Abstract
Trace amine-associated receptor 1 (TAAR1) is a member of TAAR family of G protein-coupled receptors (GPCRs). The members of this class of receptors discovered in 2001 have been found in some tissues ranging from the central nervous system to the olfactory epithelium and in some peripheral organs. The best studied receptor, TAAR1, is activated by a class of compounds named trace amines (TAs) that include compounds such as β-phenylethylamine (PEA), p-tyramine, octopamine, and tryptamine normally present at low levels in the mammalian brain. Although TA levels have been associated with many neuropsychiatric disorders, only the discovery of TAAR1 validated their physiological role. TAAR1 can modulate monoamine neurotransmission and, in particular, dopamine systems. Several studies have demonstrated that TAAR1 knockout (TAAR1-KO) mice display a supersensitive dopaminergic system, while activation of TAAR1 can reduce dopaminergic hyperactivity obtained either with pharmacological tools or present in genetic mouse model. For these reasons, TAAR1 has been proposed as a novel therapeutic target for neuropsychiatric disorders such as schizophrenia, bipolar disorder, and addiction. Moreover, several peripheral functions of TAAR1 have been described recently indicating intriguing novel TAAR1 roles in system physiology. Here we will review brain and peripheral functions mediated by TAAR1 and other TAARs.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
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 (2001) Trace amines: identification of a family of mammalian G protein-coupled receptors. Proc Natl Acad Sci U S A 98(16):8966–8971
Bunzow JR, Sonders MS, Arttamangkul S, Harrison LM, Zhang G, Quigley DI, Darland T, Suchland KL, Pasumamula S, Kennedy JL, Olson SB, Magenis RE, Amara SG, Grandy DK (2001) Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor. Mol Pharmacol 60(6):1181–1188
Grandy DK (2007) Trace amine-associated receptor 1-family archetype or iconoclast? Pharmacol Ther 116(3):355–390
Lindemann L, Hoener MC (2005) A renaissance in trace amines inspired by a novel GPCR family. Trends Pharmacol Sci 26(5):274–281
Miller GM (2012) Avenues for the development of therapeutics that target trace amine associated receptor 1 (TAAR1). J Med Chem 55(5):1809–1814
Sotnikova TD, Caron MG, Gainetdinov RR (2009) Trace amine-associated receptors as emerging therapeutic targets. Mol Pharmacol 76(2):229–235
Pei Y, Lee JA, Leo D, Gainetdinov RR, Hoener MC, Canales JJ (2014) Activation of the trace amine-associated receptor 1 prevents relapse to cocaine seeking. Neuropsychopharmacology 39:2299–2308
Bradaia A, Trube G, Stalder H, Norcross RD, Ozmen L, Wettstein JG, Pinard A, Buchy D, Gassmann M, Hoener MC, Bettler B (2009) The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system. Proc Natl Acad Sci U S A 106:20081–20086
Revel FG, Moreau JL, Gainetdinov RR, Bradaia A, Sotnikova TD, Mory R, Durkin S, Zbinden KG, Norcross R, Meyer CA, Metzler V, Chaboz S, Ozmen L, Trube G, Pouzet B, Bettler B, Caron MG, Wettstein JG, Hoener MC (2011) TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity. Proc Natl Acad Sci U S A 108(20):8485–8490
