Xie Z, Miller GM. Trace Amine-Associated Receptor 1 is a Modulator of the Dopamine Transporter. J Pharmacol Exp Ther 321: 128-136

Harvard University, Cambridge, Massachusetts, United States
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 05/2007; 321(1):128-36. DOI: 10.1124/jpet.106.117382
Source: PubMed


Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor activated by a broad range of monoamines and amphetamine-related psychostimulants. Recent studies demonstrated wide distribution of TAAR1 in brain, coexpression of TAAR1 with dopamine transporter (DAT) in a subset of dopamine neurons in both mouse and rhesus monkey substantia nigra, and monoamine transporter-modulated activation. This study explored whether TAAR1 could influence DAT-mediated dopamine uptake and efflux. Rhesus monkey TAAR1 expressed with DAT in human embryonic kidney 293 cells was dose-dependently activated by dopamine or (+)-methamphetamine. This activation resulted in large cAMP increases and a transient reduction in [3H]dopamine accumulation within the cells, which was similar to the effect of dopamine D1 receptor (D1) or forskolin treatment. In addition, TAAR1 effects on dopamine uptake could be blocked by a protein kinase A or protein kinase C (PKC) inhibitor. [3H]Dopamine efflux assays performed in Dulbecco's modified Eagle's medium displayed a TAAR1-dependent spontaneous [3H]dopamine efflux that was dose-dependently augmented by dopamine or (+)-methamphetamine and that was blocked by either methylphenidate or a PKC inhibitor. DAT cells in Krebs-HEPES buffer had an apparent spontaneous [3H]dopamine loss, but it could not be blocked by either methylphenidate or a PKC inhibitor. Taken together, this study provides evidence that TAAR1 is involved in functional regulation of DAT and suggests that TAAR1 is a potentially important target for therapeutics for methamphetamine addiction.

