TAAR1

Source: Wikipedia, the free encyclopedia.

TAAR1
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000146399

ENSMUSG00000056379

UniProt

Q96RJ0

Q923Y8

RefSeq (mRNA)

NM_138327

NM_053205

RefSeq (protein)

NP_612200

NP_444435

Location (UCSC)Chr 6: 132.64 – 132.66 MbChr 10: 23.8 – 23.8 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Trace amine-associated receptor 1 (TAAR1) is a

endogenous amines that occur in tissues at trace concentrations.[12][13] TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS;[7][12] it also affects immune system and neuroimmune system function through different mechanisms.[14][15][16][17]

TAAR1 is a high-affinity receptor for amphetamine, methamphetamine, dopamine, and trace amines which mediates some of their cellular effects in monoamine neurons within the central nervous system.[7][12]

The primary endogenous ligands of the human TAAR1 (hTAAR1) receptor, by rank order of potency, are:

β-phenethylamine > dopamine = octopamine.[6]

Discovery

TAAR1 was discovered independently by Borowski et al. and Bunzow et al. in 2001. To find the genetic variants responsible for TAAR1 synthesis, they used mixtures of oligonucleotides with sequences related to G protein-coupled receptors (GPCRs) of serotonin and dopamine to discover novel DNA sequences in rat genomic DNA and cDNA, which they then amplified and cloned. The resulting sequence was not found in any database and coded for TAAR1.[10][11] Further characterization of the functional role of TAAR1 and other receptors from this family was performed by other researchers including Raul Gainetdinov and his colleagues.[18]

Structure

TAAR1 shares structural similarities with the class A rhodopsin GPCR subfamily.[11] It has 7 transmembrane domains with short N and C terminal extensions.[19] TAAR1 is 62–96% identical with TAARs2-15, which suggests that the TAAR subfamily has recently evolved; while at the same time, the low degree of similarity between TAAR1 orthologues suggests that they are rapidly evolving.[10] TAAR1 shares a predictive peptide motif with all other TAARs. This motif overlaps with transmembrane domain VII, and its identity is NSXXNPXX[Y,H]XXX[Y,F]XWF. TAAR1 and its homologues have ligand pocket vectors that utilize sets of 35 amino acids known to be involved directly in receptor-ligand interaction.[13]

Gene

All human TAAR genes are located on a single chromosome spanning 109 kb of human chromosome 6q23.1, 192 kb of mouse chromosome 10A4, and 216 kb of rat chromosome 1p12. Each TAAR is derived from a single exon, except for TAAR2, which is coded by two exons.[13] The human TAAR1 gene is thought to be an intronless gene.[20]

Tissue distribution

blood glucose levels, and insulin release.[9] TAAR1 expression in the periphery is indicated with "x".[9]

To date, TAAR1 has been identified and cloned in five different

raphe nucleus.[6][22] hTAAR1 has also been identified in human astrocytes.[6][14]

Outside of the human central nervous system, hTAAR1 also occurs as an intracellular receptor and is primarily expressed in the

pancreatic β-cells, and white blood cells.[9][21] In the duodenum, TAAR1 activation increases glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) release;[9] in the stomach, hTAAR1 activation has been observed to increase somatostatin (growth hormone-inhibiting hormone) secretion from delta cells.[9]

hTAAR1 is the only

human trace amine-associated receptor subtype that is not expressed within the human olfactory epithelium.[23]

Location within neurons

TAAR1 is an intracellular receptor expressed within the presynaptic terminal of monoamine neurons in humans and other animals.

bioluminescence resonance energy transfer cAMP assay.[24]

Because TAAR1 is an intracellular receptor in monoamine neurons,

neurotransmitter efflux.[12] Consequently, the efficacy of a particular TAAR1 ligand in producing these effects in different monoamine neurons is a function of both its binding affinity at TAAR1 and its capacity to move across the presynaptic membrane at each type of neuron.[12] The variability between a TAAR1 ligand's substrate affinity at the various monoamine transporters accounts for much of the difference in its capacity to produce neurotransmitter release and reuptake inhibition in different types of monoamine neurons.[12] E.g., a TAAR1 ligand which can easily pass through the norepinephrine transporter, but not the serotonin transporter, will produce – all else equal
– markedly greater TAAR1-induced effects in norepinephrine neurons as compared to serotonin neurons.