Revel FG, Moreau JL, Gainetdinov RR, Ferragud A, Velazquez-Sanchez C, Sotnikova TD, Morairty SR, Harmeier A, Groebke Zbinden K, Norcross RD, Bradaia A, Kilduff TS, Biemans B, Pouzet B, Caron MG, Canales JJ, Wallace TL, Wettstein JG, Hoener MC (2012) Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics. Biol Psychiatry 72(11):934–942
Revel FG, Moreau JL, Pouzet B, Mory R, Bradaia A, Buchy D, Metzler V, Chaboz S, Groebke Zbinden K, Galley G, Norcross RD, Tuerck D, Bruns A, Morairty SR, Kilduff TS, Wallace TL, Risterucci C, Wettstein JG, Hoener MC (2013) A new perspective for schizophrenia: TAAR1 agonists reveal antipsychotic- and antidepressant-like activity, improve cognition and control body weight. Mol Psychiatry 18(5):543–556
Thorn DA, Jing L, Qiu Y, Gancarz-Kausch AM, Galuska CM, Dietz DM, Zhang Y, Li JX (2014) Effects of the trace amine associated receptor 1 agonist RO5263397 on abuse-related effects of cocaine in rats. Neuropsychopharmacology 39:2309–2316
Sandler M, Ruthven CR, Goodwin BL, Reynolds GP, Rao VA, Coppen A (1980) Trace amine deficit in depressive illness: the phenylalanine connexion. Acta Psychiatr Scand Suppl 280:29–39
Berry MD (2004) Mammalian central nervous system trace amines. Pharmacologic amphetamines, physiologic neuromodulators. J Neurochem 90(2):257–271
Boulton AA (1980) Trace amines and mental disorders. Can J Neurol Sci 7(3):261–263
Branchek TA, Blackburn TP (2003) Trace amine receptors as targets for novel therapeutics: legend, myth and fact. Curr Opin Pharmacol 3(1):90–97
Berry MD (2007) The potential of trace amines and their receptors for treating neurological and psychiatric diseases. Rev Recent Clin Trials 2(1):3–19
Liberles SD, Buck LB (2006) A second class of chemosensory receptors in the olfactory epithelium. Nature 442(7103):645–650
Sotnikova TD, Beaulieu JM, Espinoza S, Masri B, Zhang X, Salahpour A, Barak LS, Caron MG, Gainetdinov RR (2010) The dopamine metabolite 3-methoxytyramine is a neuromodulator. PLoS One 5(10):e13452
Yang HY, Neff NH (1973) Beta-phenylethylamine: a specific substrate for type B monoamine oxidase of brain. J Pharmacol Exp Ther 187(2):365–371
Durden DA, Philips SR (1980) Kinetic measurements of the turnover rates of phenylethylamine and tryptamine in vivo in the rat brain. J Neurochem 34(6):1725–1732
Philips SR, Boulton AA (1979) The effect of monoamine oxidase inhibitors on some arylalkylamines in rate striatum. J Neurochem 33(1):159–167
Grimsby J, Toth M, Chen K, Kumazawa T, Klaidman L, Adams JD, Karoum F, Gal J, Shih JC (1997) Increased stress response and beta-phenylethylamine in MAOB-deficient mice. Nat Genet 17(2):206–210
Juorio AV, Philips SR (1976) Arylalkylamines in Octopus tissues. Neurochem Res 1(5):501–509
Robertson HA, Juorio AV (1976) Octopamine and some related noncatecholic amines in invertebrate nervous systems. Int Rev Neurobiol 19:173–224
Parker EM, Cubeddu LX (1988) Comparative effects of amphetamine, phenylethylamine and related drugs on dopamine efflux, dopamine uptake and mazindol binding. J Pharmacol Exp Ther 245(1):199–210
Fuxe K, Grobecker H, Jonsson J (1967) The effect of beta-phenylethylamine on central and peripheral monoamine-containing neurons. Eur J Pharmacol 2(3):202–207
Raiteri M, Del Carmine R, Bertollini A, Levi G (1977) Effect of sympathomimetic amines on the synaptosomal transport of noradrenaline, dopamine and 5-hydroxytryptamine. Eur J Pharmacol 41(2):133–143
