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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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Trace amine associated Receptor 1 modulates behavioral effects of ethanol
Substance Abuse: Research and Treatment, 2013Co-Authors: Laurie J Lynch, Eric J Vallender, Katherine A Sullivan, James K Rowlett, Donna M Platt, Gregory M. MillerAbstract:Background: Few treatment options for alcohol use disorders (AUDs) exist and more are critically needed. Here, we assessed whether Trace amine associated Receptor 1 (TAAR1), a modulator of brain monoamine systems, is involved in the behavioral and reinforcement-related effects of ethanol and whether it could potentially serve as a therapeutic target. Methods: Wild-type (WT) and TAAR1 knockout (KO) mice (75% C57J/BL6 and 25% 129S1/Sv background) were compared in tests of ethanol consumption (two-bottle choice [TBC]), motor impairment (loss of righting reflex, [LORR], locomotor activity) and ethanol clearance (blood ethanol level [BEL]). Results: As compared with WT mice, KO mice displayed (1) significantly greater preference for and consumption of ethanol in a TBC paradigm (3%–11% vol/vol escalating over 10 weeks), with no significant difference observed in TBC with sucrose (1%–3%); (2) significantly greater sedative-like effects of acute ethanol (2.0 or 2.5 g/kg, intraperitoneal [i.p.]) manifested as LORR observed at a lower dose and for longer time, with similar BELs and rates of ethanol clearance; and (3) lower cumulative locomotor activity over 60 minutes in response to an acute ethanol challenge (1.0–2.5 g/kg, i.p.). Conclusions: The present findings are the first to implicate TAAR1 in the behavioral and reinforcement-related effects of ethanol and raise the question of whether specific drugs that target TAAR1 could potentially reduce alcohol consumption in humans with AUDs.
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Trace Amine Associated Receptor 1 Signaling in Activated Lymphocytes
Journal of Neuroimmune Pharmacology, 2012Co-Authors: Michael W. Panas, Eric J Vallender, Helen N Panas, Gregory M. MillerAbstract:Although most research to date on Trace Amine Associated Receptor 1 (TAAR1) has focused on its role in the brain, it has been recognized since its discovery in 2001 that TAAR1 mRNA is expressed in peripheral tissues as well, suggesting that this Receptor may play a role in non-neurological pathways. This study reports TAAR1 expression, signaling and functionality in rhesus monkey lymphocytes. We detected a high level of TAAR1 protein in immortalized rhesus monkey B cell lines and a significant upregulation of TAAR1 protein expression in rhesus monkey lymphocytes following PHA treatment. Through screening a wide range of signaling pathways for their upregulation following TAAR1 activation by its potent agonist methamphetamine, we identified two transcription factors, CREB and NFAT, which are commonly associated with immune activation. Furthermore, we observed a TAAR1-dependent phosphorylation of PKA and PKC following treatment with methamphetamine in transfected HEK293 cells, immortalized rhesus monkey B cells and PHA-activated rhesus monkey lymphocytes. Accordingly, the high levels of TAAR1 that we observed on lymphocytes are inducible and fully functional, capable of transmitting a signal likely via PKA and PKC activation following ligand binding. More importantly, an increase in TAAR1 Receptor expression is concomitant with lymphocyte immune activation, suggesting a possible role for TAAR1 in the generation or regulation of an immune response. TAAR1 is emerging as a potential therapeutic target, with regard to its ability to modulate brain monoamines. The current data raises the possibility that TAAR1-targeted drugs may also alter immune function.
