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Mark D Berry - One of the best experts on this subject based on the ideXlab platform.
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Trace Amines and their receptors
Pharmacological Reviews, 2018Co-Authors: Raul R Gainetdinov, Marius C Hoener, Mark D BerryAbstract:Trace Amines are endogenous compounds classically regarded as comprising β-phenylethyalmine, p-tyramine, tryptamine, p-octopamine, and some of their metabolites. They are also abundant in common foodstuffs and can be produced and degraded by the constitutive microbiota. The ability to use Trace Amines has arisen at least twice during evolution, with distinct receptor families present in invertebrates and vertebrates. The term "Trace amine" was coined to reflect the low tissue levels in mammals; however, invertebrates have relatively high levels where they function like mammalian adrenergic systems, involved in "fight-or-flight" responses. Vertebrates express a family of receptors termed Trace amine-associated receptors (TAARs). Humans possess six functional isoforms (TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9), whereas some fish species express over 100. With the exception of TAAR1, TAARs are expressed in olfactory epithelium neurons, where they detect diverse ethological signals including predators, spoiled food, migratory cues, and pheromones. Outside the olfactory system, TAAR1 is the most thoroughly studied and has both central and peripheral roles. In the brain, TAAR1 acts as a rheostat of dopaminergic, glutamatergic, and serotonergic neurotransmission and has been identified as a novel therapeutic target for schizophrenia, depression, and addiction. In the periphery, TAAR1 regulates nutrient-induced hormone secretion, suggesting its potential as a novel therapeutic target for diabetes and obesity. TAAR1 may also regulate immune responses by regulating leukocyte differentiation and activation. This article provides a comprehensive review of the current state of knowledge of the evolution, physiologic functions, pharmacology, molecular mechanisms, and therapeutic potential of Trace Amines and their receptors in vertebrates and invertebrates.
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synthesis and neurochemistry of Trace Amines
2016Co-Authors: A Pryor, S Hart, Mark D BerryAbstract:Abstract Trace Amines are endogenous compounds, found in the nervous system of all species, and consist of 2-phenylethylamine, p-tyramine, p-octopamine, and tryptamine. In vertebrates synthesis occurs by the enzymatic decarboxylation of l -amino acids via aromatic l -amino acid decarboxylase, with p-octopamine formed from p-tyramine by dopamine-β-hydroxylase. Trace amine synthesis by decarboxylation is reciprocally regulated by the pervading monoaminergic tone. Once synthesized, Trace Amines are neither stored in synaptic vesicles, released in an activity-dependent manner, nor released via exocytosis, with effects mediated by a family of Trace amine-associated receptors (TAARs). In contrast, in invertebrates Trace Amines act as traditional neurotransmitters, released in an activity-dependent manner, with effects mediated by dedicated tyramine and octopamine receptors evolutionarily distinct from TAAR. Thus the ability to synthesize and use Trace Amines in neuronal signaling appears to have arisen at least twice during evolution.
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chapter 3 synthesis and neurochemistry of Trace Amines
Trace Amines and Neurological Disorders#R##N#Potential Mechanisms and Risk Factors, 2016Co-Authors: A Pryor, S Hart, Mark D BerryAbstract:Trace Amines are endogenous compounds, found in the nervous system of all species, and consist of 2-phenylethylamine, p-tyramine, p-octopamine, and tryptamine. In vertebrates synthesis occurs by the enzymatic decarboxylation of l-amino acids via aromatic l-amino acid decarboxylase, with p-octopamine formed from p-tyramine by dopamine-β-hydroxylase. Trace amine synthesis by decarboxylation is reciprocally regulated by the pervading monoaminergic tone. Once synthesized, Trace Amines are neither stored in synaptic vesicles, released in an activity-dependent manner, nor released via exocytosis, with effects mediated by a family of Trace amine-associated receptors (TAARs). In contrast, in invertebrates Trace Amines act as traditional neurotransmitters, released in an activity-dependent manner, with effects mediated by dedicated tyramine and octopamine receptors evolutionarily distinct from TAAR. Thus the ability to synthesize and use Trace Amines in neuronal signaling appears to have arisen at least twice during evolution.