Sotnikova TD, Budygin EA, Jones SR, Dykstra LA, Caron MG, Gainetdinov RR (2004) Dopamine transporter-dependent and -independent actions of trace amine beta-phenylethylamine. J Neurochem 91(2):362–373
Wolinsky TD, Swanson CJ, Smith KE, Zhong H, Borowsky B, Seeman P, Branchek T, Gerald CP (2007) The trace amine 1 receptor knockout mouse: an animal model with relevance to schizophrenia. Genes Brain Behav 6(7):628–639
Wainscott DB, Little SP, Yin T, Tu Y, Rocco VP, He JX, Nelson DL (2007) Pharmacologic characterization of the cloned human trace amine-associated receptor 1 (TAAR1) and evidence for species differences with the rat TAAR1. J Pharmacol Exp Ther 320(1):475–485
Navarro HA, Gilmour BP, Lewin AH (2006) A rapid functional assay for the human trace amine-associated receptor 1 based on the mobilization of internal calcium. J Biomol Screen 11(6):688–693
Miller GM, Verrico CD, Jassen A, Konar M, Yang H, Panas H, Bahn M, Johnson R, Madras BK (2005) Primate trace amine receptor 1 modulation by the dopamine transporter. J Pharmacol Exp Ther 313(3):983–994
Lindemann L, Meyer CA, Jeanneau K, Bradaia A, Ozmen L, Bluethmann H, Bettler B, Wettstein JG, Borroni E, Moreau JL, Hoener MC (2008) Trace amine-associated receptor 1 modulates dopaminergic activity. J Pharmacol Exp Ther 324(3):948–956
Lewin AH, Navarro HA, Mascarella SW (2008) Structure-activity correlations for beta-phenethylamines at human trace amine receptor 1. Bioorg Med Chem 16(15):7415–7423
Barak LS, Salahpour A, Zhang X, Masri B, Sotnikova TD, Ramsey AJ, Violin JD, Lefkowitz RJ, Caron MG, Gainetdinov RR (2008) Pharmacological characterization of membrane-expressed human trace amine-associated receptor 1 (TAAR1) by a bioluminescence resonance energy transfer cAMP biosensor. Mol Pharmacol 74(3):585–594
Zhang J, Pacifico R, Cawley D, Feinstein P, Bozza T (2013) Ultrasensitive detection of amines by a trace amine-associated receptor. J Neurosci 33(7):3228–3239
Babusyte A, Kotthoff M, Fiedler J, Krautwurst D (2013) Biogenic amines activate blood leukocytes via trace amine-associated receptors TAAR1 and TAAR2. J Leukoc Biol 93(3):387–394
Lindemann L, Ebeling M, Kratochwil NA, Bunzow JR, Grandy DK, Hoener MC (2005) Trace amine-associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors. Genomics 85(3):372–385
Duan J, Martinez M, Sanders AR, Hou C, Saitou N, Kitano T, Mowry BJ, Crowe RR, Silverman JM, Levinson DF, Gejman PV (2004) Polymorphisms in the trace amine receptor 4 (TRAR4) gene on chromosome 6q23.2 are associated with susceptibility to schizophrenia. Am J Hum Genet 75(4):624–638
Xie Z, Miller GM (2007) Trace amine-associated receptor 1 is a modulator of the dopamine transporter. J Pharmacol Exp Ther 321(1):128–136
Pae CU, Drago A, Kim JJ, Patkar AA, Jun TY, De Ronchi D, Serretti A (2010) TAAR6 variations possibly associated with antidepressant response and suicidal behavior. Psychiatry Res 180(1):20–24
Wasik AM, Millan MJ, Scanlan T, Barnes NM, Gordon J (2012) Evidence for functional trace amine associated receptor-1 in normal and malignant B cells. Leuk Res 36(2):245–249
Panas MW, Xie Z, Panas HN, Hoener MC, Vallender EJ, Miller GM (2012) Trace amine associated receptor 1 signaling in activated lymphocytes. J Neuroimmune Pharmacol 7(4):866–876