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augmentation of methamphetamine induced behaviors in transgenic mice lacking the Trace amine associated Receptor 1
Pharmacology Biochemistry and Behavior, 2012Co-Authors: Cindy Achatmendes, Eric J Vallender, Laurie J Lynch, Katherine A Sullivan, Gregory M. MillerAbstract:The Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled Receptor that is functionally activated by amphetamine-based psychostimulants, including amphetamine, methamphetamine and MDMA. Previous studies have shown that in transgenic mice lacking the TAAR1 gene (TAAR1 knockout; KO) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild-type (WT) mice. Further, the psychostimulant effects of cocaine can be diminished by selective activation of TAAR1. These findings suggest that TAAR1 might be implicated in the rewarding properties of psychostimulants. To investigate the role of TAAR1 in the rewarding effects of drugs of abuse, the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and TAAR1 KO mice. In locomotor activity studies, both single and repeated exposure to d-amphetamine or methamphetamine generated significantly higher levels of total distance traveled in TAAR1 KO mice compared to WT mice. In conditioned place preference (CPP) studies, TAAR1 KO mice acquired methamphetamine-induced CPP earlier than WT mice and retained CPP longer during extinction training. In morphine-induced CPP, both WT and KO genotypes displayed similar levels of CPP. Results from locomotor activity studies suggest that TAAR1 may have a modulatory role in the behavioral sensitization to amphetamine-based psychostimulants. That methamphetamine-but not morphine-induced CPP was augmented in TAAR1 KO mice suggests a selective role of TAAR1 in the conditioned reinforcing effects of methamphetamine. Collectively, these findings provide support for a regulatory role of TAAR1 in methamphetamine signaling.
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avenues for the development of therapeutics that target Trace amine associated Receptor 1 taar1
Journal of Medicinal Chemistry, 2012Co-Authors: Gregory M. MillerAbstract:G protein-coupled Receptors (GPCRs) play an inordinately large role in human health. They are the targets of many clinically relevant medications and are also candidate therapeutic targets under current investigation for a wide spectrum of diseases. Drugs targeting GPCRs are used as antihypertensives, anti-allergenic/asthmatics, antipsychotics, and to treat numerous other disorders across a broad spectrum of diseases. One recent study focusing on the DrugBank database found that 19% of all human drug targets are GPCRs and ~36% of all drugs currently approved for market target GPCRs.1 Accordingly, GPCRs are by far the single largest protein family for drug targets; currently, 63 of 200 drugs with the highest sales volume in the United States target GPCRs. Further, this overrepresentation of GPCRs has been steady since the early 1980s and continues to this day.1,2
Zhihua Xie - One of the best experts on this subject based on the ideXlab platform.
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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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Functional Evolution of the Trace Amine Associated Receptors in Mammals and the Loss of TAAR1 in Dogs
BMC evolutionary biology, 2010Co-Authors: Eric J Vallender, Zhihua Xie, Susan V. Westmoreland, Gregory M. MillerAbstract:Background: The Trace amine associated Receptor family is a diverse array of GPCRs that arose before the first vertebrates walked on land. Trace amine associated Receptor 1 (TAAR1) is a wide spectrum aminergic Receptor that acts as a modulator in brain monoaminergic systems. Other Trace amine associated Receptors appear to relate to environmental perception and show a birth-and-death pattern in mammals similar to olfactory Receptors. Results: Across mammals, avians, and amphibians, the TAAR1 gene is intact and appears to be under strong purifying selection based on rates of amino acid fixation compared to neutral mutations. We have found that in dogs it has become a pseudogene. Our analyses using a comparative genetics approach revealed that the pseudogenization event predated the emergence of the Canini tribe rather than being coincident with canine domestication. By assessing the effects of the TAAR1 agonist b-phenylethylamine on [ 3 H]dopamine uptake in canine striatal synaptosomes and comparing the degree and pattern of uptake inhibition to that seen in other mammals, including TAAR1 knockout mice, wild type mice and rhesus monkey, we found that the TAAR1 pseudogenization event resulted in an uncompensated loss of function. Conclusion: The gene family has seen expansions among certain mammals, notably rodents, and reductions in others, including primates. By placing the Trace amine associated Receptors in an evolutionary context we can better understand their function and their potential associations with behavior and neurological disease.
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Trace Amine-Associated Receptor 1 as a Monoaminergic Modulator in Brain
Biochemical pharmacology, 2009Co-Authors: Zhihua Xie, Gregory M. MillerAbstract:Abstract Brain monoaminergic systems play critical roles in mood, cognition, emotion, reward, learning and attention, and aberrance in brain monoaminergic activity is associated with a variety of neuropsychiatric disorders/diseases. The present commentary focuses on Trace Amine-Associated Receptor 1 (TAAR1) and its potential regulatory roles in brain monoaminergic systems. TAAR1 was discovered in 2001 and has been established to be a G-protein-coupled Receptor signaling through the cAMP pathway. This Receptor is activated by a broad spectrum of agonists, although there are notable species differences in ligand efficacy and potency. TAAR1 is expressed and widely distributed in brain monoaminergic systems and co-localized with the dopamine transporter in a subset of dopaminergic neurons in rhesus monkey and mouse brain substantia nigra. TAAR1 activation by the common biogenic amines, the Trace amine β-phenylethylamine and methamphetamine alters the monoamine transporter function in both mouse and rhesus monkey brain synaptosomes, suggesting a modulatory role for this Receptor in the presynaptic regulation of monoaminergic activity. However, little is known about other functional roles of TAAR1 in the brain. With a purpose to promote further studies on this Receptor, we herein discuss the recent findings that provide insights into the functional significance and biological relevance of this Receptor as a modulator in brain monoaminergic systems.