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Trace Amines and their receptors in the control of cellular homeostasis
Trace Amines and Neurological Disorders#R##N#Potential Mechanisms and Risk Factors, 2016Co-Authors: Mark D BerryAbstract:Abstract Trace amine-associated receptors (TAARs) are a vertebrate, G-protein-coupled, family of receptors found throughout the body. Within the CNS, TAAR1, for which the endogenous Trace Amines p-tyramine and 2-phenylethylamine are high-affinity agonists, activation has been shown to decrease dopaminergic tone, an effect mediated via regulation of both pre- and postsynaptic D2-like dopamine receptors. This occurs in a biased manner, with only the β-arrestin signaling pathway modified. Consistent with this, TAAR1 agonists decrease the self-administration and reinforcing properties of various drugs of abuse, and exhibit an activity profile predictive of beneficial effects in schizophrenia. There is also evidence that TAAR1 may play a role in controlling energy metabolism, although whether this is mediated centrally or peripherally is unknown. All TAAR, with the exception of TAAR1, also function as olfactory receptors mediating innate behavioral responses to various conspecific and heterospecific urinary cues.
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membrane permeability of Trace Amines evidence for a regulated activity dependent nonexocytotic synaptic release
Synapse, 2013Co-Authors: Mark D Berry, Mithila R Shitut, Ahmed Almousa, Jane Alcorn, Bruno TomberliAbstract:Both pre- and post-synaptic effects of Trace Amines have been demonstrated. The putative inTracellular location of Trace Amine-Associated Receptors necessitate that membrane transport processes be present in order for post-synaptic effects to occur. Here we examine the ability of Trace Amines to cross synthetic (Fluorosomes) and native (synaptosomes) lipid bilayer membranes. Trace Amines readily crossed Fluorosome membranes by simple diffusion, p-tyramine (P = 0.01) and tryptamine (P = 0.0004) showing significantly faster diffusion than dopamine and 5-HT, respectively, with diffusion half-lives of 13.5 ± 4.1 (p-tyramine) and 6.8 ± 0.7 seconds (tryptamine). Similarly, release of [3H]p-tyramine and [3H]2-phenylethylamine from pre-loaded synaptosomes occurred significantly quicker than did [3H]dopamine (P = 0.0001), with half lives of 38.9 (p-tyramine), 7.8 (2-phenylethylamine) and 133.6 seconds (dopamine). This was, however, significantly slower than the diffusion mediated passage across Fluorosome membranes (P = 0.0001), suggesting a role for transporters in mediating Trace amine release. Further, a pronounced shoulder region was observed in the synaptosome [3H]p-tyramine release curve, suggesting that multiple processes regulate release. No such shoulder region was present for [3H]dopamine release. Surprisingly, both [3H]p-tyramine (P = 0.001) and [3H]2-phenylethylamine (P = 0.0001) release from synaptosomes was significantly decreased under depolarizing conditions. As expected, depolarization significantly increased [3H]dopamine release. The data presented indicate that the release of p-tyramine and 2-phenylethylamine from neuronal terminals occurs by a different mechanism than dopamine, and does not involve classical exocytosis. The data are consistent with an initial release of Trace Amines by simple diffusion, followed by an activity-dependent regulation of synaptic levels via one or more transporter proteins. Synapse 67:656–667, 2013. © 2013 Wiley Periodicals, Inc.
Gregory M. Miller - One of the best experts on this subject based on the ideXlab platform.
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Actions of Trace Amines in the Brain-Gut-Microbiome Axis via Trace Amine-Associated Receptor-1 (TAAR1)
Cellular and Molecular Neurobiology, 2020Co-Authors: Katlynn Bugda Gwilt, Dulce Pamela González, Neva Olliffe, Haley Oller, Rachel Hoffing, Marissa Puzan, Sahar El Aidy, Gregory M. MillerAbstract:Trace Amines and their primary receptor, Trace Amine-Associated Receptor-1 (TAAR1) are widely studied for their involvement in the pathogenesis of neuropsychiatric disorders despite being found in the gastrointestinal tract at physiological levels. With the emergence of the “brain-gut-microbiome axis,” we take the opportunity to review what is known about Trace Amines in the brain, the defined sources of Trace Amines in the gut, and emerging understandings on the levels of Trace Amines in various gastrointestinal disorders. Similarly, we discuss localization of TAAR1 expression in the gut, novel findings that TAAR1 may be implicated in inflammatory bowel diseases, and the reported comorbidities of neuropsychiatric disorders and gastrointestinal disorders. With the emergence of TAAR1 specific compounds as next-generation therapeutics for schizophrenia (Roche) and Parkinson’s related psychoses (Sunovion), we hypothesize a therapeutic benefit of these compounds in clinical trials in the brain-gut-microbiome axis, as well as a potential for thoughtful manipulation of the brain-gut-microbiome axis to modulate symptoms of neuropsychiatric disease.