Chiellini G, Frascarelli S, Ghelardoni S, Carnicelli V, Tobias SC, DeBarber A, Brogioni S, Ronca-Testoni S, Cerbai E, Grandy DK, Scanlan TS, Zucchi R (2007) Cardiac effects of 3-iodothyronamine: a new aminergic system modulating cardiac function. FASEB J 21(7):1597–1608
Di Cara B, Maggio R, Aloisi G, Rivet JM, Lundius EG, Yoshitake T, Svenningsson P, Brocco M, Gobert A, De Groote L, Cistarelli L, Veiga S, De Montrion C, Rodriguez M, Galizzi JP, Lockhart BP, Coge F, Boutin JA, Vayer P, Verdouw PM, Groenink L, Millan MJ (2011) Genetic deletion of trace amine 1 receptors reveals their role in auto-inhibiting the actions of ecstasy (MDMA). J Neurosci 31(47):16928–16940
Reese EA, Bunzow JR, Arttamangkul S, Sonders MS, Grandy DK (2007) Trace amine-associated receptor 1 displays species-dependent stereoselectivity for isomers of methamphetamine, amphetamine, and para-hydroxyamphetamine. J Pharmacol Exp Ther 321(1):178–186
Barak LS, Ferguson SS, Zhang J, Caron MG (1997) A beta-arrestin/green fluorescent protein biosensor for detecting G protein-coupled receptor activation. J Biol Chem 272(44):27497–27500
Kim KM, Gainetdinov RR, Laporte SA, Caron MG, Barak LS (2005) G protein-coupled receptor kinase regulates dopamine D3 receptor signaling by modulating the stability of a receptor-filamin-beta-arrestin complex. A case of autoreceptor regulation. J Biol Chem 280(13):12774–12780
Xie Z, Westmoreland SV, Bahn ME, Chen GL, Yang H, Vallender EJ, Yao WD, Madras BK, Miller GM (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 321(1):116–127
Asghar SJ, Tanay VA, Baker GB, Greenshaw A, Silverstone PH (2003) Relationship of plasma amphetamine levels to physiological, subjective, cognitive and biochemical measures in healthy volunteers. Hum Psychopharmacol 18(4):291–299
Bowyer JF, Young JF, Slikker W, Itzak Y, Mayorga AJ, Newport GD, Ali SF, Frederick DL, Paule MG (2003) Plasma levels of parent compound and metabolites after doses of either d-fenfluramine or d-3,4-methylenedioxymethamphetamine (MDMA) that produce long-term serotonergic alterations. Neurotoxicology 24(3):379–390
Hart ME, Suchland KL, Miyakawa M, Bunzow JR, Grandy DK, Scanlan TS (2006) Trace amine-associated receptor agonists: synthesis and evaluation of thyronamines and related analogues. J Med Chem 49(3):1101–1112
Scanlan TS, Suchland KL, Hart ME, Chiellini G, Huang Y, Kruzich PJ, Frascarelli S, Crossley DA, Bunzow JR, Ronca-Testoni S, Lin ET, Hatton D, Zucchi R, Grandy DK (2004) 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat Med 10(6):638–642
Tan ES, Groban ES, Jacobson MP, Scanlan TS (2008) Toward deciphering the code to aminergic G protein-coupled receptor drug design. Chem Biol 15(4):343–353
Frascarelli S, Ghelardoni S, Chiellini G, Vargiu R, Ronca-Testoni S, Scanlan TS, Grandy DK, Zucchi R (2008) Cardiac effects of trace amines: pharmacological characterization of trace amine-associated receptors. Eur J Pharmacol 587(1–3):231–236
Snead AN, Miyakawa M, Tan ES, Scanlan TS (2008) Trace amine-associated receptor 1 (TAAR1) is activated by amiodarone metabolites. Bioorg Med Chem Lett 18(22):5920–5922
Snead AN, Santos MS, Seal RP, Miyakawa M, Edwards RH, Scanlan TS (2007) Thyronamines inhibit plasma membrane and vesicular monoamine transport. ACS Chem Biol 2(6):390–398