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cloning expression and functional analysis of rhesus monkey Trace amine associated Receptor 6 evidence for lack of monoaminergic association
Journal of Neuroscience Research, 2008Co-Authors: Zhihua Xie, Eric J Vallender, Susan V. Westmoreland, Mary E Bahn, Hong Yang, Shelli L Kirstein, Gregory M. MillerAbstract:Several recent studies report an association between Trace Amine-Associated Receptor 6 (TAAR6) and susceptibility to schizophrenia and bipolar affective disorder in humans. However, endogenous TAAR6 agonists and the Receptor signaling profile and brain distribution remain unclear. Here, we clone TAAR6 from the rhesus monkey and use transfected cells to investigate whether this Receptor interacts with brain monoamines and a psychostimulant drug to trigger cAMP signaling or exTracellular signal-regulated kinase (ERK) phosphorylation, while investigating its expression profile in the rhesus monkey brain. Unlike TAAR1, rhesus monkey TAAR6 did not alter cAMP levels in response to 10 microM of monoamines (dopamine, norepinephrine, serotonin, beta-phenylethylamine (beta-PEA), octopamine, tryptamine, and tyramine) or methamphetamine in stably transfected cells in vitro. Real-time cell electronic sensing analysis indicated that the Receptor did not alter cell impedance or change the effect of forskolin on cell impedance at exposure to 20 microM of each monoamine, suggesting a lack of either Gs or Gi-linked signaling. Whereas kappa opioid Receptor activation led to ERK phosphorylation at exposure to 1 microM U69593, rhesus monkey TAAR6 had no such effect at exposure to 10 microM of monoamines or methamphetamine. Membrane and cell surface localization of TAAR6 was confirmed by immunocytochemistry, biotinylation, and Western blot testing with a TAAR6 antibody in the transfected cells. Real-time reverse transcriptase-polymerase chain reaction amplification showed that TAAR6 mRNA was undetectable in selected rhesus monkey brain regions. Together, the data reveal that TAAR6 is unresponsive to brain monoamines and is not expressed in rhesus monkey brain monoaminergic nuclei, suggesting TAAR6 lacks direct association with brain monoaminergic neuronal function.
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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.
Eric J Vallender - One of the best experts on this subject based on the ideXlab platform.
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Trace amine associated Receptor 1 modulates behavioral effects of ethanol
Substance Abuse: Research and Treatment, 2013Co-Authors: Laurie J Lynch, Eric J Vallender, Katherine A Sullivan, James K Rowlett, Donna M Platt, Gregory M. MillerAbstract:Background: Few treatment options for alcohol use disorders (AUDs) exist and more are critically needed. Here, we assessed whether Trace amine associated Receptor 1 (TAAR1), a modulator of brain monoamine systems, is involved in the behavioral and reinforcement-related effects of ethanol and whether it could potentially serve as a therapeutic target. Methods: Wild-type (WT) and TAAR1 knockout (KO) mice (75% C57J/BL6 and 25% 129S1/Sv background) were compared in tests of ethanol consumption (two-bottle choice [TBC]), motor impairment (loss of righting reflex, [LORR], locomotor activity) and ethanol clearance (blood ethanol level [BEL]). Results: As compared with WT mice, KO mice displayed (1) significantly greater preference for and consumption of ethanol in a TBC paradigm (3%–11% vol/vol escalating over 10 weeks), with no significant difference observed in TBC with sucrose (1%–3%); (2) significantly greater sedative-like effects of acute ethanol (2.0 or 2.5 g/kg, intraperitoneal [i.p.]) manifested as LORR observed at a lower dose and for longer time, with similar BELs and rates of ethanol clearance; and (3) lower cumulative locomotor activity over 60 minutes in response to an acute ethanol challenge (1.0–2.5 g/kg, i.p.). Conclusions: The present findings are the first to implicate TAAR1 in the behavioral and reinforcement-related effects of ethanol and raise the question of whether specific drugs that target TAAR1 could potentially reduce alcohol consumption in humans with AUDs.