Receptor oligomers

TAAR1 forms GPCR oligomers with monoamine autoreceptors in neurons in vivo.[25][26] These and other reported TAAR1 hetero-oligomers include:

Ligands

Trace amine-associated receptor 1
Negative allosteric modulators
N/A
External resources
IUPHAR/BPS364
DrugBankQ96RJ0
HMDBHMDBP10805

Agonists

Trace amines

For a more comprehensive list, see Trace amine § List of trace amines.

m-octopamine, and synephrine. These share structural similarities with the three common monoamines: serotonin, dopamine, and norepinephrine. Each ligand has a different potency, measured as increased cyclic AMP
(cAMP) concentration after the binding event.

The rank order of potency for the primary endogenous ligands at hTAAR1 is:

β-phenethylamine > dopamine = octopamine.[6]

Thyronamines

Thyronamines are molecular derivatives of the thyroid hormone and are very important for endocrine system function. 3-Iodothyronamine (T1AM) is the most potent TAAR1 agonist yet discovered, although it lacks monoamine transporter affinity and therefore has little effect in monoamine neurons of the central nervous system. Activation of TAAR1 by T1AM results in the production of large amounts of cAMP. This effect is coupled with decreased body temperature and cardiac output
.

Synthetic

Partial agonists

Inverse agonists

Neutral antagonists

As of early 2018, no neutral antagonists for hTAAR1 have been characterized.[6]

Function

Phenethylamine and amphetamine in a TAAR1-localized dopamine neuron
A pharmacodynamic model of amphetamine and TAAR1
via AADC
The image above contains clickable links
Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT.
CAMKIIα-dependent pathway, in turn producing dopamine efflux.[41][42]

Monoaminergic systems

Before the discovery of TAAR1, trace amines were believed to serve very limited functions. They were thought to induce noradrenaline release from sympathetic nerve endings and compete for catecholamine or serotonin binding sites on cognate receptors, transporters, and storage sites.[28] Today, they are believed to play a much more dynamic role by regulating monoaminergic systems in the brain.

One of the downstream effects of active TAAR1 is to increase

presynaptic 5-HT1A) have the opposite effect of TAAR1, and together these receptors provide a regulatory system for monoamines.[12] Notably, amphetamine and trace amines possess high binding affinities for TAAR1, but not for monoamine autoreceptors.[12][7] The effect of TAAR1 agonists on monoamine transporters in the brain appears to be site-specific.[12] Imaging studies indicate that monoamine reuptake inhibition by amphetamine and trace amines is dependent upon the presence of TAAR1 co-localization in the associated monoamine neurons.[12] As of 2010, co-localization of TAAR1 and the dopamine transporter (DAT) has been visualized in rhesus monkeys, but co-localization of TAAR1 with the norepinephrine transporter (NET) and the serotonin transporter (SERT) has only been evidenced by messenger RNA (mRNA) expression.[12]

In neurons with co-localized TAAR1, TAAR1 agonists increase the concentrations of the associated monoamines in the

presynaptic neuron either through DAT or by diffusing across the neuronal membrane directly.[12] As a consequence of DAT uptake, amphetamine and trace amines produce competitive reuptake inhibition at the transporter.[12] Upon entering the presynaptic neuron, these compounds activate TAAR1 which, through protein kinase A (PKA) and protein kinase C (PKC) signaling, causes DAT phosphorylation. Phosphorylation by either protein kinase can result in DAT internalization (non-competitive reuptake inhibition), but PKC-mediated phosphorylation alone induces reverse transporter function (dopamine efflux).[12][43]

Immune system

See also: Neuroimmune system

Expression of TAAR1 on lymphocytes is associated with activation of lymphocyte immuno-characteristics.[16] In the immune system, TAAR1 transmits signals through active PKA and PKC phosphorylation cascades.[16] In a 2012 study, Panas et al. observed that methamphetamine had these effects, suggesting that, in addition to brain monoamine regulation, amphetamine-related compounds may have an effect on the immune system.[16] A recent paper showed that, along with TAAR1, TAAR2 is required for full activity of trace amines in PMN cells.[17]

B cells.[6]

EAAT2 levels and function in these cells;[14] this has been implicated in methamphetamine-induced pathologies of the neuroimmune system.[14]

Clinical significance

Low

human chromosome 6 – the same chromosome that codes for TAAR1 – have been linked to schizophrenia.[13]

Medical reviews from February 2015 and 2016 noted that TAAR1-selective ligands have significant therapeutic potential for treating psychostimulant addictions (e.g., cocaine, amphetamine, methamphetamine, etc.).[7][8] Despite wide distribution outside of the CNS and PNS, TAAR1 does not affect hematological functions and the regulation of thyroid hormones across different stages of ageing. Such data represent that future TAAR1-based therapies should exert little hematological effect and thus will likely have a good safety profile.[47]

