Trace amine-associated receptor 1 is a modulator of the dopamine transporter.
ABSTRACT 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.
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ABSTRACT: Modafinil, in its two clinical formulations (Provigil(®) and Nuvigil(®)), is a widely prescribed wake-promoting therapeutic agent. It binds competitively to the cell-membrane dopamine (DA) transporter and is dependent on catecholaminergic (dopaminergic and adrenergic) signaling for its wake-promoting effects. The clinical spectrum of effects for modafinil is distinct from the effects seen with other catecholaminergic agents. Relative to other commonly used agents that act through catecholaminergic mechanisms, modafinil has a relatively low abuse potential, produces wakefulness with an attenuated compensatory sleep recovery thereafter, and does not ameliorate cataplexy in narcolepsy. These clinically relevant phenomenological differences between modafinil and agents such as amphetamines and cocaine do not eliminate catecholaminergic effects as a possible mediator of its wake-promoting action; they merely reflect its unique pharmacological profile. Modafinil is an exceptionally weak, but apparently very selective, DA transporter inhibitor. The pharmacodynamic response to modafinil, as measured by DA levels in brain microdialyzate, is protracted relative to other agents that act via catecholaminergic mechanisms. The conformational constraints on the interaction of modafinil with the DA transporter - and probably, as a consequence, its effects on trace amine receptor signaling in the catecholaminergic cell - are unique among catecholaminergic agents. These unique pharmacological properties of modafinil should be considered both in seeking to thoroughly understand its putatively elusive mechanism of action and in the design of novel therapeutic agents.Frontiers in Neurology 01/2013; 4:139.
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ABSTRACT: Recent pharmacological studies has been shown the importance of trace amine-associated receptor, type 1 (TAAR1), a subtype of trace amine receptors, as a prospective target receptor for novel neuroleptics. In the present article, the author shows D-neuron research in psychiatric field. Although dopamine (DA) dysfunction is a well-known hypothesis of etiology of schizophrenia, its molecular basis has not yet been clarified. To explain this, modulating function of trace amines on DA neurotransmission was considered. The TAAR1 has a large number of ligands, including tyramine, β-phenylethylamine and methamphetamine that influence on human mental state. Reduced stimulation of TAAR1 on DA neurons in the midbrain ventral tegmental area (VTA) has been revealed to increase firing frequency of VTA DA neurons. Previously, the author and her colleagues reported D-neuron decrease in the striatum including nucleus accumbens of postmortem brains of patients with schizophrenia. This implies the decrease of trace amine synthesis and consequent reduction of TAAR1 stimulation on terminals of midbrain VTA DA neurons, and may lead to mesolimbic DA hyperactivity in schizophrenia. Striatal D-neuron decrease of postmortem brains, due to neural stem cell dysfunction in the subventricular zone of lateral ventricle, might be pivotal in etiology of schizophrenia. The new “D-cell hypothesis”, in which D-neurons and TAAR1 are involved, is concordant with recent reports showing effectiveness of TAAR1 ligands for schizophrenia model animals.Journal of Community Medicine & Health Education. 07/2013; 3(4):221.
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ABSTRACT: The trace amine-associated receptor 1 (TAAR1) has emerged as a promising target for medication development in addiction due to its ability to regulate dopamine (DA) transmission. We tested in rats the efficacy of RO5203648 and RO5256390, partial and full TAAR1 agonists, respectively, in models of cocaine relapse. Using a model of context-induced relapse, both RO5203648 and RO5256390 dose-dependently suppressed cocaine seeking after a 2-week period of withdrawal from chronic cocaine self-administration. In a model of extinction-reinstatement, RO5203648 completely inhibited cocaine-primed reinstatement of cocaine seeking. At doses that effectively suppressed cocaine seeking neither RO5203648 nor RO5256390 altered responding maintained by a natural reward. Moreover, fast-scan cyclic voltammetry data showed that RO5203648 prevented cocaine-induced DA overflow in the nucleus accumbens without altering DA half-life, suggesting that the partial TAAR1 agonist attenuated cocaine-stimulated DA overflow by mechanisms other than direct interference with DA uptake. Collectively, these data provide strong evidence in support of TAAR1 as a neuropharmacological target for the treatment of cocaine addiction.Neuropsychopharmacology accepted article peview online, 11 April 2014. doi:10.1038/npp.2014.88.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 04/2014; · 8.68 Impact Factor