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Trace Amine Associated Receptor 1 Signaling in Activated Lymphocytes
Journal of Neuroimmune Pharmacology, 2012Co-Authors: Michael W. Panas, Eric J Vallender, Helen N Panas, Gregory M. MillerAbstract:Although most research to date on Trace Amine Associated Receptor 1 (TAAR1) has focused on its role in the brain, it has been recognized since its discovery in 2001 that TAAR1 mRNA is expressed in peripheral tissues as well, suggesting that this Receptor may play a role in non-neurological pathways. This study reports TAAR1 expression, signaling and functionality in rhesus monkey lymphocytes. We detected a high level of TAAR1 protein in immortalized rhesus monkey B cell lines and a significant upregulation of TAAR1 protein expression in rhesus monkey lymphocytes following PHA treatment. Through screening a wide range of signaling pathways for their upregulation following TAAR1 activation by its potent agonist methamphetamine, we identified two transcription factors, CREB and NFAT, which are commonly associated with immune activation. Furthermore, we observed a TAAR1-dependent phosphorylation of PKA and PKC following treatment with methamphetamine in transfected HEK293 cells, immortalized rhesus monkey B cells and PHA-activated rhesus monkey lymphocytes. Accordingly, the high levels of TAAR1 that we observed on lymphocytes are inducible and fully functional, capable of transmitting a signal likely via PKA and PKC activation following ligand binding. More importantly, an increase in TAAR1 Receptor expression is concomitant with lymphocyte immune activation, suggesting a possible role for TAAR1 in the generation or regulation of an immune response. TAAR1 is emerging as a potential therapeutic target, with regard to its ability to modulate brain monoamines. The current data raises the possibility that TAAR1-targeted drugs may also alter immune function.
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augmentation of methamphetamine induced behaviors in transgenic mice lacking the Trace amine associated Receptor 1
Pharmacology Biochemistry and Behavior, 2012Co-Authors: Cindy Achatmendes, Eric J Vallender, Laurie J Lynch, Katherine A Sullivan, Gregory M. MillerAbstract:The Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled Receptor that is functionally activated by amphetamine-based psychostimulants, including amphetamine, methamphetamine and MDMA. Previous studies have shown that in transgenic mice lacking the TAAR1 gene (TAAR1 knockout; KO) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild-type (WT) mice. Further, the psychostimulant effects of cocaine can be diminished by selective activation of TAAR1. These findings suggest that TAAR1 might be implicated in the rewarding properties of psychostimulants. To investigate the role of TAAR1 in the rewarding effects of drugs of abuse, the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and TAAR1 KO mice. In locomotor activity studies, both single and repeated exposure to d-amphetamine or methamphetamine generated significantly higher levels of total distance traveled in TAAR1 KO mice compared to WT mice. In conditioned place preference (CPP) studies, TAAR1 KO mice acquired methamphetamine-induced CPP earlier than WT mice and retained CPP longer during extinction training. In morphine-induced CPP, both WT and KO genotypes displayed similar levels of CPP. Results from locomotor activity studies suggest that TAAR1 may have a modulatory role in the behavioral sensitization to amphetamine-based psychostimulants. That methamphetamine-but not morphine-induced CPP was augmented in TAAR1 KO mice suggests a selective role of TAAR1 in the conditioned reinforcing effects of methamphetamine. Collectively, these findings provide support for a regulatory role of TAAR1 in methamphetamine signaling.