Research

A large candidate gene association study published in September 2011 found significant differences in TAAR1 allele frequencies between a cohort of fibromyalgia patients and a chronic pain-free control group, suggesting this gene may play an important role in the pathophysiology of the condition; this possibly presents a target for therapeutic intervention.[48]

In preclinical research on rats, TAAR1 activation in pancreatic cells promotes

GLP-1 secretion;[49][non-primary source needed] therefore, TAAR1 is potentially a biological target for the treatment of obesity and diabetes.[49][non-primary source needed
]

Lack of TAAR1 does not significantly affect sexual motivation and routine lipid and metabolic blood biochemical parameters, suggesting that future TAAR1-based therapies should have a favorable safety profile.[50]

Notes

  1. ^ In dopamine, norepinephrine, and serotonin neurons, the primary membrane transporters are DAT, NET, and SERT respectively.[12]
  2. GSK3 pathway.[7][27]

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000146399 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000056379 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: TAAR1 trace amine associated receptor 1".
  6. ^ a b c d e f g h i j Maguire JJ, Davenport AP (20 February 2018). "Trace amine receptor: TA1 receptor". IUPHAR/BPS Guide to PHARMACOLOGY. International Union of Basic and Clinical Pharmacology. Retrieved 16 July 2018.
    Tissue Distribution
    CNS (region specific) & several peripheral tissues:
    Stomach > amygdala, kidney, lung, small intestine > cerebellum, dorsal root ganglion, hippocampus, hypothalamus, liver, medulla oblongata, pancreas, pituitary gland, pontine reticular formation, prostate, skeletal muscle, spleen. ...
    Leukocytes ...Pancreatic islet β cells ... Primary Tonsillar B Cells ... Circulating leukocytes of healthy subjects (upregulation occurs upon addition of phytohaemagglutinin).
    Species: Human ...
    In the brain (mouse, rhesus monkey) the TA1 receptor localises to neurones within the momaminergic pathways and there is emerging evidence for a modulatory role for TA1 on function of these systems. Co-expression of TA1 with the dopamine transporter (either within the same neurone or in adjacent neurones) implies direct/indirect modulation of CNS dopaminergic function. In cells expressing both human TA1 and a monoamine transporter (DAT, SERT or NET) signalling via TA1 is enhanced [26,48,50–51]. ...
    Functional Assays ...
    Mobilization of internal calcium in RD-HGA16 cells transfected with unmodified human TA1
    Response measured: Increase in cytopasmic calcium ...
    Measurement of cAMP levels in human cultured astrocytes.
    Response measured: cAMP accumulation ...
    Activation of leukocytes
    Species: Human
    Tissue: PMN, T and B cells
    Response measured: Chemotactic migration towards TA1 ligands (β-Phenylethylamine, tyramine and 3-iodothyronamine), trace amine induced IL-4 secretion (T-cells) and trace amine induced regulation of T cell marker RNA expression, trace amine induced IgE secretion in B cells.
  7. ^
    PMID 26644139
    . TAAR1 is a high-affinity receptor for METH/AMPH and DA ... This original observation of TAAR1 and DA D2R interaction has subsequently been confirmed and expanded upon with observations that both receptors can heterodimerize with each other under certain conditions ... Additional DA D2R/TAAR1 interactions with functional consequences are revealed by the results of experiments demonstrating that in addition to the cAMP/PKA pathway (Panas et al., 2012) stimulation of TAAR1-mediated signaling is linked to activation of the Ca++/PKC/NFAT pathway (Panas et al.,2012) and the DA D2R-coupled, G protein-independent AKT/GSK3 signaling pathway (Espinoza et al., 2015; Harmeier et al., 2015), such that concurrent TAAR1 and DA DR2R activation could result in diminished signaling in one pathway (e.g. cAMP/PKA) but retention of signaling through another (e.g., Ca++/PKC/NFA)
  8. ^
    PMID 26092759
    . TAAR1 is largely located in the intracellular compartments both in neurons (Miller, 2011), in glial cells (Cisneros and Ghorpade, 2014) and in peripheral tissues (Grandy, 2007) ... Existing data provided robust preclinical evidence supporting the development of TAAR1 agonists as potential treatment for psychostimulant abuse and addiction. ... Given that TAAR1 is primarily located in the intracellular compartments and existing TAAR1 agonists are proposed to get access to the receptors by translocation to the cell interior (Miller, 2011), future drug design and development efforts may need to take strategies of drug delivery into consideration (Rajendran et al., 2010).
  9. ^
    PMID 28723415
    .
  10. ^
    PMID 11459929
    .
  11. ^
    PMID 11723224
    .
  12. ^
    PMID 21073468
    .
  13. ^
    PMID 15718104
    .
  14. ^
    PMID 24950453
    . TAAR1 overexpression significantly decreased EAAT-2 levels and glutamate clearance ... METH treatment activated TAAR1 leading to intracellular cAMP in human astrocytes and modulated glutamate clearance abilities. Furthermore, molecular alterations in astrocyte TAAR1 levels correspond to changes in astrocyte EAAT-2 levels and function.
  15. PMID 22935971
    .
  16. ^
    PMID 22038157
    .
  17. ^
    S2CID 206996784
    .
  18. PMID 29941461
    .
  19. PMID 19482011
    .
  20. ^ "TAAR1". The Human Protein Atlas. Retrieved 24 August 2017.
  21. ^
    S2CID 209339614
    .
  22. S2CID 578835
    .
  23. S2CID 2864195
    .
  24. ^
    PMID 18524885
    .
  25. ^
    PMID 26093041
    .
    TAAR1 peripheral and immune localization/functions: It is important to note that in addition to the brain, TAAR1 is also expressed in the spinal cord (Gozal et al., 2014) and periphery (Revel et al., 2012c). It has been shown that TAAR1 is expressed and regulates immune function in rhesus monkey leukocytes (Babusyte et al., 2013; Nelson et al., 2007; Panas et al., 2012). In granulocytes, TAAR1 is necessary for chemotaxic migration of cells towards TAAR1 agonists. In addition, TAAR1 signaling in B and T cells can trigger immunoglobulin and cytokine release, respectively (Babusyte et al., 2013). TAAR1 is also expressed in the islets of Langerhans, stomach and intestines based on LacZ staining patterns carried out on TAAR1-KO LacZ mice (Revel et al., 2012c). Interestingly, the administration of selective TAAR1 partial agonist RO5263397 reverses the side effect of weight gain observed with the antipsychotic olanzapine, indicating that peripheral TAAR1 signalling can regulate metabolic homeostasis (Revel et al., 2012b). ...

