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Traceamine

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Traceamine

Trace amines (TAs) are endogenous biogenic amines and closely related to biogenic amine neurotransmitters.1 They are formed by decarboxylation of aromatic amino acids and occur in vertebrates only in small amounts (order of magnitude 1/100 of the corresponding neurotransmitters). In contrast, they are abundant in invertebrates, where they are involved in an equivalent of the mammalian adrenergic system and the fight-and-flight response. Invertebrates do not possess TAAR.2
Trace amines are involved in the regulation of dopamine, glutamate and serotonin neurotransmitter metabolism in the brain.2
At high concentrations, they act similarly to amphetamines at the presynapse on the release, reuptake, and biosynthesis of catecholamines and indoleamines. At low concentrations, they exhibit modulatory effects at the postsynapse, enhancing the activity of other neurotransmitters, especially dopamine and serotonin.3

1. Traceamine

1.1. Dopamine-related trace amines

  • Β-Phenylethylamine
  • N-methylphenylethylamine
    • Secondary trace amine
    • N-methylphenylethylamine derivatives, some of which can cross the brain-blood barrier, are found in Ginkgo biloba extracts4
  • P-Tyramine
  • N-methylptryramine
    • Secondary trace amine
  • 3-Methoxytyramine
    • Dopamine metabolite

1.2. Norepinephrine-related trace amines

  • Octopamine
  • Synephrine
    • Secondary trace amine

1.3. Serotonin-related trace amines

  • Tryptamine
  • N-methylptryptamine
    • Secondary trace amine

1.4. TAAR agonists

  • 3-methoxytyramine (3-MT)5
    • Catecholamine neurotransmitter metabolite
    • Main degradative of dopamine in the extracellular space
  • Normetanephrine6
    • Catecholamine neurotransmitter metabolite
  • Dimethylethylamine (DMEA)7
  • Trimethylamine7
    • Catecholamine neurotransmitter metabolite
  • Isoamylamine8
    • Catecholamine neurotransmitter metabolite
    • Especially at the mTAAR3 (mouse TAAR-3)
  • 3-Iodothyronamine (3IT)9
    • An endogenous thyroid hormone metabolite
  • Putrescine10
    • Polyamine
  • Cadaverine10
    • Polyamine
  • Possibly agmatine, spermine and spermidine2
  • N-methylphenylethylamine1
    • N-methylated metabolites of PEA
  • N-methyltyramine11
    • N-methylated metabolites of TYR
  • N,N-dimethyltryptamine (DMT)2
    • N-methyl metabolite of TRP
  • Dopamine
  • Serotonin

1.5. Sources of trace amines

Aged cheeses, fermented meats, red wine, soy products and chocolate have been shown to be enriched in one or more of the aromatic amino acids PEA, TYR and TRP. Seafood showed high levels of gmatin, cadaverin, OCT, PEA, putrescine, spermidine, spermine, TRP, and TYR.2 Tofu also contains high levels of aromatic amino acids.12 Aromatic amino acids in foods, nevertheless, hardly reach the concentration to bind hTAAR, with the exception of hTAAR1 and hTAAR9 in the stomach.12

  • Decarboxylation of aromatic amino acids occurs in different cell types, so trace amines can theoretically be generated in them:2
    • Nerve cells
    • Glial cells
    • Blood vessels
    • Cells of the gastrointestinal tract
    • Kidney
    • Liver
    • Lungs
    • Stomach
      • Serotonergic AADC, especially in the pylorus12

In the brain, cells capable of producing trace amines by aromatic L-amino acid decarboxylase (AADC) were found in the following areas:13

  • Raphe nuclei (serotonergic, very strong AADC)
  • Pons ventral (serotonergic, very strong AADC)
  • Medulla ventral (serotonergic, very strong AADC)
  • Mesencephalic reticular formation (dopaminergic, moderate to strong AADC)
  • Substantia nigra (dopaminergic, moderate to strong AADC)
  • VTA (domapinergic, moderate to severe AADC)
  • Locus coeruleus (noradrenergic, moderate to strong AADC)
  • Subcoeruleus nuclei (noradrenergic, moderate to strong AADC)
  • Median and ventrolateral parts of the intermediate reticular nucleus in the medulla oblongata (noradrenergic/adrenergic, moderate AADC)
  • Forebrain: few nonaminergic AADC-positive neurons (D neurons); these were not detectable in other brain parts in humans.