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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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Functional Evolution of the Trace Amine Associated Receptors in Mammals and the Loss of TAAR1 in Dogs
BMC evolutionary biology, 2010Co-Authors: Eric J Vallender, Zhihua Xie, Susan V. Westmoreland, Gregory M. MillerAbstract:Background: The Trace amine associated Receptor family is a diverse array of GPCRs that arose before the first vertebrates walked on land. Trace amine associated Receptor 1 (TAAR1) is a wide spectrum aminergic Receptor that acts as a modulator in brain monoaminergic systems. Other Trace amine associated Receptors appear to relate to environmental perception and show a birth-and-death pattern in mammals similar to olfactory Receptors. Results: Across mammals, avians, and amphibians, the TAAR1 gene is intact and appears to be under strong purifying selection based on rates of amino acid fixation compared to neutral mutations. We have found that in dogs it has become a pseudogene. Our analyses using a comparative genetics approach revealed that the pseudogenization event predated the emergence of the Canini tribe rather than being coincident with canine domestication. By assessing the effects of the TAAR1 agonist b-phenylethylamine on [ 3 H]dopamine uptake in canine striatal synaptosomes and comparing the degree and pattern of uptake inhibition to that seen in other mammals, including TAAR1 knockout mice, wild type mice and rhesus monkey, we found that the TAAR1 pseudogenization event resulted in an uncompensated loss of function. Conclusion: The gene family has seen expansions among certain mammals, notably rodents, and reductions in others, including primates. By placing the Trace amine associated Receptors in an evolutionary context we can better understand their function and their potential associations with behavior and neurological disease.
Raul R Gainetdinov - One of the best experts on this subject based on the ideXlab platform.
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putative Trace amine associated Receptor 5 taar5 agonist α neta increases electrocorticogram gamma rhythm in freely moving rats
Cellular and Molecular Neurobiology, 2020Co-Authors: D R Belov, Evgeniya V Efimova, Zoia S Fesenko, Kristina A Antonova, S F Kolodyazhny, Anton M Lakstygal, Raul R GainetdinovAbstract:Cortical gamma rhythm is involved in transmission of information (communication) between brain areas that are believed to be involved in the pathogenesis of cognitive dysfunctions. Trace amines represent a group of endogenous biogenic amines that are known to be involved in modulation of function of classical monoamines, such as dopamine. To evaluate potential modulatory influence of a specific Receptor for Trace amines Trace Amine-Associated Receptor 5 (TAAR5) on the dopamine system, we used HPLC measurements of dopamine and its metabolites in the mouse striatum following administration of the putative TAAR5 agonist α-NETA. Administration of α-NETA caused significant modulation of dopaminergic system as evidenced by an altered dopamine turnover rate in the striatum. Then, to evaluate potential modulatory influence of TAAR5 on the rat brain gamma rhythm, we investigated the changes of electrocorticogram (ECoG) spectral power in the gamma-frequency range (40–50 Hz) following administration of the putative TAAR5 agonist α-NETA. In addition, we analyzed the changes of spatial synchronization of gamma oscillations of rat ECoG by multichannel recording. Significant complex changes were observed in the ECoG spectrum, including an increase in the spectral power in the ranges of delta (1 Hz), theta (7 Hz), and gamma rhythms (40–50 Hz) after the introduction of α-NETA. Furthermore, a decrease in the spatial synchronization of gamma oscillations of 40-50 Hz and its increase for theta oscillations of 7 Hz were detected after the introduction of α-NETA. In conclusion, putative TAAR5 agonist α-NETA can modulate striatal dopamine transmission and cause significant alterations of gamma rhythm of brain activity in a manner consistent with schizophrenia-related deficits described in humans and experimental animals. These observations suggest a role of TAAR5 in the modulation of cognitive functions affected in brain pathologies.
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The Action of TAAR1 Agonist RO5263397 on Executive Functions in Rats.
Cellular and molecular neurobiology, 2019Co-Authors: A Dorotenko, Raul R Gainetdinov, Antonina Dolgorukova, M. A. Tur, Nikita Bortnikov, Irina V Belozertseva, Edwin Zvartau, I. SukhanovAbstract:Trace Amine-Associated Receptor 1 (TAAR1) is a widely recognized new perspective target for the neuropsychiatric pharmacological treatment. Despite a growing number of studies investigating TAAR1 role in the animal models of different pathologies, information of TAAR1 agonists impact on executive cognitive functions is limited. The goal of the present study was to evaluate the activity of highly selective partial TAAR1 agonist RO5263397 on various executive cognitive functions. The results of the present study demonstrated that the pretreatment with RO5263397 was able to increase attention and decrease cognitive flexibility in rats. The analysis of the RO5263397 action on impulsivity demonstrated that the TAAR1 activation failed to affect premature responding but was able to slightly modify impulsive choice. Problem solving was resistant to the pharmacological intervention.