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normal thermoregulatory responses to 3 iodothyronamine Trace Amines and amphetamine like psychostimulants in Trace amine associated receptor 1 knockout mice
Journal of Neuroscience Research, 2010Co-Authors: Helen N Panas, Thomas S Scanlan, Zhihua Xie, Laurie J Lynch, Eric J Vallender, Guolin Chen, Spencer K Lynn, Gregory M. MillerAbstract:3-Iodothyronamine (T1AM) is a metabolite of thyroid hormone. It is an agonist at Trace amine-associated receptor 1 (TAAR1), a recently identified receptor involved in monoaminergic regulation and a potential novel therapeutic target. Here, T1AM was studied using rhesus monkey TAAR1 and/or human dopamine transporter (DAT) co-transfected cells, and wild-type (WT) and TAAR1 knock-out (KO) mice. The IC(50) of T1AM competition for binding of the DAT-specific radio-ligand [(3)H]CFT was highly similar in DAT cells, WT striatal synaptosomes and KO striatal synaptosomes (0.72-0.81 microM). T1AM inhibition of 10 nM [(3)H]dopamine uptake (IC(50): WT, 1.4 + or - 0.5 microM; KO, 1.2 + or - 0.4 microM) or 50 nM [(3)H]serotonin uptake (IC(50): WT, 4.5 + or - 0.6 microM; KO, 4.7 + or - 1.1 microM) in WT and KO synaptosomes was also highly similar. Unlike other TAAR1 agonists that are DAT substrates, TAAR1 signaling in response to T1AM was not enhanced in the presence of DAT as determined by CRE-luciferase assay. In vivo, T1AM induced robust hypothermia in WT and KO mice equivalently and dose dependently (maximum change degrees Celsius: 50 mg/kg at 60 min: WT -6.0 + or - 0.4, KO -5.6 + or - 1.0; and 25 mg/kg at 30 min: WT -2.7 + or - 0.4, KO -3.0 + or - 0.2). Other TAAR1 agonists including beta-phenylethylamine (beta-PEA), MDMA (3,4-methylenedioxymethamphetamine) and methamphetamine also induced significant, time-dependent thermoregulatory responses that were alike in WT and KO mice. Therefore, TAAR1 co-expression does not alter T1AM binding to DAT in vitro nor T1AM inhibition of [(3)H]monoamine uptake ex vivo, and TAAR1 agonist-induced thermoregulatory responses are TAAR1-independent. Accordingly, TAAR1-directed compounds will likely not affect thermoregulation nor are they likely to be cryogens.
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β phenylethylamine alters monoamine transporter function via Trace amine associated receptor 1 implication for modulatory roles of Trace Amines in brain
Journal of Pharmacology and Experimental Therapeutics, 2008Co-Authors: Zhihua Xie, Gregory M. MillerAbstract: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.
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primate Trace amine receptor 1 modulation by the dopamine transporter
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Gregory M. Miller, Christopher D Verrico, Amy K Jassen, Martha Konar, Hong Yang, Helen N Panas, Mary E Bahn, Ryan T Johnson, Bertha K MadrasAbstract:Recently identified Trace amine receptors are potential direct targets for drugs of abuse, including amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). We cloned full-length rhesus monkey Trace amine receptor 1 (rhTA1) that was 96% homologous to human TA1. The Trace Amines tyramine and β-phenylethylamine (PEA) and the monoamine transporter substrates (±)-amphetamine and (±)-MDMA stimulated cAMP accumulation in rhTA1-expressing cell lines, as measured by a cAMP response element-luciferase assay. Cocaine did not stimulate cAMP accumulation in rhTA1 cells, but it blocked [3H]PEA transport mediated by the dopamine transporter. Cotransfection with the human dopamine transporter enhanced PEA-, amphetamine-, and MDMA-mediated rhTA1 receptor activation, but it diminished tyramine activation of rhTA1. Because TA1 (EGFP-rhTA1 chimera) was largely inTracellular, conceivably the dopamine transporter can facilitate access of specific agonists to inTracellular TA1. rhTA1 mRNA expression was detected in rhesus monkey substantia nigra, implying that TA1 may be colocalized with the dopamine transporter in dopamine neurons. In summary, primate TA1 receptors are direct targets of Trace Amines, amphetamine, and MDMA. These receptors could also be indirect targets of amphetamine, MDMA, and cocaine through modification of monoamine transporter function. Conceivably, rhTA1 receptors may be located on pre- or postsynaptic membranes. Interference with the carrier function of monoamine transporters with a consequent rise of exTracellular levels of Trace Amines could activate these receptors. The cloning of a highly homologous TA1 from rhesus monkey and demonstration that rhTA1 receptors are activated by drugs of abuse, indicate that nonhuman primates may serve to model physiological and pharmacological TA1-mediated responses in humans.