    Monoamine transporters and SLC22A carrier subfamily transport TAAR1 ligand: Studies using the rhesus monkey TAAR1 have shown that this receptor interacts with the monoamine transporters DAT, SERT, and NET in HEK cells (Miller et al., 2005; Xie and Miller, 2007; Xie et al., 2007). It has been hypothesized that TAAR1 interaction with these transporters might provide a mechanism by which TAAR1 ligands can enter the cytoplasm and bind to TAAR1 in intracellular compartments. A recent study has shown that in rat neonatal motor neurons, trace-amine specific signalling requires the presence and function of the transmembrane solute carrier SLC22A but not that of monoamine transporters (DAT, SERT, and NET) (Gozal et al., 2014). Specifically, it was shown that addition of β-PEA, tyramine, or tryptamine induced locomotor like activity (LLA) firing patterns of these neurons in the presence of N-Methyl D-Aspartate. Temporally, it was found that the trace amine induction of LLA is delayed compared to serotonin and norepinephrine induced LLA, indicating the target site for the trace amines is not located on the plasma membrane and could perhaps be intracellular. Importantly, blocking of SLC22A with pentamidine abolished trace amine induced LLA, indicating that trace amine induced LLA does not act on receptors found on the plasma membrane but requires their transport to the cytosol by SLC22A for induction of LLA.
  26. ^
    PMID 25878061
    . Moreover, in ADRA2A/TAAR1 hetero-oligomers, the capacity of NorEpi to stimulate Gi/o signaling is reduced by co-stimulation with 3-T1AM. The present study therefore points to a complex spectrum of signaling modification mediated by 3-T1AM at different G protein-coupled receptors.
  27. S2CID 41667764
    . Interaction of TAAR1 with D2R altered the subcellular localization of TAAR1 and increased D2R agonist binding affinity.
  28. ^
    PMID 17088868
    . Other biogenic amines are present in the central nervous system at very low concentrations in the order of 0.1–10 nm, representing <1% of total biogenic amines (Berry, 2004). For these compounds, the term 'trace amines' was introduced. Although somewhat loosely defined, the molecules generally considered to be trace amines include para-tyramine, meta-tyramine, tryptamine, β-phenylethylamine, para-octopamine and meta-octopamine (Berry, 2004) (Figure 2).
  29. ^
    PMID 19364908
    .
  30. PMID 25765500
    .
  31. ^
    S2CID 10829497
    . Several series of substituted phenylethylamines were investigated for activity at the human TAAR1 (Table 2). A surprising finding was the potency of phenylethylamines with substituents at the phenyl C2 position relative to their respective C4-substituted congeners. In each case, except for the hydroxyl substituent, the C2-substituted compound had 8- to 27-fold higher potency than the C4-substituted compound. The C3-substituted compound in each homologous series was typically 2- to 5-fold less potent than the 2-substituted compound, except for the hydroxyl substituent. The most potent of the 2-substituted phenylethylamines was 2-chloro-β-PEA, followed by 2-fluoro-β-PEA, 2-bromo-β-PEA, 2-methoxy-β-PEA, 2-methyl-β-PEA, and then 2-hydroxy-β-PEA.
    The effect of β-carbon substitution on the phenylethylamine side chain was also investigated (Table 3). A β-methyl substituent was well tolerated compared with β-PEA. In fact, S-(–)-β-methyl-β-PEA was as potent as β-PEA at human TAAR1. β-Hydroxyl substitution was, however, not tolerated compared with β-PEA. In both cases of β-substitution, enantiomeric selectivity was demonstrated.
    In contrast to a methyl substitution on the β-carbon, an α-methyl substitution reduced potency by ~10-fold for d-amphetamine and 16-fold for l-amphetamine relative to β-PEA (Table 4). N-Methyl substitution was fairly well tolerated; however, N,N-dimethyl substitution was not.