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taar5 Receptor agonist affects sensory gating in rats
Neuroscience Letters, 2018Co-Authors: Aleksander A. Aleksandrov, Veronika M. Knyazeva, Anna . Volnova, Elena S. Dmitrieva, Andrey S. Gerasimov, Raul R GainetdinovAbstract:Abstract Trace amines are structurally close to classical monoamines and dysregulation in Trace amines and/or their Receptors might contribute to pathology of mental disorders. The study was aimed to investigate the effect of recently identified Trace Amine-Associated Receptor 5 (TAAR5) agonist 2-(alpha-naphthoyl)ethyltrimethylammonium iodide (alpha-NETA) on sensory gating (SG) in awake freely moving rats. SG was studied in paired-click paradigm and SG index was calculated as difference in event related potentials component N40 amplitudes to the first and second stimulus in the pair. The 1 mg/kg dose of alpha-NETA as well as the control injection of saline had no significant effects on the SG index. However, higher doses of alpha-NETA (3 and 5 mg/kg) significantly decreased the SG index. The change in the SG index was mainly due to a decrease in the N40 amplitude, and the 5 mg/kg dose caused the N40 decrease both in response to the first and second stimulus in the pair. Thus, TAAR5 activation can influence SG, indicating the potential role of Trace amines and TAAR5 in sensory information dosing.
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Increased context-dependent conditioning to amphetamine in mice lacking TAAR1
'Elsevier BV', 2016Co-Authors: I. Sukhanov, L. Caffino, E.v. Efimova, S. Espinoza, T.d. Sotnikova, L. Cervo, F. Fumagalli, Raul R GainetdinovAbstract:Given the recent evidence indicating that amphetamine derivatives may also act as direct agonists of the G protein-coupled Trace Amine-Associated Receptor 1 (TAAR1), we hypothesized that TAAR1 could contribute to the reinforcing and addictive properties of amphetamines. Accordingly, the present study aimed to investigate the role of TAAR1 in the effects of psychostimulants by analyzing context-dependent sensitization and conditioned place preference (CPP) to d-amphetamine (AMPH) in TAAR1-KO mice. In context-dependent sensitization experiment, TAAR1-KO mice showed higher conditioned locomotor responses compared to wild-type mice. In the CPP test, TAAR1-KO animals were also more sensitive to priming-induced reinstatement of AMPH-induced conditioned place preference (CPP) than wild type mice. Importantly, saline-treated and AMPH-treated mice lacking TAAR1 demonstrated significant alterations in the total levels and phosphorylation of the critical subunit of NMDA glutamate Receptors, GluN1, in the striatum, suggesting a role of TAAR1 in the modulation of frontostriatal glutamate transmission; this effect could underlie the observed alterations in conditioning processes. In conclusion, our data suggest that TAAR1 Receptors play an inhibitory role with respect to conditioned responses to AMPH by modulating, at least in part, corticostriatal glutamate transmissio
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insights into the structure and pharmacology of the human Trace amine associated Receptor 1 htaar1 homology modelling and docking studies
Chemical Biology & Drug Design, 2013Co-Authors: Elena Cichero, Raul R Gainetdinov, Stefano Espinoza, Livio Brasili, Paola FossaAbstract:Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled Receptor that belongs to the family of TAAR Receptors and responds to a class of compounds called Trace amines, such as β-phenylethylamine (β-PEA) and 3-iodothyronamine (T(1)AM). The Receptor is known to have a very rich pharmacology and could be also activated by other classes of compounds, including adrenergic and serotonergic ligands. It is expected that targeting TAAR1 could provide a novel pharmacological approach to correct monoaminergic dysfunctions found in several brain disorders, such as schizophrenia, depression, attention deficit hyperactivity disorder and Parkinson's disease. Only recently, the first selective TAAR1 agonist RO5166017 has been identified. To explore the molecular mechanisms of protein-agonist interaction and speed up the identification of new chemical entities acting on this biomolecular target, we derived a homology model for the hTAAR1. The putative protein-binding site has been explored by comparing the hTAAR1 model with the β(2)-adrenoReceptor binding site, available by X-ray crystallization studies, and with the homology modelled 5HT(1A) Receptor. The obtained results, in tandem with docking studies performed with RO5166017, β-PEA and T(1)AM, provided an opportunity to reasonably identify the hTAAR1 key residues involved in ligand recognition and thus define important starting points to design new agonists.