The enzyme aromatic L-amino acid decarboxylase encoded by the AADC gene occurs in different forms that cause dopaminergic and serotonergic decarboxylase

  • Dopaminerg: 3,4-dihydroxyphenylalanine decarboxylase
  • Serotonerg: 5-hydroxytryptophan decarboxylase

1.6. Regulation of AADC

The aromatic L-amino acid decarboxylase (AADC), by means of which trace amines are produced from precursors, is itself subject to regulatory influences:

  • PH value changes14
  • Denaturation14
  • Destruction of dopaminergic cells only reduced dopaminergic 3,4-dihydroxyphenylalanine decarboxylase, not serotonergic 5-hydroxytryptophan decarboxylase activity, which actually increased.15 In contrast, another study found that destruction of dopaminergic as well as serotonergic neurons both reduced dopaminergic as well as serotonergic AADC equally.16
  • Serotonergic 5-hydroxytryptophan decarboxylase activity and dopaminergic 3,4-dihydroxyphenylalanine decarboxylase showed divergent activity maxima depending on ph, temperature, and substrate concentrations:17
    • AADC serotonergic activity:
      • In soluble as well as particulate cell fractions17
      • Pyridoxal-5-phosphate doubles these17
      • Pyridoxal-P antagonists hardly affect them at all17
      • Serotonergic AADC is potentiated by 3-isobutyl-1-methylxanthine.12
    • AADC dopaminergic activity:
      • Only in soluble cell fractions17
      • Distribution corresponded to lactic acid dehydrogenase17
      • Pyridoxal-5-phosphate increases this 20-fold18
      • Carboxyl scavengers inhibit them completely17

1.7. Trace amines storage

Unlike dopamine and norepinephrine, trace amines are not stored in synaptic vesicles. They diffuse from the nerve cell directly and easily through the plasma membranes.2

2. Trace amine receptors

Trace amine receptors (since 2005: TAAR, trace amine associated receptor) have been found in nucleus accumbens and substantia nigra. They are predominantly G-protein-coupled receptors, which thus increase cAMP when bound to trace amines.
While other animals may have more TAAR (fish have over 100), humans have as hTAAR:
hTAAR are each functional receptors controlled by their own genes, except for hTAAR3, -4 and -7, which are encoded by pseudogenes. In addition, there are said to be hundreds of orphan hTAAR.12

2.1. HTAAR1 (TA-1, TAR-1, TRAR-1)

TAAR1 are found most abundantly in the amygdala in both mouse and human brains
TAAR1 are predominantly localized intracellularly, allowing for presynaptic and postsynaptic action.2

2.1.1. TAAR1 agonists

  • Commitment affinity
    • Tyramine > β-phenylethylamine > dopamine = octopamine19
    • Β-PEA > tyramine > tryptamine > synephrine > dopamine > octopamine > serotonin > histamine > norepinephrine20.
    • S(+)-amphetamine >> P-hydroxymethamphetamine > R(-)-amphetamine > (+)-methamphetamine > R(-)-apomorphine >> 1,2,3,4-tetrahydroisoquinoline > selegiline > d-LSD > haloperidol > chlorpromazine > phencyclidine > fluoxetine > cocaine > pargyline, promazine, clozapine, risperidone, clorgyline20.
  • Tyramine (TYR)19
  • Β-Phenylethylamine (PEA)19
  • Dopamine (DA)21
  • Octopamine (OCT)19
  • Amphetamine (AMP)622
    • Methylphenidate (MPH) is not a TAAR-1 agonist but could activate it indirectly by blocking the transport of trace amines by monoamine transporters or orphan transporters.22
  • 3,4-Methylenedioxymethamphetamine (MDMA)622
  • Lysergic acid diethylamide (LSD)622
  • Ergoline derivatives622
  • Ractopamine23, an additive in cattle feed for pigs, cattle and turkeys in the USA (not uncritically viewed there and increasingly rarely used); banned in EU and Russia
  • L-isoleucine could be a TAAR1 ligand
    • Isoleucine is a blood-brain barrier-permeable amino acid found especially in poultry, meat, legumes, and cheese
  • Phenylethanolamine appears to be a weak TAAR1 ligand2
  • Mephedrone24
    • Cathinone derivative
    • Weak TAAR1 agonist
  • Methylenedioxypyrovalerone24
    • Cathinone derivative
    • Weak TAAR1 agonist
  • Some monoamine transporters seem to support the activation of TAAR-1
  • Dopamine transporter (DAT)21
  • Norepinephrine transporter (NET)21
  • Serotonin transporter (SERT)21
  • D2 autoreceptors appear to inhibit TAAR-121
  • In the body, TAAR1 regulates nutrient-induced hormone secretion, making TAAR1 a potential therapeutic target in diabetes and obesity2
  • TAAR1 can regulate immune responses by controlling leukocyte differentiation and activation.2

Effect of TAAR agonists.