Kehr W (1976) 3-Methoxytyramine as an indicator of impulse-induced dopamine release in rat brain in vivo. Naunyn Schmiedebergs Arch Pharmacol 293(3):209–215
Rajput AH, Fenton ME, Di Paolo T, Sitte H, Pifl C, Hornykiewicz O (2004) Human brain dopamine metabolism in levodopa-induced dyskinesia and wearing-off. Parkinsonism Relat Disord 10(4):221–226
Xuehong L, Grandy DK, Janowsky AJ (2014) Ractopamine, a livestock feed additive, is a full agonist at trace amine-associated receptor 1. J Pharmacol Exp Ther 350:124–129
Tallman KR, Grandy DK (2012) A decade of pharma discovery delivers new tools targeting trace amine-associated receptor 1. Neuropsychopharmacology 37(12):2553–2554
Cichero E, Espinoza S, Gainetdinov RR, Brasili L, Fossa P (2013) Insights into the structure and pharmacology of the human trace amine-associated receptor 1 (hTAAR1): homology modelling and docking studies. Chem Biol Drug Des 81(4):509–516
Reese EA, Norimatsu Y, Grandy MS, Suchland KL, Bunzow JR, Grandy DK (2014) Exploring the determinants of trace amine-associated receptor 1’s functional selectivity for the stereoisomers of amphetamine and methamphetamine. J Med Chem 57(2):378–390
Sandler M, Reynolds GP (1976) Does phenylethylamine cause schizophrenia? Lancet 1(7950):70–71
D’Andrea G, Terrazzino S, Fortin D, Cocco P, Balbi T, Leon A (2003) Elusive amines and primary headaches: historical background and prospectives. Neurol Sci 24(Suppl 2):S65–S67
Shirkande S, O’Reilly R, Davis B, Durden D, Malcom D (1995) Plasma phenylethylamine levels of schizophrenic patients. Can J Psychiatry 40(4):221
Potkin SG, Karoum F, Chuang LW, Cannon-Spoor HE, Phillips I, Wyatt RJ (1979) Phenylethylamine in paranoid chronic schizophrenia. Science 206(4417):470–471
Seeman P, Weinshenker D, Quirion R, Srivastava LK, Bhardwaj SK, Grandy DK, Premont RT, Sotnikova TD, Boksa P, El-Ghundi M, O’Dowd BF, George SR, Perreault ML, Mannisto PT, Robinson S, Palmiter RD, Tallerico T (2005) Dopamine supersensitivity correlates with D2High states, implying many paths to psychosis. Proc Natl Acad Sci U S A 102(9):3513–3518
Millan MJ (2000) Improving the treatment of schizophrenia: focus on serotonin (5-HT)(1A) receptors. J Pharmacol Exp Ther 295(3):853–861
Barnes NM, Sharp T (1999) A review of central 5-HT receptors and their function. Neuropharmacology 38(8):1083–1152
Gardier AM, Malagie I, Trillat AC, Jacquot C, Artigas F (1996) Role of 5-HT1A autoreceptors in the mechanism of action of serotoninergic antidepressant drugs: recent findings from in vivo microdialysis studies. Fundam Clin Pharmacol 10(1):16–27
Leo D, Mus L, Espinoza S, Hoener MC, Sotnikova TD, Gainetdinov RR (2014) Taar1-mediated modulation of presynaptic dopaminergic neurotransmission: role of D2 dopamine autoreceptors. Neuropharmacology 81:283–291
Espinoza S, Salahpour A, Masri B, Sotnikova TD, Messa M, Barak LS, Caron MG, Gainetdinov RR (2011) Functional interaction between trace amine-associated receptor 1 and dopamine D2 receptor. Mol Pharmacol 80(3):416–425
Xie Z, Westmoreland SV, Miller GM (2008) Modulation of monoamine transporters by common biogenic amines via trace amine-associated receptor 1 and monoamine autoreceptors in human embryonic kidney 293 cells and brain synaptosomes. J Pharmacol Exp Ther 325(2):629–640