David K. Grandy - One of the best experts on this subject based on the ideXlab platform.
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Trace amine associated Receptor 1 localization at the apical plasma membrane domain of fisher rat thyroid epithelial cells is confined to cilia
European thyroid journal, 2015Co-Authors: Joanna Szumska, David K. Grandy, Maren Rehders, Heike Biebermann, Josef Köhrle, Maria Qatato, Dagmar Fuhrer, Klaudia BrixAbstract:Background: The Trace Amine-Associated Receptor 1 (Taar1) is one member of the Taar family of G-protein-coupled Receptors (GPCR) accepting various biogenic amines as ligands. It has been proposed that Taar1 mediates rapid, membrane-initiated effects of thyronamines, the endogenous decarboxylated and deiodinated relatives of the classical thyroid hormones T4 and T3. Objectives: Although the physiological actions of thyronamines in general and 3-iodothyronamine (T1AM) in particular are incompletely understood, studies published to date suggest that synthetic T1AM-activated Taar1 signaling antagonizes thyromimetic effects exerted by T3. However, the location of Taar1 is currently unknown. Methods: To fill this gap in our knowledge we employed immunofluorescence microscopy and a polyclonal antibody to detect Taar1 protein expression in thyroid tissue from Fisher rats, wild-type and taar1-deficient mice, and in the polarized FRT cells. Results: With this approach we found that Taar1 is expressed in the membranes of subcellular compartments of the secretory pathway and on the apical plasma membrane of FRT cells. Three-dimensional analyses further revealed Taar1 immunoreactivity in cilial extensions of postconfluent FRT cell cultures that had formed follicle-like structures. Conclusions: The results suggest Taar1 transport along the secretory pathway and its accumulation in the primary cilium of thyrocytes. These findings are of significance considering the increasing interest in the role of cilia in harboring functional GPCR. We hypothesize that thyronamines can reach and activate Taar1 in thyroid follicular epithelia by acting from within the thyroid follicle lumen, their potential site of synthesis, as part of a nonclassical mechanism of thyroid autoregulation.
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ractopamine a livestock feed additive is a full agonist at Trace amine associated Receptor 1
Journal of Pharmacology and Experimental Therapeutics, 2014Co-Authors: Xuehong Liu, David K. Grandy, Aaron JanowskyAbstract:Ractopamine (RAC) is fed to an estimated 80% of all beef, swine, and turkey raised in the United States. It promotes muscle mass development, limits fat deposition, and reduces feed consumption. However, it has several undesirable behavioral side effects in livestock, especially pigs, including restlessness, agitation, excessive oral-facial movements, and aggressive behavior. Numerous in vitro and in vivo studies suggest RAC’s physiological actions begin with its stimulation of β1- and β2-adrenergic Receptor–mediated signaling in skeletal muscle and adipose tissue; however, the molecular pharmacology of RAC’s psychoactive effects is poorly understood. Using human cystic fibrosis transmembrane conductance regulator (hCFTR) chloride channels as a sensor for inTracellular cAMP, we found that RAC and p-tyramine (TYR) produced concentration-dependent increases in chloride conductance in oocytes coexpressing hCFTR and mouse Trace amine–associated Receptor 1 (mTAAR1), which was completely reversed by the Trace amine–associated Receptor 1 (TAAR1)–selective antagonist EPPTB [N-(3-ethoxyphenyl)-4-pyrrolidin-1-yl-3-trifluoromethylbenzamide]. Oocytes coexpressing hCFTR and the human β2-adrenergic Receptor showed no response to RAC or TYR. These studies demonstrate that, contrary to expectations, RAC is not an agonist of the human β2-adrenergic Receptor but rather a full agonist for mTAAR1. Since TAAR1-mediated signaling can influence cardiovascular tone and behavior in several animal models, our finding that RAC is a full mTAAR1 agonist supports the idea that this novel mechanism of action influences the physiology and behavior of pigs and other species. These findings should stimulate future studies to characterize the pharmacological, physiological, and behavioral actions of RAC in humans and other species exposed to this drug.
