Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists[1] – and hence, monoaminergic neuromodulators[2][3][4] – that are structurally and metabolically related to classical monoamine neurotransmitters.[5] Compared to the classical monoamines, they are present in trace concentrations.[5] They are distributed heterogeneously throughout the mammalian brain and peripheral nervous tissues and exhibit high rates of metabolism.[5][6] Although they can be synthesized within parent monoamine neurotransmitter systems,[7] there is evidence that suggests that some of them may comprise their own independent neurotransmitter systems.[2]
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Trace amines play significant roles in regulating the quantity of monoamine neurotransmitters in the synaptic cleft of monoamine neurons with co-localized TAAR1.[6] They have well-characterized presynaptic amphetamine-like effects on these monoamine neurons via TAAR1 activation;[3][4] specifically, by activating TAAR1 in neurons they promote the release[note 1] and prevent reuptake of monoamine neurotransmitters from the synaptic cleft as well as inhibit neuronal firing.[6][8] Phenethylamine and amphetamine possess analogous pharmacodynamics in human dopamine neurons, as both compounds induce efflux from vesicular monoamine transporter 2 (VMAT2)[7][9] and activate TAAR1 with comparable efficacy.[6]
Like dopamine, norepinephrine, and serotonin, the trace amines have been implicated in a vast array of human disorders of affect and cognition, such as ADHD,[3][4][10] depression[3][4] and schizophrenia,[2][3][4] among others.[3][4][10] Trace aminergic hypo-function is particularly relevant to ADHD, since urinary and plasma phenethylamine concentrations are significantly lower in individuals with ADHD relative to controls and the two most commonly prescribed drugs for ADHD, amphetamine and methylphenidate, increase phenethylamine biosynthesis in treatment-responsive individuals with ADHD.[3][11] A systematic review of ADHD biomarkers also indicated that urinary phenethylamine levels could be a diagnostic biomarker for ADHD.[11]
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minor
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Phenethylaminergic trace amines (shown in yellow) and the catecholamines are derived from the amino acid L-phenylalanine.
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The human trace amines include:
While not trace amines themselves, the classical monoamines norepinephrine, serotonin, and histamine are all partial agonists at the human TAAR1 receptor;[6] dopamine is a high-affinity agonist at human TAAR1.[8][17][18] N-Methyltryptamine and N,N-dimethyltryptamine are endogenous amines in humans, however, their human TAAR1 binding has not been determined as of 2015.[update][2]
Trace amines are so-named because they are present in the nervous system at trace or very concentrations.[19] These concentrations are much lower than for classical monoamine neurotransmitters like serotonin, dopamine, and norepinephrine.[19] However, the rapid metabolic turnover of trace amines, consequent to strong susceptibility to monoamine oxidases, is suggestive that they may be present as chemical synapses at much higher concentrations than predicted by steady-state measures.[19]
A thorough review of trace amine-associated receptors that discusses the historical evolution of this research particularly well is that of Grandy.[20]
Certain trace amines (e.g., phenethylamine) functionally inhibit the vesicular monoamine transporter VMAT2, while others do not (e.g., octopamine). The trace amines that do not inhibit VMAT2 function in monoamine neurons do not release neurotransmitters as effectively as those which do.
Berry MD (January 2007). "The potential of trace amines and their receptors for treating neurological and psychiatric diseases". Rev Recent Clin Trials. 2 (1): 3–19. doi:10.2174/157488707779318107. PMID 18473983. changes in trace amines, in particular PE, have been identified as a possible factor for the onset of attention deficit/hyperactivity disorder (ADHD) [5, 27, 43, 78]. PE has been shown to induce hyperactivity and aggression, two of the cardinal clinical features of ADHD, in experimental animals [100]. Hyperactivity is also a symptom of phenylketonuria, which as discussed above is associated with a markedly elevated PE turnover [44]. Further, amphetamines, which have clinical utility in ADHD, are good ligands at trace amine receptors [2]. Of possible relevance in this aspect is modafanil, which has shown beneficial effects in ADHD patients [101] and has been reported to enhance the activity of PE at TAAR1 [102]. Conversely, methylphenidate, which is also clinically useful in ADHD, showed poor efficacy at the TAAR1 receptor [2]. In this respect it is worth noting that the enhancement of functioning at TAAR1 seen with modafanil was not a result of a direct interaction with TAAR1 [102].
