Rhesus Monkey Trace Amine-Associated Receptor 1 Signaling: Enhancement by Monoamine Transporters and Attenuation by the D2 Autoreceptor in Vitro

Xie, Zhihua; Westmoreland, Susan V.; Bahn, Mary E.; Chen, Guo-Lin; Yang, Hong; Vallender, Eric J.; Yao, Wei‐Dong; Madras, Bertha K.; Miller, Gregory M.

doi:10.1124/jpet.106.116863

Cited by 103 publications

(156 citation statements)

References 37 publications

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“…Immunoblot verified that both the functional B6-and the non-functional D2-like receptors were expressed in transfected HEK-293 cells. Confocal microscopic analysis of GFPtagged constructs corroborated the immunoblot data, and indicated that both forms of TAAR1 are cytosolic, consistent with previous reports (Bunzow et al, 2001;Xie et al, 2007).…”

Section: Taar1 Function and Ma Consuming Micesupporting

confidence: 76%

Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits

Harkness

Shi

Janowsky

et al. 2015

Neuropsychopharmacol

149

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Continued methamphetamine (MA) use is dependent on a positive MA experience and is likely attenuated by sensitivity to the aversive effects of MA. Bidirectional selective breeding of mice for high (MAHDR) or low (MALDR) voluntary consumption of MA demonstrates a genetic influence on MA intake. Quantitative trait locus (QTL) mapping identified a QTL on mouse chromosome 10 that accounts for greater than 50% of the genetically-determined differences in MA intake in the MAHDR and MALDR lines. The trace amine-associated receptor 1 gene (Taar1) is within the confidence interval of the QTL and encodes a receptor (TAAR1) that modulates monoamine neurotransmission and at which MA serves as an agonist. We demonstrate the existence of a non-functional allele of Taar1 in the DBA/2J mouse strain, one of the founder strains of the selected lines, and show that this non-functional allele co-segregates with high MA drinking and with reduced sensitivity to MA-induced conditioned taste aversion (CTA) and hypothermia. The functional Taar1 allele, derived from the other founder strain, C57BL/6J, segregates with low MA drinking and heightened sensitivity to MA-induced CTA and hypothermia. A role for TAAR1 in these phenotypes is corroborated in Taar1 transgenic mice: Taar1 knockout mice consume more MA and exhibit insensitivity to MA-induced CTA and hypothermia, compared with Taar1 wild-type mice. These are the first data to show that voluntary MA consumption is, in part, regulated by TAAR1 function. Behavioral and physiological studies indicate that TAAR1 function increases sensitivity to aversive effects of MA, and may thereby protect against MA use.

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Section: Taar1 Function and Ma Consuming Micesupporting

confidence: 76%

Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits

Harkness

Shi

Janowsky

et al. 2015

Neuropsychopharmacol

149

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“…We previously demonstrated that TAAR1 could modulate DAT function and that the dopamine D2 autoreceptor (D2s) could attenuate TAAR1 signaling in vitro (Xie and Miller, 2007;Xie et al, 2007b). We have also reported TAAR1 and DAT colocalization in a subset of dopamine neurons in rhesus monkey and mouse substantia nigra (Xie et al, 2007b).…”

mentioning

confidence: 97%

“…TAAR1 is a G protein-coupled receptor that is widely expressed in brain monoaminergic nuclei (Borowsky et al, 2001;Miller et al, 2005;Xie et al, 2007b) and is activated by a wide spectrum of compounds, including common biogenic amines, trace amines, and amphetamine-like psychostimulant drugs, such as methamphetamine (Bunzow et al, 2001;Miller et al, 2005;Xie et al, 2007b). We previously demonstrated that TAAR1 could modulate DAT function and that the dopamine D2 autoreceptor (D2s) could attenuate TAAR1 signaling in vitro (Xie and Miller, 2007;Xie et al, 2007b).…”