The selective TAAR1 partial agonist RO5203648 has antipsychotic, antidepressant, and some anxiolytic effects. It increased dopamine in the VTA and serotonin in the raphe nuclei. RO5203648 attenuated addictive behaviors and significantly promoted attention, cognitive performance, and alertness.25
The selective TAAR1 agonist RO5166017 inhibited the firing frequency of dopaminergic neurons in the VTA and serotonergic neurons in the raphe nuclei. The firing frequency of noradrenergic neurons in the locus coeruleus remained unchanged. RO5166017 altered the desensitization rate and agonist potency at 5-HT(1A) receptors in dorsal raphe nuclei. RO5166017 decreased stress-induced hyperthermia by acting at TAAR1. RO5166017 decreased dopamine-dependent hyperactivity in cocaine-treated, DAT-KO, and NMDA antagonist-treated mice.26
The partial TAAR1 agonist RO5263397 reduced intravenous self-administration of METH in rodents with chronic exposure to psychostimulants.27

2.1.2. TAAR1 antagonists

EPPTB (N-(3-ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide)28

2.1.3. Occurrence of TAAR1

  • Hypothalamus29
  • Preoptic area29
  • VTA29
  • Amygdala29
  • Dorsal raphe nucleus29
  • Nucleus tractus solitarii29
  • Parahippocampal area (rhinal cortices)29
  • Nucleus tractus solitaire29
  • Subiculum29
  • Not in
    • Olfactory bulb29
    • Purkinje cells of the cerebellum29
  • HTAAR1 (also) occurs in the stomach and there especially in the pylorus12

2.1.4. TAAR1 and the dopaminergic system

Trace amines and dopamine show complex interactions. TAAR1 regulate dopamine, which is associated with the high expression of TAAR1 in VTA and substantia nigra.2

  • The trace amines β-PEA and TYR are synthesized in dopaminergic terminals but are not stored in vesicles. β-PEA and TYR diffuse readily across plasma membranes
  • β-PEA and TYR recovery is performed via OCT2
  • D2R presynaptic inhibits PEA/TYR synthesis
  • Degradation of dopamine by COMT generates 3-MT (TAAR1 agonist)
  • Extracellular 3-M, extracellular PEA, and extracellular TYR are agonists of the TAAR1/D2R heteromeric complex presynaptically as well as postsynaptically
  • Dopamine appears to induce c-FOS luciferase expression via TAAR1, but only in the presence of DAT21
  • TAAR1 agonists decrease the firing rate of dopaminergic neurons in the VTA28

2.2. HTAAR2 (GPR58)

2.3. HTAAR3 (GPR57P)

2.4. HTAAR4 (TA2, TA2P, 5-HT4P)

2.5. HTAAR5 (PNR)

Agonists of hTAAR5 are:

  • Dimethylethylamine (DMEA)7
  • Trimethylamine (TRA)7
  • Do not bind to hTAAR5:7
    • Dimethylamine
    • Methylamine
    • Trimethylphosphine
    • Cyclohexylamine
    • N-methylpiperidine
    • Pyridine
    • Β-Phenylethylamine
    • Skatol
    • Ethanolamine
    • Putrescine
    • Isobutylamine
    • Dimethylbutylamine

2.6. HTAAR6 (TA4, TRAR4)

TAAR-630
* Is associated with schizophrenia and bipolar disorder in humans
* Not G-protein coupled
* Does not bind to monoamines (unlike TAAR-1)
* Does not occur in monoaminergic brain regions in the rhesus monkey

2.7. HTAAR7 (TA12, TAAR7a a.o.)

Other former names and isoforms include TA15 (TAAR7d), TA14 (TAAR7e), TA13P (TAAR7f), TA9 (TAAR 7g), TA6 (TAAR7h).2

2.8. HTAAR8 (TA5, TRAR5, TAR5, GPR102)

Other earlier designations and isoforms are TA11 (TAAR8a), TA7 (TAAR8b), TA10 (TAAR8c).2

2.9. HTAAR9 (TA3, TRAR3, TAR3)

  • HTAAR9 is not G protein-coupled12
  • HTAAR9 (also) occurs in the stomach12

3. Degradation of trace amines

3.1. Resume

It is possible that PEA is resumed by the OCT2 transporter.31
If this proves to be true, it would provide an approach for drug interventions.