More direct evidence has been obtained recently for a role of trace amines in ADHD. Urinary PE levels have been reported to be decreased in ADHD patients in comparison to both controls and patients with autism [103-105]. Evidence for a decrease in PE levels in the brain of ADHD patients has also recently been reported [4]. In addition, decreases in the urine and plasma levels of the PE metabolite phenylacetic acid and the precursors phenylalanine and tyrosine have been reported along with decreases in plasma tyramine [103]. Following treatment with methylphenidate, patients who responded positively showed a normalization of urinary PE, whilst non-responders showed no change from baseline values [105].
Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends Pharmacol. Sci. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID 15860375. In addition to the main metabolic pathway, TAs can also be converted by nonspecific N-methyltransferase (NMT) [22] and phenylethanolamine N-methyltransferase (PNMT) [23] to the corresponding secondary amines (e.g. synephrine [14], N-methylphenylethylamine and N-methyltyramine [15]), which display similar activities on TAAR1 (TA1) as their primary amine precursors...Both dopamine and 3-methoxytyramine, which do not undergo further N-methylation, are partial agonists of TAAR1 (TA1). ...
The dysregulation of TA levels has been linked to several diseases, which highlights the corresponding members of the TAAR family as potential targets for drug development. In this article, we focus on the relevance of TAs and their receptors to nervous system-related disorders, namely schizophrenia and depression; however, TAs have also been linked to other diseases such as migraine, attention deficit hyperactivity disorder, substance abuse and eating disorders [7,8,36]. Clinical studies report increased β-PEA plasma levels in patients suffering from acute schizophrenia [37] and elevated urinary excretion of β-PEA in paranoid schizophrenics [38], which supports a role of TAs in schizophrenia. As a result of these studies, β-PEA has been referred to as the body's 'endogenous amphetamine' [39]
Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacol. Ther. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID 19948186. Trace amines are metabolized in the mammalian body via monoamine oxidase (MAO; EC 1.4.3.4) (Berry, 2004) (Fig. 2) ... It deaminates primary and secondary amines that are free in the neuronal cytoplasm but not those bound in storage vesicles of the sympathetic neurone ... Similarly, β-PEA would not be deaminated in the gut as it is a selective substrate for MAO-B which is not found in the gut ...
Brain levels of endogenous trace amines are several hundred-fold below those for the classical neurotransmitters noradrenaline, dopamine and serotonin but their rates of synthesis are equivalent to those of noradrenaline and dopamine and they have a very rapid turnover rate (Berry, 2004). Endogenous extracellular tissue levels of trace amines measured in the brain are in the low nanomolar range. These low concentrations arise because of their very short half-life ...
Offermanns, S; Rosenthal, W, eds. (2008). Encyclopedia of Molecular Pharmacology (2nd ed.). Berlin: Springer. pp. 1219–1222. ISBN 978-3540389163. Sotnikova TD, Caron MG, Gainetdinov RR (August 2009). "Trace amine-associated receptors as emerging therapeutic targets". Mol. Pharmacol. 76 (2): 229–35. doi:10.1124/mol.109.055970. PMC 2713119. PMID 19389919. Although the functional role of trace amines in mammals remains largely enigmatic, it has been noted that trace amine levels can be altered in various human disorders, including schizophrenia, Parkinson's disease, attention deficit hyperactivity disorder (ADHD), Tourette syndrome, and phenylketonuria (Boulton, 1980; Sandler et al., 1980). It was generally held that trace amines affect the monoamine system indirectly via interaction with plasma membrane transporters [such as plasma membrane dopamine transporter (DAT)] and vesicular storage (Premont et al., 2001; Branchek and Blackburn, 2003; Berry, 2004; Sotnikova et al., 2004). ...