Nicola B Mercuri - One of the best experts on this subject based on the ideXlab platform.
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effects of Trace Amines on the dopaminergic mesencephalic system
Trace Amines and Neurological Disorders#R##N#Potential Mechanisms and Risk Factors, 2016Co-Authors: Ada Ledonne, Nicola B MercuriAbstract:Abstract Trace Amines (TAs) are a class of endogenous compounds, which are heterogeneously distributed throughout the mammalian brain and peripheral nervous tissues, despite being at relatively low levels. It is now largely accepted that TAs are not pure inactive byproducts of amino acid metabolism but, instead, are considered important neuromodulators involved in the regulation of key brain physiological functions. This chapter presents an overview of the close interplay between TAs and dopamine, also discussing recent experimental evidence on the neuromodulatory effects of TAs on the activity of mesencephalic dopaminergic (DAergic) system, supporting the potential involvement of TAs in several physiological and pathological conditions associated with the activity of the DAergic mesencephalic system.
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electrophysiological effects of Trace Amines on mesencephalic dopaminergic neurons
Frontiers in Systems Neuroscience, 2011Co-Authors: Ada Ledonne, Giorgio Bernardi, Nicola Berretta, Alessandro Davoli, Giada Ricciardo Rizzo, Nicola B MercuriAbstract:Trace Amines (TAs) are a class of endogenous compounds strictly related to classic monoamine neurotransmitters with regard to their structure, metabolism, and tissue distribution. Although the presence of TAs in mammalian brain has been recognized for decades, until recently they were considered to be by-products of amino acid metabolism or as "false" neurotransmitters. The discovery in 2001 of a new family of G-protein-coupled receptors (GPCRs), namely Trace Amines receptors, has re-ignited interest in TAs. In particular, two members of the family, Trace amine receptor 1 (TA(1)) and Trace amine receptor 2 (TA(2)), were shown to be highly sensitive to these endogenous compounds. Experimental evidence suggests that TAs modulate the activity of catecholaminergic neurons and that TA dysregulation may contribute to neuropsychiatric disorders, including schizophrenia, attention deficit hyperactivity disorder, depression and Parkinson's disease, all of which are characterized by altered monoaminergic networks. Here we review recent data concerning the electrophysiological effects of TAs on the activity of mesencephalic dopaminergic neurons. In the context of recent data obtained with TA(1) receptor knockout mice, we also discuss the mechanisms by which the activation of these receptors modulates the activity of these neurons. Three important new aspects of TAs action have recently emerged: (a) inhibition of firing due to increased release of dopamine; (b) reduction of D2 and GABA(B) receptor-mediated inhibitory responses (excitatory effects due to disinhibition); and (c) a direct TA(1) receptor-mediated activation of GIRK channels which produce cell membrane hyperpolarization. While the first two effects have been well documented in our laboratory, the direct activation of GIRK channels by TA(1) receptors has been reported by others, but has not been seen in our laboratory (Geracitano et al., 2004). Further research is needed to address this point, and to further characterize the mechanism of action of TAs on dopaminergic neurons.
