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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Available from: Marius C Hoener, Jan 03, 2016
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    • "It has been demonstrated that the firing rate of dopaminergic neurons in the ventral tegmental area (VTA) was higher in the TAAR1 knockout mice compared with wild-type mice. The endogenous TAAR1 agonist p-tyramine decreased the spike frequency of VTA dopaminergic neurons in wild-type mice (Lindemann et al., 2008). RO5166017 also decreased the firing of DA neurons in a manner similar to p-tyramine (Revel et al., 2011). "
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    ABSTRACT: Background: As a modulator of dopaminergic system, trace amine-associated receptor 1 (TAAR1) has been shown playing a critical role in regulating the rewarding properties of addicted drugs. It has been demonstrated that activation of TAAR1 decreased the abuse-related behaviors of cocaine in rats. However, the role of TAAR1 in specific stages of cocaine reward memory is still unclear. Methods: Here, using cocaine-induced conditioned place preference (CPP) model, we tested the effects of a selective TAAR1 agonist RO5166017 on the expression, reconsolidation, and extinction of cocaine reward memory. Results: We found that RO5166017 inhibited the expression but not retention of cocaine-induced CPP. RO5166017 had no effect on the reconsolidation of cocaine reward memory. Pretreatment RO5166017 before extinction hindered the formation of extinction long-term memory. RO5166017 did not affect the movement during the CPP test, indicating the inhibitory effect of RO5166017 on the expression of cocaine-induced CPP was not caused by locomotion inhibition. Using cocaine intravenous self-administration model, we found that the combined TAAR1 partial agonist RO5263397 with extinction had no effect on the following cue- and drug-induced reinstatement of cocaine-seeking behavior. Repeated administration of the TAAR1 agonist during extinction showed a continually inhibitory effect on the expression of cocaine reward memory both in cocaine-induced CPP and cocaine self-administration models. Conclusions: Taken together, these results indicated that activation of TAAR1 specifically inhibited the expression of cocaine reward memory. The inhibitory effect of TAAR1 agonists on cocaine reward memory suggests that TAAR1 agonists could be a promising agent to prevent cocaine relapse.
    Preview · Article · Jan 2016 · The International Journal of Neuropsychopharmacology
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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: Objective: 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. Methods: We investigated the peripheral human tissue distribution of TAAR1 by immunohistochemistry and tested the effect of a small molecule TAAR1 agonist on insulin secretion in vitro using INS1E cells and human islets and on glucose tolerance in C57Bl6, and db/db mice. Body weight effects were investigated in obese DIO mice. Results: TAAR1 activation by a selective small molecule agonist increased glucose-dependent insulin secretion in INS1E cells and human islets and elevated plasma PYY and GLP-1 levels in mice. In diabetic db/db mice, the TAAR1 agonist normalized glucose excursion during an oral glucose tolerance test. Sub-chronic treatment of diet-induced obese (DIO) mice with the TAAR1 agonist resulted in reduced food intake and body weight. Furthermore insulin sensitivity was improved and plasma triglyceride levels and liver triglyceride content were lower than in controls. Conclusions: We have identified TAAR1 as a novel integrator of metabolic control, which acts on gastrointestinal and pancreatic islet hormone secretion. Thus TAAR1 qualifies as a novel and promising target for the treatment of type 2 diabetes and obesity.
    Full-text · Article · Nov 2015 · Molecular Metabolism
    • "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.
    No preview · Article · Jun 2015 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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