.

 

[Haoma]

I'm very interested to know what role the TAAR1 plays in ones immune process.

I know this is probably oversimplifying it, but from reading lots of info on the TAAR1 it seems like one of its main actions is an endogenous DAT inhibitor.

Can anyone elaborate how it would have a calming effect if it's effecting your dopamine system?

 

[Dr. Drugs]

I know this is probably oversimplifying it, but from reading lots of info on the TAAR1 it seems like one of its main actions is an endogenous DAT inhibitor.

Can anyone elaborate how it would have a calming effect if it's effecting your dopamine system?

I read a study of mice with the TAAR1 gene knocked out that sheds some light on your question. The knockout mice showed decreased response to d-amphetamine compared to wild type. It seems like the TAAR1 receptor decreases dopaminergic activity in response to stimuli, which I believe would cause a calming effect.

Link: Trace Amine-Associated Receptor 1 Modulates Dopaminergic Activity
http://m.jpet.aspetjournals.org/content/324/3/948.full
Full text seems to be freely available.

Excuse the brevity of my reply; I'm writing this on my phone while waiting at the bank. I find these lesser-known receptors very interesting and will do more research later.

 

[Haoma]

Seems contradictory to me that it would be a DAT inhibitor and still decrease dopaminergic activity.

The endogenous TAAR1 agonist p-tyramine specifically decreased the spike frequency of these neurons in wild-type but not in Taar1 knockout mice

In brain synaptosomes, beta-PEA significantly inhibited uptake and induced efflux of [3H]dopamine and [3H]serotonin in striatal and [3H]norepinephrine in thalamic synaptosomes of rhesus monkeys and wild-type mice

I know this area of research is in its infancy, but can someone elaborate what their take on the action is of TAAR1 on DA action is? I just can't wrap my mind around how spike frequency would be decreased during DAT inhibition + increased efflux. The only theory I can come up with is it has contradictory actions, decreasing DA activity (somehow) stronger than it's action of DAT inhibition + efflux.

 

[Haoma]

The endogenous TAAR1 agonist p-tyramine specifically decreased the spike frequency of these neurons in wild-type but not in Taar1 knockout mice

Sounds like a reason amphetamines paradoxically calms ADD sufferers.

 

[cannibalsnail]

Its not paradoxical. Novel behaviour raises Dopamine levels. ADHD sufferers constantly engage in novel activity to keep levels high. For hyperactive type this involves physical activity, for inattentive this is elaborate daydreaming. Hence when they receive stimulants they no longer engage in these behaviours and exhibit "calm".

Would selective TAAR agonists e.g. http://en.wikipedia.org/wiki/EPPTB or http://en.wikipedia.org/wiki/RO5166017 have any value as stimulants, recreational or medical?

 

[i are spectre]

http://en.wikipedia.org/wiki/3-iodothyronamine

interesting thread, good one! future blood pressure/CO meds

 

[DJHENRU]

TAARs also seem to be important for sensing of pheromones in some mammals too.
what they do in humans is a bit of an unknown.

Hmm today I had 4fa and was biking and pulled off to this spot where it reeked of discusting roadkill.
Got back home and redosed and wam! Couldnt stop smelling the deadmice in my house... Disturbing.
Probably not add, but wanted to tell you

 

[atrollappears]

Its not paradoxical. Novel behaviour raises Dopamine levels. ADHD sufferers constantly engage in novel activity to keep levels high. For hyperactive type this involves physical activity, for inattentive this is elaborate daydreaming. Hence when they receive stimulants they no longer engage in these behaviours and exhibit "calm".

Well, this what used to be the big hypothesis about ADHD, but it doesn't really seem to be the case. Rather, cortical DA actually seems to promote behavioral inhibition, which may be why stimulants treat hyperactive ADHD. As for inattentives, well, stimulants usually don't work that well for them (amphetamine actually makes mine worse if I'm not already focused when I take it), and when they do I'd ascribe it, simplistically, to the NE actions. Pseudoephedrine works wonders for me, wish it crossed the BBB better and wasn't regulated to hell...

As far as the seemingly paradoxical role of the TAAR1, yes, that struck me too. My guess is that it inhibits the DA release caused by amphetamine, but increases basal efflux. Plenty of things do this... acetyl-L-carnitine, for example.

 

[cannibalsnail]

Ritalin works for my PI-ADD. I'm not super focused by I work like a normal person does.