4 Reads
    • "TAAR1 belongs to a family of G protein-coupled receptors that was found to be activated by trace amines (TAs) (Borowsky et al., 2001; Bunzow et al., 2001), a group of endogenous amines that have long been implicated in the psychoactive actions of motor stimulants (Berry, 2004; Burchett and Hicks, 2006). TAAR1 is expressed in brain monoaminergic nuclei and colocalized with the DAT in a subset of DA neurons (Borowsky et al., 2001; Lindemann et al., 2008; Xie and Miller, 2007). Genetic deletion of Taar1 leads to elevated spontaneous discharge of DA neurons in the ventral tegmental area (VTA) (Lindemann et al., 2008), increased DA level in the nucleus accumbens (NAc) (Leo et al., 2014), enhanced sensitivity to psychostimulantinduced hyperactivity, and conditioned place preference (CPP) (Achat- Mendes et al., 2012) and elevated striatal DA release (Lindemann et al., 2008; Wolinsky et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The newly discovered trace amine-associated receptor 1 (TAAR1) has emerged as a promising target for medication development in stimulant addiction due to its ability to regulate dopamine (DA) function and modulate stimulants' effects. Recent findings indicate that TAAR1 activation blocks some of the abuse-related physiological and behavioural effects of cocaine. However, findings from existing self-administration studies are inconclusive due to the very limited range of cocaine unit doses tested. Here, in order to shed light on the influence of TAAR1 on cocaine's reward and reinforcement, we studied the effects of partial and full activation of TAAR1on (1) the dose-response curve for cocaine self-administration and (2) cocaine-induced changes in intracranial self-stimulation (ICSS). In the first experiment, we examined the effects of the selective full and partial TAAR1 agonists, RO5256390 and RO5203648, on self-administration of five unit-injection doses of cocaine (0.03, 0.1, 0.2, 0.45 and 1mg/kg/infusion). Both agonists induced dose-dependent downward shifts in the cocaine dose-response curve, indicating that both partial and full TAAR1 activation decrease cocaine reinforcing efficacy. In the second experiment, RO5256390 and the partial agonist, RO5263397, dose-dependently prevented cocaine-induced lowering of ICSS thresholds. Taken together, these data demonstrated that TAAR1 stimulation effectively suppresses the rewarding and reinforcing effects of cocaine in self-administration and ICSS models, supporting the candidacy of TAAR1 as a drug discovery target for cocaine addiction. Copyright © 2015. Published by Elsevier Inc.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 06/2015; 63. DOI:10.1016/j.pnpbp.2015.05.014 · 3.69 Impact Factor
  • Source
    • "TAs have been implicated in brain reward and in the reinforcing properties of psychostimulants (Gilbert and Cooper, 1983; Shannon and Thompson, 1984), albeit their independent role as neurotransmitters was not recognized until TAAR1 was discovered and characterized (Borowsky et al., 2001; Bunzow et al., 2001). TAAR1 shares overlapping distribution in the brain with mesolimbic DA pathways (Borowsky et al., 2001; Lindemann et al., 2008), is co-localized with the DAT in a subset of DA neurons (Xie and Miller, 2007), and interacts with both the DAT and the D2 DA autoreceptor (D2R) to modulate DA transmission (Xie et al., 2007, 2008; Espinoza et al., 2011). These observations suggest that TAAR1 regulates DA activity and has the potential to serve as a pharmacological target to modulate DA dysregulation that results from chronic stimulant exposure. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The newly discovered trace amine-associated receptor 1 (TAAR1) has the ability to regulate both dopamine function and psychostimulant action. Here, we tested in rats the ability of RO5203648, a selective TAAR1 partial agonist, to modulate the physiological and behavioural effects of methamphetamine (METH). In experiment 1, RO5203468 dose- and time-dependently altered METH-induced locomotor activity, manifested as an early attenuation followed by a late potentiation of METH’s stimulating effects. In experiment 2, rats received a 14-day treatment regimen during which RO5203648 was co-administered with METH. RO5203648 dose-dependently attenuated METH-stimulated hyperactivity, with the effects becoming more apparent as the treatments progressed. After chronic exposure and 3-day withdrawal, rats were tested for locomotor sensitization. RO5203648 administration during the sensitizing phase prevented the development of METH sensitization. However, RO5203648, at the high dose, cross-sensitized with METH. In experiment 3, RO5203648 dose-dependently blocked METH self-administration without affecting operant responding maintained by sucrose, and exhibited lack of reinforcing efficacy when tested as a METH’s substitute. Neurochemical data showed that RO5203648 did not affect METH-mediated DA efflux and uptake inhibition in striatal synaptosomes. In vivo, however, RO5203648 was able to transiently inhibit METH-induced accumulation of extracellular DA levels in the nucleus accumbens. Taken together, these data highlight the significant potential of TAAR1 to modulate METH’s neurochemical and behavioural effects.
    Frontiers in Neuroscience 02/2015; 9(39). DOI:10.3389/fnins.2015.00039 · 3.66 Impact Factor
  • Source
    • ", while older studies have shown trace amines post - synaptically modulate mon - oamine neurotransmission ( Paterson , 1988 , 1993 ) . TAAR1 - mediated regulation of dopamine D 2 receptor ( Bradaia et al . , 2009 ; Espinoza et al . , 2011 ; Wolinsky et al . , 2007 ) , as well as 5 - HT 1a receptor ( Espinoza et al . , 2011 ; Revel et al . , 2011 ; Xie et al . , 2007 ) medi - ated effects has also been reported . In contrast , no effect of trace amines on dopamine D 1 receptor ligand binding was observed ( Berry , 2011 ) . The potential in - tracellular localization of TAAR1 necessitates that trace amines readily cross cell membranes in order to act post - synaptically . This has previously been ass"
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Synapse 10/2013; 67(10). DOI:10.1002/syn.21670 · 2.13 Impact Factor
Show more