  32. PMID 26985297
    .
  33. ^
    PMID 21525407
    .
  34. S2CID 27334223
    .
  35. PMID 38004497
    .
  36. PMID 19892733
    .
  37. ^
    PMID 21272013
    . VMAT2 is the CNS vesicular transporter for not only the biogenic amines DA, NE, EPI, 5-HT, and HIS, but likely also for the trace amines TYR, PEA, and thyronamine (THYR) ... [Trace aminergic] neurons in mammalian CNS would be identifiable as neurons expressing VMAT2 for storage, and the biosynthetic enzyme aromatic amino acid decarboxylase (AADC). ... AMPH release of DA from synapses requires both an action at VMAT2 to release DA to the cytoplasm and a concerted release of DA from the cytoplasm via "reverse transport" through DAT.
  38. PMID 27141430
    . Despite the challenges in determining synaptic vesicle pH, the proton gradient across the vesicle membrane is of fundamental importance for its function. Exposure of isolated catecholamine vesicles to protonophores collapses the pH gradient and rapidly redistributes transmitter from inside to outside the vesicle. ... Amphetamine and its derivatives like methamphetamine are weak base compounds that are the only widely used class of drugs known to elicit transmitter release by a non-exocytic mechanism. As substrates for both DAT and VMAT, amphetamines can be taken up to the cytosol and then sequestered in vesicles, where they act to collapse the vesicular pH gradient.
  39. ^
    PMID 21772817
    . inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABAB receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA1 receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization.
  40. ^ a b mct (28 January 2012). "TAAR1". GenAtlas. University of Paris. Retrieved 29 May 2014.
    " • tonically activates inwardly rectifying K(+) channels, which reduces the basal firing frequency of dopamine (DA) neurons of the ventral tegmental area (VTA)"
  41. PMID 25033183
    . AMPH also increases intracellular calcium (Gnegy et al., 2004) that is associated with calmodulin/CamKII activation (Wei et al., 2007) and modulation and trafficking of the DAT (Fog et al., 2006; Sakrikar et al., 2012). ... For example, AMPH increases extracellular glutamate in various brain regions including the striatum, VTA and NAc (Del Arco et al., 1999; Kim et al., 1981; Mora and Porras, 1993; Xue et al., 1996), but it has not been established whether this change can be explained by increased synaptic release or by reduced clearance of glutamate. ... DHK-sensitive, EAAT2 uptake was not altered by AMPH (Figure 1A). The remaining glutamate transport in these midbrain cultures is likely mediated by EAAT3 and this component was significantly decreased by AMPH
  42. PMID 23968642
    . AMPH and METH also stimulate DA efflux, which is thought to be a crucial element in their addictive properties [80], although the mechanisms do not appear to be identical for each drug [81]. These processes are PKCβ– and CaMK–dependent [72, 82], and PKCβ knock-out mice display decreased AMPH-induced efflux that correlates with reduced AMPH-induced locomotion [72].
  43. PMID 19325074
    .
  44. ^
    PMID 15860375
    . 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]
  45. ^
    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.
  46. 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].
  47. S2CID 199511689
    .
  48. PMID 21905019
    .
  49. ^
    PMID 26844206
    .
  50. PMID 35625001
    .

This article incorporates text from the United States National Library of Medicine, which is in the public domain.


External links

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