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.

14 Reads
    • "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. "
    [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
    • "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). "
    [Show abstract] [Hide abstract]
    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
    • "Taar1 − / − mice also display greater locomotor stimulation to amphetamine and MA (Achat-Mendes et al, 2012; Lindemann et al, 2008; Wolinsky et al, 2007), consistent with the idea that TAAR1 function is important for counteracting some MA effects. However, the role of TAAR1 function in sensitivity to aversive effects of MA has not been examined. "
    [Show abstract] [Hide abstract]
    ABSTRACT: 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 cosegregates 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 MAinduced CTA and hypothermia, compared to Taar1 wildtype 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 increases sensitivity to aversive effects of MA, and may thereby protect against MA use.
    Neuropsychopharmacology 03/2015; · 7.05 Impact Factor
Show more