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Trace Amines depress d2 autoreceptor mediated responses on midbrain dopaminergic cells
British Journal of Pharmacology, 2010Co-Authors: Ada Ledonne, Mauro Federici, Giorgio Bernardi, Michela Giustizieri, Mauro Pessia, Paola Imbrici, Mark J Millan, Nicola B MercuriAbstract:Background and purpose: Although Trace Amines (TAs) are historically considered ‘false neurotransmitters’ on the basis of their ability to induce catecholamine release, there is evidence that they directly affect neuronal activity via TA receptors, ligand-gated receptor channels and/or σ receptors. Here, we have investigated the effects of two TAs, tyramine (TYR) and β-phenylethylamine (β-PEA), on electrophysiological responses of substantia nigra pars compacta (SNpc) dopaminergic cells to the D2 receptor agonist, quinpirole. Experimental approach: Electrophysiological recordings of D2 receptor-activated G-protein-gated inward rectifier K+ channel (GIRK) currents were performed on dopaminergic cells from midbrain slices of mice and on Xenopus oocytes expressing D2 receptors and GIRK channels. Key results: TYR and β-PEA reversibly reduced D2 receptor-activated GIRK currents in a concentration-dependent manner on SNpc neurones. The inhibitory effect of TAs was still present in transgenic mice with genetically deleted TA1 receptors and they could not be reproduced by the selective TA1 agonist, o-phenyl-3-iodotyramine (O-PIT). Pretreatment with antagonists of σ1 and σ2 receptors did not block TA-induced effects. In GTPγS-loaded neurones, the irreversibly-activated GIRK-current was still reversibly reduced by β-PEA. Moreover, β-PEA did not affect basal or dopamine-evoked GIRK-currents in Xenopus oocytes. Conclusions and implications: TAs reduced dopamine-induced responses on SNpc neurones by acting at sites different from TA1, σ-receptors, D2 receptors or GIRK channels. Although their precise mechanism of action remains to be identified, TAs, by antagonizing the inhibitory effects of dopamine, may render dopaminergic neurones less sensitive to autoreceptor feedback inhibition and hence enhance their sensitivity to stimulation.
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Trace Amines reduce gabab receptor mediated presynaptic inhibition at gabaergic synapses of the rat substantia nigra pars compacta
Brain Research, 2005Co-Authors: Nicola Berretta, Giorgio Bernardi, Michela Giustizieri, Nicola B MercuriAbstract:Trace Amines (TAs) act in the mammalian brain through amphetamine-like effects and as endogenous agonists of specific receptors. We now show that tyramine and beta-phenylethylamine, in the presence of specific dopamine (DA) receptor antagonists, inhibit the GABA(B)-dependent presynaptic inhibition of GABAergic inputs to midbrain DA neurons. Our results further extend the role of TAs as neuromodulators and propose a novel mechanism by which they modulate DA neurons.
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Trace Amines depress gabab response in dopaminergic neurons by inhibiting g βγ gated inwardly rectifying potassium channels
Molecular Pharmacology, 2005Co-Authors: Mauro Federici, Raffaella Geracitano, Giorgio Bernardi, Alessandro Tozzi, Patrizia Longone, Silvia Di Angelantonio, Peter C Bengtson, Nicola B MercuriAbstract:Trace Amines (TAs) are present in the central nervous system in which they up-regulate catecholamine release and are implicated in the pathogenesis of addiction, attention-deficit/hyper-activity disorder, Parkinson's disease, and schizophrenia. By using inTracellular and patch-clamp recordings from dopaminergic cells in the rat midbrain slices, we report a depressant postsynaptic action of two TAs, beta-phenylethylamine (beta-PEA) and tyramine (TYR) on the GABA(B)-mediated slow inhibitory postsynaptic potential and baclofen-activated outward currents. beta-PEA and TYR activated G-proteins, interfering with the coupling between GABA(B) receptors and G-betagamma-gated inwardly rectifying potassium channels. This is the first demonstration that beta-PEA and TYR depress inhibitory synaptic potentials in neurons of the central nervous system, supporting their emerging role as neuromodulators.
Kenneth J Broadley - One of the best experts on this subject based on the ideXlab platform.