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exploring the determinants of Trace amine associated Receptor 1 s functional selectivity for the stereoisomers of amphetamine and methamphetamine
Journal of Medicinal Chemistry, 2014Co-Authors: Edmund A Reese, James R Bunzow, Katherine L Suchland, Yohei Norimatsu, Madeline Grandy, David K. GrandyAbstract:Amphetamines are widely abused drugs that interfere with dopamine transport and storage. Recently, however, another mechanism of action was identified: stereoselective activation of the GαS protein-coupled Trace Amine-Associated Receptor 1 (TAAR1). To identify structural determinants of this stereoselectivity, we functionally evaluated six mutant Receptors in vitro and then used homology modeling and dynamic simulation to predict drug affinities. Converting Asp102 to Ala rendered mouse and rat TAAR1 (mTAAR1 and rTAAR1, respectively) insensitive to β-phenylethylamine, amphetamine (AMPH), and methamphetamine (METH). Mutating Met268 in rTAAR1 to Thr shifted the concentration–response profiles for AMPH and METH isomers rightward an order of magnitude, whereas replacing Thr268 with Met in mTAAR1 resulted in profiles leftward shifted 10–30-fold. Replacing Asn287 with Tyr in rTAAR1 produced a mouselike Receptor, while the reciprocal mTAAR1 mutant was rTAAR1-like. These results confirm TAAR1 is an AMPH/METH recep...
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The Molecular Basis of Species-Specific Ligand Activation of Trace Amine-Associated Receptor 1 (TAAR1)
ACS Chemical Biology, 2009Co-Authors: Edwin S. Tan, David K. Grandy, John C. Naylor, Eli S. Groban, Matthew P. Jacobson, James R Bunzow, Thomas S ScanlanAbstract:The Trace Amine-Associated Receptor 1 (TAAR1) is an aminergic G protein-coupled Receptor (GPCR) potently activated by 3-iodothyronamine (1), an endogenous derivative of thyroid hormone. Structure−activity relationship studies on 1 and related agonists showed that the rat and mouse species of TAAR1 accommodated structural modifications and functional groups on the ethylamine portion and the biaryl ether moiety of the molecule. However, the two Receptors clearly exhibited distinct, species-specific ligand preferences despite being remarkably similar with 93% sequence similarity. In this study, we generated single and double mutants of rat and mouse TAAR1 to probe the molecular recognition of agonists and the underlying basis for the ligand selectivity of rat and mouse TAAR1. Key, nonconserved specificity determinant residues in transmembranes helices 4 and 7 within the ligand binding site appear to be the primary source of a number of the observed ligand preferences. Residue 7.39 in transmembrane 7 dictated...
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Trace amine associated Receptor 1 family archetype or iconoclast
Pharmacology & Therapeutics, 2007Co-Authors: David K. GrandyAbstract:Abstract Interest has recently been rekindled in Receptors that are activated by low molecular weight, noncatecholic, biogenic amines that are typically found as Trace constituents of various vertebrate and invertebrate tissues and fluids. The timing of this resurgent focus on Receptors activated by the “Trace amines” (TA) β-phenylethylamine (PEA), tyramine (TYR), octopamine (OCT), synephrine (SYN), and tryptamine (TRYP) is the direct result of 2 publications that appeared in 2001 describing the cloning of a novel G protein-coupled Receptor (GPCR) referred to by their discoverers Borowsky et al. as TA1 and Bunzow et al. as TA Receptor 1 (TAR1). When heterologously expressed in Xenopus laevis oocytes and various eukaryotic cell lines, recombinant rodent and human TAR dose-dependently couple to the stimulation of adenosine 3′,5′-monophosphate (cAMP) production. Structure–activity profiling based on this functional response has revealed that in addition to the TA, other biologically active compounds containing a 2-carbon aliphatic side chain linking an amino group to at least 1 benzene ring are potent and efficacious TA Receptor agonists with amphetamine (AMPH), methamphetamine, 3-iodothyronamine, thyronamine, and dopamine (DA) among the most notable. Almost 100 years after the search for TAR began, numerous TA1/TAR1-related sequences, now called TA-associated Receptors (TAAR), have been identified in the genome of every species of vertebrate examined to date. Consequently, even though heterologously expressed TAAR1 fits the pharmacological criteria established for a bona fide TAR, a major challenge for those working in the field is to discern the in vivo pharmacology and physiology of each purported member of this extended family of GPCR. Only then will it be possible to establish whether TAAR1 is the family archetype or an iconoclast.