3.1. Metabolization

Degradation of trace amines occurs primarily via MAO-A and MAO-B,32, and semicarbazide-sensitive amine oxidase (SSAO; also known as vascular adhesion protein-1 (VAP-1) amine oxidase, copper containing 3 (AOC3)). Catabolism via cytochromes P450 seems possible but secondary.2

4. Interaction dopamine system / trace amine system

The dopamine system and the TAAR1 system interact in complex ways:233

  • TAAR1 is a dopamine and amphetamine receptor that interacts with DAT and D2 receptors. TAAR1 plays an important role in regulating the addiction-related effects of stimulants34 and the dopaminergic system35
  • TAAR1 can migrate to the cell surface after heterodimerization with D2R, an effect that promotes D2R signaling, although this occurs through the Gi signal transduction cascade rather than the β-arrestin-2 pathway
  • Presynaptic D2R activation via the Gi signal transduction cascade leads to inhibition of PEA/TYR synthesis
  • Dopamine is degraded extracellularly by COMT to 3-MT. 3-MT is a TAAR-1 agonist that, like extracellular PEA and TYR, can activate the TAAR1/D2R heteromeric complex at both pre- and postsynaptic membranes.
  • There are no interactions between D1R and TAAR1

The TAAR1 ligands PEA and TYR exhibit indirect sympathomimetic effects similar to those of amphetamine,3637 38 e.g., reuptake inhibition and displacement of monoamine neurotransmitters from vesicles. However, this occurs only at very high levels of at least 10 µM, (arguably 100 times the usual physiological concentrations)3339 40 or when extremely high doses of more than 25 mg/kg) PEA/TYR are administered.41
Octapamine shows similar indirect sympathomimetic responses42
Several amphetamine derivatives bind to TAAR1, see above
Unlike amphetamine (and other drugs), PEA does not elicit a conditioned taste aversion response.43

5. Traceamine and ADHD

Endogenous trace amines have been associated with AD(HHD) since the mid-1980s
Some studies found significantly decreased levels of β-phenethylamine (PEA), phenylacetyl acid (PAA), phenylanaline, and P-tyrosine in the urine of children with ADHD or ASD, as well as PAA, phenylanaline, and tyramine in the plasma.4445 46 32
MPH like AMP normalize urinary PEA concentrations in boys with ADHD.46
Another small study found elevated tryptophan blood levels in ADHD-HI correlated with hyperactivity.47

A very small study found in ADHD:48

  • 4-Pyridoxic acid (4PA) / tryptophan (TRP) ratio reduced
  • Indoxyl sulfate (IND) / tryptophan (TRP) ratio reduced
  • Indoxyl sulfate (IND) / kynurenine (KYN) ratio reduced
  • TRP (tryptophan) tripled
  • KYN (kynurenine) more than doubled
  • 3-HOKYN (3-hydroxykynurenine) more than doubled
    • 3-HOKYN is toxic.
  • KA (kynurenic acid) strongly increased
  • IND (indoxyl sulfate) reduced

indicating a dramatically impaired activity of pyridoxine-dependent enzymes and a congenital disorder of B6 metabolism (as in epilepsy). The KYN / TRP ratio represents an index of indoleamine 2,3-dioxygenase activity, the enzyme limiting tryptohan degradation. The 3-HOAA / 3-HOKYN ratio is considered an index of kynureninase activity. MPH appears to increase kynurenic acid and decrease quinolinic acid in plasma ADHD. MPH did not alter TRP degradation but created a kind of balance between some of the detected metabolites, but not in the 4PA/TRP, IND/TRP, or IND/KYN ratio. Long-term treatment with pyridoxine normalized ADHD symptoms without serious side effects.48

Another study found no significant abnormalities of tryptophan, tyrosine, or phenylalanine in children with ADHD, although decreased blood levels of these substances tended to correlate with ADHD.49


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  5. Sotnikova, Beaulieu, Espinoza, Masri, Zhang, Salahpour, Barak, Caron, Gainetdinov (2010): The dopamine metabolite 3-methoxytyramine is a neuromodulator. PLoS One. 2010 Oct 18;5(10):e13452. doi: 10.1371/journal.pone.0013452. Erratum in: PLoS One. 2010;5(10) doi: 10.1371/annotation/a2019934-b1cc-4781-80cb-9e09fc7ff6dc. PMID: 20976142; PMCID: PMC2956650.