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functional evaluation of the receptors mediating vasoconstriction of rat aorta by Trace Amines and amphetAmines
European Journal of Pharmacology, 2013Co-Authors: Kenneth J Broadley, Martina Fehler, William R Ford, Emma Jane KiddAbstract:Trace Amines including β-phenylethylamine (β-PEA) and amphetAmines classically exert pharmacological actions via indirect sympathomimetic mechanisms. However, there is evidence for other mechanisms and this study explores the receptors mediating vasoconstriction in rat aorta. β-PEA, d-amphetamine, MDMA, cathinone and methylphenidate caused concentration-dependent contractions of rat isolated aortic rings which were unaffected by prazosin (1 μM), ICI-118,551 (1 μM), cocaine (10 μM) and pargyline (10 μM), to inhibit α1- and β2-adrenoceptors, neuronal transport and monoamine oxidase (MAO), respectively. Octopamine concentration–response curves, however, were shifted to the right. In the presence of the inhibitors, the rate of onset of octopamine contractions was slowed. Lineweaver–Burk analysis of the kinetics of the response generated different KM values for octopamine in the absence (2.35×10−6 M) and presence (6.09×10−5 M) of inhibitors, indicating mediation by different receptors. Tryptamine-induced vasoconstriction also resisted blockade by adrenergic inhibitors and the 5-HT1A, 1B, 1D and 5-HT2A receptor antagonists, methiothepin (50 nM) and ketanserin (30 nM), respectively. Trace Amines and amphetAmines therefore exert vasoconstriction independently of adrenoceptors, neuronal transport and 5-HT receptor activation. There was no evidence of tachyphylaxis or cross-tachyphylaxis of the vasoconstriction to these Amines. Tyramine was a partial agonist and in its presence, β-PEA, d-amphetamine and octopamine were antagonised indicating that they all act through a common receptor for which tyramine serves as an antagonist. We conclude that the vasoconstriction is via TAAR-1, because of structural similarities between Amines, ability to stimulate recombinant Trace amine-associated receptor 1 (TAAR-1) and the presence of TAAR-1 in rat aorta.
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the vascular effects of Trace Amines and amphetAmines
Pharmacology & Therapeutics, 2010Co-Authors: Kenneth J BroadleyAbstract:Trace Amines, including tyramine, beta-phenylethylamine (beta-PEA), tryptamine and octopamine, are biologically active Amines mostly based on phenylethylamine, occurring in the body in Trace amounts. They are a diverse group of naturally occurring and synthetic Amines, which are also found in the diet and in herbal plants, such as ephedrine and cathinone. They include amphetamine and its analogues, such as MDMA ('ecstasy'), and synthetic proprietary sympathomimetic agents such as phenylpropanolamine and pseudoephedrine. On the vascular system they cause vasoconstriction and a rise in blood pressure. This effect is the basis of their use as nasal decongestants. For over 50 years, they have been assumed to be indirectly acting sympathomimetic Amines, their responses being due to the release of noradrenaline from sympathetic neurones. There are, however, results that suggest that this is not their only mechanism of action and that they may also exert direct vascular effects independent of a noradrenergic mechanism. Recently, a group of novel Trace amine-associated receptors (TAARs) have been cloned and identified in the brain and peripheral tissues including blood vessels. Trace Amines bind to these cloned receptors and it is suggested that their vasoconstrictor effects can in part be attributed to this mechanism. This review describes the cardiovascular pharmacology of this diverse group of Amines, their structures and uses and their endogenous synthesis and metabolism. The review also considers their clinical relevance as constituents of the diet, as therapeutic agents (ritodrine, phenylpropanolamine, and pseudoephedrine) and as drugs of abuse (amphetamine, 'ecstasy') and their mechanisms of action.
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differential vasopressor actions of selected biogenic Amines including Trace Amines in the rat isolated perfused mesenteric vascular network