Furthermore, DAT-deficient mice provide a model to investigate the inhibitory actions of amphetamines on hyperactivity, the feature of amphetamines believed to be important for their therapeutic action in ADHD (Gainetdinov et al., 1999; Gainetdinov and Caron, 2003). It should be noted also that the best-established agonist of TAAR1, β-PEA, shared the ability of amphetamine to induce inhibition of dopamine-dependent hyperactivity of DAT-KO mice (Gainetdinov et al., 1999; Sotnikova et al., 2004).
Furthermore, if TAAR1 could be proven as a mediator of some of amphetamine's actions in vivo, the development of novel TAAR1-selective agonists and antagonists could provide a new approach for the treatment of amphetamine-related conditions such as addiction and/or disorders in which amphetamine is used therapeutically. In particular, because amphetamine has remained the most effective pharmacological treatment in ADHD for many years, a potential role of TAAR1 in the mechanism of the "paradoxical" effectiveness of amphetamine in this disorder should be explored.
Scassellati C, Bonvicini C, Faraone SV, Gennarelli M (October 2012). "Biomarkers and attention-deficit/hyperactivity disorder: a systematic review and meta-analyses". J. Am. Acad. Child Adolesc. Psychiatry. 51 (10): 1003–1019.e20. doi:10.1016/j.jaac.2012.08.015. PMID 23021477. Although we did not find a sufficient number of studies suitable for a meta-analysis of PEA and ADHD, three studies20,57,58 confirmed that urinary levels of PEA were significantly lower in patients with ADHD compared with controls. ... Administration of D-amphetamine and methylphenidate resulted in a markedly increased urinary excretion of PEA,20,60 suggesting that ADHD treatments normalize PEA levels. ... Similarly, urinary biogenic trace amine PEA levels could be a biomarker for the diagnosis of ADHD,20,57,58 for treatment efficacy,20,60 and associated with symptoms of inattentivenesss.59 ... With regard to zinc supplementation, a placebo controlled trial reported that doses up to 30 mg/day of zinc were safe for at least 8 weeks, but the clinical effect was equivocal except for the finding of a 37% reduction in amphetamine optimal dose with 30 mg per day of zinc.110
Khan MZ, Nawaz W (October 2016). "The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system". Biomed. Pharmacother. 83: 439–449. doi:10.1016/j.biopha.2016.07.002. PMID 27424325. Wainscott DB, Little SP, Yin T, Tu Y, Rocco VP, He JX, Nelson DL (January 2007). "Pharmacologic characterization of the cloned human trace amine-associated receptor1 (TAAR1) and evidence for species differences with the rat TAAR1". The Journal of Pharmacology and Experimental Therapeutics. 320 (1): 475–85. doi:10.1124/jpet.106.112532. PMID 17038507. S2CID 10829497. Maguire JJ, Davenport AP (19 July 2016). "Trace amine receptor: TA1 receptor". IUPHAR/BPS Guide to PHARMACOLOGY. International Union of Basic and Clinical Pharmacology. Retrieved 22 September 2016. Rank order of potency
tyramine > β-phenylethylamine > octopamine = dopamine
Borowsky B, Adham N, Jones KA, Raddatz R, Artymyshyn R, Ogozalek KL, Durkin MM, Lakhlani PP, Bonini JA, Pathirana S, Boyle N, Pu X, Kouranova E, Lichtblau H, Ochoa FY, Branchek TA, Gerald C (July 2001). "Trace amines: identification of a family of mammalian G protein-coupled receptors". Proc Natl Acad Sci U S A. 98 (16): 8966–8971. doi:10.1073/pnas.151105198. PMC 55357. PMID 11459929.