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  7. [Wallrabenstein, Kuklan, Weber, Zborala, Werner, Altmüller, Becker, Schmidt, Hatt, Hummel, Gisselmann \(2013\): Human trace amine-associated receptor TAAR5 can be activated by trimethylamine. PLoS One. 2013;8\(2\):e54950. doi: 10.1371/journal.pone.0054950. PMID: 23393561; PMCID: PMC3564852.](https://pubmed.ncbi.nlm.nih.gov/12479782/)

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  9. Scanlan, Suchland, Hart, Chiellini, Huang, Kruzich, Frascarelli, Crossley, Bunzow, Ronca-Testoni, Lin, Hatton, Zucchi, Grandy (2004): 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat Med. 2004 Jun;10(6):638-42. doi: 10.1038/nm1051. PMID: 15146179.

  10. Hussain, Saraiva, Ferrero, Ahuja, Krishna, Liberles, Korsching (2013): High-affinity olfactory receptor for the death-associated odor cadaverine. Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19579-84. doi: 10.1073/pnas.1318596110. PMID: 24218586; PMCID: PMC3845148.

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  12. Ohta, Takebe, Murakami, Takahama, Morimura (2017): Tyramine and β-phenylethylamine, from fermented food products, as agonists for the human trace amine-associated receptor 1 (hTAAR1) in the stomach. Biosci Biotechnol Biochem. 2017 May;81(5):1002-1006. doi: 10.1080/09168451.2016.1274640. PMID: 28084165.

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  18. ähnlich: Siow, Dakshinamurti (1985): Effect of pyridoxine deficiency on aromatic L-amino acid decarboxylase in adult rat brain. Exp Brain Res. 1985;59(3):575-81. doi: 10.1007/BF00261349. PMID: 3875501.

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  20. Wolinsky, Swanson, Smith, Zhong, Borowsky, Seeman, Branchek, Gerald (2007): The Trace Amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia. Genes Brain Behav. 2007 Oct;6(7):628-39. doi: 10.1111/j.1601-183X.2006.00292.x. PMID: 17212650.

  21. Xie, Westmoreland, Bahn, Chen, Yang, Vallender, Yao, Madras, Miller (2007): Rhesus monkey trace amine-associated receptor 1 signaling: enhancement by monoamine transporters and attenuation by the D2 autoreceptor in vitro. J Pharmacol Exp Ther. 2007 Apr;321(1):116-27. doi: 10.1124/jpet.106.116863. PMID: 17234900.

  22. Miller, Verrico, Jassen, Konar, Yang, Panas, Bahn, Johnson, Madras (2005): Primate trace amine receptor 1 modulation by the dopamine transporter. J Pharmacol Exp Ther. 2005 Jun;313(3):983-94. doi: 10.1124/jpet.105.084459. PMID: 15764732.

  23. Liu, Grandy, Janowsky (2014): Ractopamine, a livestock feed additive, is a full agonist at trace amine-associated receptor 1. J Pharmacol Exp Ther. 2014 Jul;350(1):124-9. doi: 10.1124/jpet.114.213116. PMID: 24799633; PMCID: PMC4170122.

  24. Simmler, Buchy, Chaboz, Hoener, Liechti (2016): In Vitro Characterization of Psychoactive Substances at Rat, Mouse, and Human Trace Amine-Associated Receptor 1. J Pharmacol Exp Ther. 2016 Apr;357(1):134-44. doi: 10.1124/jpet.115.229765. PMID: 26791601.

  25. Revel, Moreau, Gainetdinov, Ferragud, Velázquez-Sánchez, Sotnikova, Morairty, Harmeier, Groebke Zbinden, Norcross, Bradaia, Kilduff, Biemans, Pouzet, Caron, Canales, Wallace, Wettstein, Hoener (2012): Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics. Biol Psychiatry. 2012 Dec 1;72(11):934-42. doi: 10.1016/j.biopsych.2012.05.014. PMID: 22705041.

  26. Revel, Moreau, Gainetdinov, Bradaia, Sotnikova, Mory, Durkin, Zbinden, Norcross, Meyer, Metzler, Chaboz, Ozmen, Trube, Pouzet, Bettler, Caron, Wettstein, Hoener (2011): TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proc Natl Acad Sci U S A. 2011 May 17;108(20):8485-90. doi: 10.1073/pnas.1103029108. PMID: 21525407; PMCID: PMC3101002.

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