Xie Z, Miller GM (2009) Trace amine-associated receptor 1 as a monoaminergic modulator in brain. Biochem Pharmacol 78(9):1095–1104
Xie Z, Miller GM (2008) Beta-phenylethylamine alters monoamine transporter function via trace amine-associated receptor 1: implication for modulatory roles of trace amines in brain. J Pharmacol Exp Ther 325(2):617–628
Sukhanov I, Espinoza S, Yakovlev DS, Hoener MC, Sotnikova TD, Gainetdinov RR (2014) TAAR1-dependent effects of apomorphine in mice. Int J Neuropsychopharmacol 17:1683–1693
Costall B, Naylor RJ, Nohria V (1978) Climbing behaviour induced by apomorphine in mice: a potential model for the detection of neuroleptic activity. Eur J Pharmacol 50(1):39–50
Sulzer D (2011) How addictive drugs disrupt presynaptic dopamine neurotransmission. Neuron 69(4):628–649
Achat-Mendes C, Lynch LJ, Sullivan KA, Vallender EJ, Miller GM (2012) Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1. Pharmacol Biochem Behav 101(2):201–207
Lynch LJ, Sullivan KA, Vallender EJ, Rowlett JK, Platt DM, Miller GM (2013) Trace amine associated receptor 1 modulates behavioral effects of ethanol. Subst Abuse 7:117–126
Fuchs RA, Branham RK, See RE (2006) Different neural substrates mediate cocaine seeking after abstinence versus extinction training: a critical role for the dorsolateral caudate-putamen. J Neurosci 26(13):3584–3588
Thorn DA, Zhang C, Zhang Y, Li JX (2014) The trace amine associated receptor 1 agonist RO5263397 attenuates the induction of cocaine behavioral sensitization in rats. Neurosci Lett 566:67–71
Zucchi R, Chiellini G, Scanlan TS, Grandy DK (2006) Trace amine-associated receptors and their ligands. Br J Pharmacol 149(8):967–978
Panas HN, Lynch LJ, Vallender EJ, Xie Z, Chen GL, Lynn SK, Scanlan TS, Miller GM (2010) Normal thermoregulatory responses to 3-iodothyronamine, trace amines and amphetamine-like psychostimulants in trace amine associated receptor 1 knockout mice. J Neurosci Res 88:1962–1969
Nelson DA, Tolbert MD, Singh SJ, Bost KL (2007) Expression of neuronal trace amine-associated receptor (TAAR) mRNAs in leukocytes. J Neuroimmunol 192(1–2):21–30
Meredith EJ, Holder MJ, Chamba A, Challa A, Drake-Lee A, Bunce CM, Drayson MT, Pilkington G, Blakely RD, Dyer MJ, Barnes NM, Gordon J (2005) The serotonin transporter (SLC6A4) is present in B-cell clones of diverse malignant origin: probing a potential anti-tumor target for psychotropics. FASEB J 19(9):1187–1189
Chamba A, Holder MJ, Jarrett RF, Shield L, Toellner KM, Drayson MT, Barnes NM, Gordon J (2010) SLC6A4 expression and anti-proliferative responses to serotonin transporter ligands chlomipramine and fluoxetine in primary B-cell malignancies. Leuk Res 34(8):1103–1106
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Espinoza, S., Gainetdinov, R.R. (2014). Neuronal Functions and Emerging Pharmacology of TAAR1. In: Krautwurst, D. (eds) Taste and Smell. Topics in Medicinal Chemistry, vol 23. Springer, Cham. https://doi.org/10.1007/7355_2014_78
Download citation
DOI: https://doi.org/10.1007/7355_2014_78
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-48925-4
Online ISBN: 978-3-319-48927-8
eBook Packages: Chemistry and Materials ScienceChemistry and Material Science (R0)