Autonomic and Autacoid Pharmacology, 2009Co-Authors: M A Anwar, William R Ford, Kenneth J BroadleyAbstract:Introduction Regulation of vascular reactivity of the mesenteric vascular bed is not completely known. There is substantial information on contractile response to catecholAmines and serotonin of the splanchnic vascular bed, but little information exists on how Trace Amines influence vascular tone (1). The purpose of the present investigation was to compare vasoconstrictor responses of selected classic [noradrenaline (NA), methoxamine (M), serotonin (S)] and Trace Amines [meta-synephrine (SE, phenylephrine), tryptamine (TRP), tyramine (TYR) and beta-phenylethylamine (B-PEA)] in the rat mesenteric circulation. We tested the hypothesis that potency of Trace Amines will be moderate compared to the other monoAmines. Method Thirty-six male Sprague-Dawley rats (280–340 g body weight) were killed by concussion and cervical dislocation. The superior mesenteric artery was cannulated and the mesenteric arterial bed excised and placed in a perfusion chamber (2). The bed was perfused at a constant flow rate (4 mL min-1) with Krebs’ bicarbonate solution, warmed to 37°C and gassed (5% CO2 in O2), final pH 7.4. Perfusion pressure was monitored by means of a pressure transducer (Elcomatic EM 750) connected to a computer data acquisition system (AD Instruments Powerlab Chart 5). Dose-response curves were constructed for NA, M, S, SE, TRP, TYR and B-PEA by bolus doses (range of 0.01–1000 nmoles) of agonists injected in a 100 μL volume. ED50 (the dose required to produce half of the maximum effect, EMax) and EMax values were calculated and results expressed as mean ± SEM, n represents the number of animals used. Results Sensitivity (ED50) of monoAmines followed the order: S (2.9 ± 0.6, n = 6) > NA (16.1 ± 4.3, n = 6) = SE (20.2 ± 4.6, n = 6) > TRP (35.2 ± 6.3, n = 6) = M (53.2 ± 12.2, n = 5). The efficacy (EMax) sequence was of the rank order: NA (162 ± 20) = SE (139 ± 5) = M (125 ± 22) > S (51 ± 6) = TRP (38 ± 3). Both, Tyr (n = 4) and B-PEA (n = 3) yielded no vasoconstrictor effects on rat mesenteric vascular bed; however, we have recently shown that both of these molecules generate vasodepressor responses in this arterial network (3). Discussion Compounds producing dose-related contractions of the mesenteric vascular tree increase vascular resistance and hence may regulate arterial blood pressure. Nevertheless, additional work is warranted to delineate the effects produced at the recently cloned Trace amine associated receptors (TAARs) from those, if any, of the classic amine receptors in the mesenteric circulation. Also, to determine their mechanism of action, and to further define the physiological and physiopathological (hypertension and diabetes) roles of TAARs. The outcome of which may open new avenues for therapeutic interventions. Acknowledgements M.A.A. was a recipient of a Wellcome Trust Fellowship. References Grandy, D.K. (2007). Pharmacol. Ther., 116, 355–390. McGregor, D.D. (1965). J. Physiol.,177, 21–30. Broadley, K.J. et al. (2008). Br. J. Nutr., Nov 19, e1–8.
Alan A. Boulton - One of the best experts on this subject based on the ideXlab platform.
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the Trace Amines and their acidic metabolites in depression an overview
Progress in Neuro-psychopharmacology & Biological Psychiatry, 1994Co-Authors: Bruce A. Davis, Alan A. BoultonAbstract:1. Investigations of the role of the Trace Amines (phenylethylamine, tryptamine, m- and p-tyramine) and their acidic metabolites (phenylacetic, indoleacetic, m- and p-hydroxyphenylacetic acids) in depression are reviewed. 2. The evidence for the phenylethylamine hypothesis of depression is mixed. 3. Reduced phenylacetic acid levels in urine, plasma and CSF and changes in those levels during treatment with antidepressants show potential as state markers for depression. 4. Impaired p-tyramine conjugation following a tyramine challenge may be a good trait marker for depression.
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effects of monoamine oxidase inhibitors on the acid metabolites of some Trace Amines and of dopamine in the rat striatum
Biochemical Pharmacology, 1993Co-Authors: Lillian E Dyck, David A. Durden, Alan A. BoultonAbstract:The effects of the administration of selective and non-selective inhibitors of monoamine oxidase (MAO) on the concentrations of three Trace acid metabolites [phenylacetic acid (PAA); m-hydroxyphenylacetic acid (mHPAA); and p-hydroxyphenylacetic acid (pHPAA)] and of an acid metabolite of dopamine [3,4-dihydroxyphenylacetic acid (DOPAC)] in the rat striatum were determined. Administration of brofaromine (1-100 mg/kg, s.c.) a type AMAO inhibitor, dose-dependently decreased DOPAC and mHPAA levels. pHPAA levels were decreased by 100 mg/kg brofaromine, but PAA levels were unaffected. Doses of deprenyl of less than 100 mg/kg, i.p., had no effect on any of the acids, while 100 mg/kg decreased DOPAC, mHPAA and pHPAA but not PAA levels. Clorgyline, pargyline and tranylcypromine treatment decreased the levels of DOPAC, mHPAA and pHPAA but not PAA. Administration of alpha-monofluoromethyldopa, an inhibitor of aromatic amino acid decarboxylase, decreased the levels of all four acids. It was concluded that deamination of the respective parent amine by type A MAO is primarily responsible for the synthesis of DOPAC and mHPAA, but that another pathway contributes to pHPAA synthesis. It appears that either PAA arises predominantly independently from the actions of MAO or that is removal via transport or further metabolism regulates its concentration.
