Trace Amine-Associated Receptor 1 Modulates Dopaminergic Activity

Pharmaceuticals Division, Central Nervous System Research, Department PRDNP5 CH, Bldg. 70/331, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 04/2008; 324(3):948-56. DOI: 10.1124/jpet.107.132647
Source: PubMed


The recent identification of the trace amine-associated receptor (TAAR)1 provides an opportunity to dissociate the effects of trace amines on the dopamine transporter from receptor-mediated effects. To separate both effects on a physiological level, a Taar1 knockout mouse line was generated. Taar1 knockout mice display increased sensitivity to amphetamine as revealed by enhanced amphetamine-triggered increases in locomotor activity and augmented striatal release of dopamine compared with wild-type animals. Under baseline conditions, locomotion and extracellular striatal dopamine levels were similar between Taar1 knockout and wild-type mice. Electrophysiological recordings revealed an elevated spontaneous firing rate of dopaminergic neurons in the ventral tegmental area of Taar1 knock-out mice. The endogenous TAAR1 agonist p-tyramine specifically decreased the spike frequency of these neurons in wild-type but not in Taar1 knockout mice, consistent with the prominent expression of Taar1 in the ventral tegmental area. Taken together, the data reveal TAAR1 as regulator of dopaminergic neurotransmission.

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    • "Upon activation , TAAR1 signals via Gas proteins leading to increased intracellular cAMP levels [1,4e6]. Taar1 knockout mice expressing the LacZ gene under control of the Taar1 promoter (Taar1 À/À /LacZ) demonstrated TAAR1 expression in restricted areas of the brain, where it modulates monoaminergic neurotransmission [2] [7]. Therefore, TAAR1 recently emerged as a novel target for the treatment of psychiatric disorders [7e9]. "
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    ABSTRACT: Type 2 diabetes and obesity are emerging pandemics in the 21st century creating worldwide urgency for the development of novel and safe therapies. We investigated trace amine-associated receptor 1 (TAAR1) as a novel target contributing to the control of glucose homeostasis and body weight.
    Molecular Metabolism 11/2015; DOI:10.1016/j.molmet.2015.09.015
    • "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). Taken together, these observations indicate that TAAR1 is a key neuromodulator of DA transmission. "
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    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
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    • "Recently, TAAR1 functions have been extensively characterized, with particular attention paid to its role in the modulation of the midbrain dopamine system and its possible implications in psychiatric diseases (Borowsky et al, 2001; Bunzow et al, 2001; Lindemann and Hoener, 2005; Sotnikova et al, 2009; Leo et al, 2014; Sukhanov et al, 2014). TAAR1 knockout (TAAR1-KO) mice display a higher sensitivity to amphetamine and other psychostimulants (Wolinsky et al, 2007; Lindemann et al, 2008; Di Cara et al, 2011), and seem to have a supersensitive dopaminergic system (Wolinsky et al, 2007; Lindemann et al, 2008), making them an interesting model relevant for schizophrenia (Wolinsky et al, 2007). Accordingly, both full and partial TAAR1-selective agonists are efficacious in experimental rodent models of psychosis, such as pharmacologic or genetic mouse models of hyperdopaminergia, further supporting the idea that TAAR1 could represent a novel target for psychiatric diseases (Sotnikova et al, 2009; Espinoza and Gainetdinov, 2014). "
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    ABSTRACT: Trace Amine-Associated Receptor 1 (TAAR1) is a G protein-coupled receptor expressed in the mammalian brain and known to influence subcortical monoaminergic transmission. Monoamines, such as dopamine, play also an important role within the prefrontal cortex (PFC) circuitry, which is critically involved in high order cognitive processes. TAAR1 selective ligands have shown potential antipsychotic, antidepressant and pro-cognitive effects in experimental animal models; however, it remains unclear if TAAR1 can affect PFC-related processes and functions. In this study, we document distinct pattern of expression of TAAR1 in the PFC, as well as altered subunit composition and deficient functionality of the glutamate N-methyl-D-aspartate (NMDA) receptors in the pyramidal neurons of layer V of PFC in mice lacking TAAR1. The dysregulated cortical glutamate transmission in TAAR1-KO mice was associated with aberrant behaviors in several tests, indicating a perseverative and impulsive phenotype of mutants. Conversely, pharmacological activation of TAAR1 with selective agonists reduced premature impulsive responses observed in the fixed-interval conditioning schedule in normal mice. Our study indicates that TAAR1 plays an important role in the modulation of NMDA receptor-mediated glutamate transmission in the PFC and related functions. Furthermore, these data suggest that development of TAAR1-based drugs could provide a novel therapeutic approach for the treatment of disorders related to aberrant cortical functions.Neuropsychopharmacology accepted article preview online, 09 March 2015. doi:10.1038/npp.2015.65.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 03/2015; 40(9). DOI:10.1038/npp.2015.65 · 7.05 Impact Factor
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