mentioning

confidence: 99%

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

Xie¹,

Westmoreland²,

Miller³

2008

J Pharmacol Exp Ther

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In brain monoaminergic systems, common biogenic amines, including dopamine, norepinephrine, and serotonin, serve as neurotransmitters. Monoamine autoreceptors provide feedback regulation in neurotransmitter release, and monoamine transporters clear the released neurotransmitters to control synaptic signaling. Recently, trace amine-associated receptor 1 (TAAR1) has been found to be expressed in brain monoaminergic nuclei and activated by common biogenic amines in vitro. This study used transfected cells and brain synaptosomes to evaluate the interaction of common biogenic amines with TAAR1 and monoamine autoreceptors and explore their modulatory effects on monoamine transporters. We confirmed that TAAR1 was activated by dopamine, norepinephrine, and serotonin and demonstrated that TAAR1 signaling was attenuated by monoamine autoreceptors at exposure to dopamine, norepinephrine, and serotonin. In transfected cells, TAAR1 in response to dopamine, norepinephrine, and serotonin significantly inhibited uptake and promoted efflux of H]serotonin, respectively, when the monoamine autoreceptors were blocked. By comparing the effects of dopamine, norepinephrine, and serotonin in monkey and wild-type mouse synaptosomes to their effects in TAAR1 knockout mouse synaptosomes, we deduced that TAAR1 activity inhibited uptake and promoted efflux by monoamine transporters and that monoamine autoreceptors exerted opposite effects. These data provide the first evidence that common biogenic amines modulate monoamine transporter function via both TAAR1 and monoamine autoreceptors, which may balance monoaminergic activity.Common biogenic amines are neurotransmitters in brain that are synthesized and packaged in monoaminergic neurons and released into synaptic clefts to interact with presynaptic and postsynaptic receptors. Monoamine transporters, including dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT), clear the released neurotransmitters to terminate neural signaling (Uhl and Johnson, 1994;Masson et al., 1999) and are functionally or dynamically regulated by various chemicals, including psychostimulants and antidepressants (Sulzer et al., 1995;Gutman and Owens, 2006;Fleckenstein et al., 2007). Aberrant transport of common biogenic amines by monoamine transporters in brain is associated with a variety of neuropsychiatric disorders/diseases, such as anxiety, depression, Parkinson's disease, schizophrenia, suicide, and drug abuse/addiction (Klimek et al., 1997;Arango et al., 2002;Schmitt et al., 2006;Serretti et al., 2006). Monoamine autoreceptors, residing on the presynaptic membranes of monoaminergic neurons, monitor and respond to the released common biogenic amines to provide feedback regulation of Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.107.135079. ABBREVIATIONS:DAT, dopamine transporter; 5-HT 1A and 5-HT 1B , subtype A and B of serotonin receptor 1; ␣ 2A and ␣ 2B , subtype A and B of alpha adrenal rec...

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“…Thus TAAR1 is the only subtype phylogenetically conserved in the mammalian brain [20]. Interestingly, Taar1 is expressed throughout the limbic and monoaminergic systems [21,22], thus providing a unique opportunity to modulate ascending aminergic systems specifically, particularly DA and serotonin. Studies with transgenic mice lacking Taar1 (Taar1 -/-mice) revealed that TAAR1 negatively regulates dopaminergic neurotransmission.…”

Section: Paving An Indirect Path To Treat Addictionmentioning

confidence: 99%

The Trace of Non-classical Biogenic Amines: A New Road to Addiction Recovery

Canales¹

2013

J Addict Res Ther

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Stimulant abuse is prevalent according to recent global epidemiological studies. Research into treatment for problematic stimulant abuse has yet to find a suitable pharmacotherapeutic agent to assist with detoxification, withdrawal and relapse prevention. The newly discovered trace amine-associated receptor 1 (TAAR1) constitutes a novel receptor target for medication development with significant potential to treat the pathological changes produced by chronic drug exposure, especially stimulant abuse. Here, I briefly review evidence indicating that TAAR1 modulates the activity of the dopamine system and strongly influences the neurochemical and behavioral actions of psychomotor stimulants. The evidence discussed confirms the view that TAAR1 is a promising candidate receptor for the design of new effective addiction therapies. The Classical Direct ApproachThe classical biogenic amines have been under the spotlight in the fields of neuropharmacology and neuropsychiatry for the past 50 years. Historically, the search for treatments for psychopathological disorders such as depression, anxiety and schizophrenia has focused on the receptors, transporters and metabolic pathways for three catecholamines -dopamine (DA), norepinephrine and epinephrine-, histamine and serotonin, and to a lesser extent on amino acid transmitters and their receptors. Biogenic amines play a fundamental role in modulating a wide variety of physiological and behavioural processes, including autonomic function, hormone regulation and motor control, and are believed to contribute critically to emotional and cognitive function, neurotoxicity and mental disease [1][2][3]. The advent of drugs aimed at these classical targets to treat affective and psychotic disorders remains to this date the single most relevant advance in pharmacotherapy but the discovery of these drugs was serendipitous. It did not derive from the identification of the neuronal and circuitlevel alterations underlying psychiatric illness. This lack of mechanistic understanding hampered the progress and further development of therapeutic agents. An area in which development of pharmacological treatments has been particularly difficult is addiction and addictiverelated disorders, most notably addiction to cocaine and amphetaminetype substances. Stimulant addiction is widely recognized for its treatment challenges [4,5]. Although several forms of non-specific pharmacology are currently in use, including anti-depressants and antiepileptic drugs, there are no specific and proven medications that can be used to facilitate detoxification, enhance retention in psychotherapy and generally promote quicker recovery from chronic stimulant abuse.Changes in DA transmission are critical for understanding the acute and long-term effects of chronic stimulant exposure. The ability of cocaine-like drugs to maintain self-administration in rodents is correlated with their potency in inhibiting the dopamine transporter (DAT) [6]. Moreover, the self-reported "high" induced by stimulants in humans appears ...

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Rhesus Monkey Trace Amine-Associated Receptor 1 Signaling: Enhancement by Monoamine Transporters and Attenuation by the D2 Autoreceptor in Vitro

Cited by 103 publications

References 37 publications

Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits

Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits

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

The Trace of Non-classical Biogenic Amines: A New Road to Addiction Recovery

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