Trace amine associated receptor 1 modulates behavioral effects of ethanol.

BACKGROUND: Few treatment options for alcohol use disorders (AUDs) exist and more are critically needed. Here, we assessed whether trace amine associated receptor 1 (TAAR1), a modulator of brain monoamine systems, is involved in the behavioral and reinforcement-related effects of ethanol and whether it could potentially serve as a therapeutic target. METHODS: Wild-type (WT) and TAAR1 knockout (KO) mice (75% C57J/BL6 and 25% 129S1/Sv background) were compared in tests of ethanol consumption (two-bottle choice [TBC]), motor impairment (loss of righting reflex, [LORR], locomotor activity) and ethanol clearance (blood ethanol level [BEL]). RESULTS: As compared with WT mice, KO mice displayed (1) significantly greater preference for and consumption of ethanol in a TBC paradigm (3%-11% vol/vol escalating over 10 weeks), with no significant difference observed in TBC with sucrose (1%-3%); (2) significantly greater sedative-like effects of acute ethanol (2.0 or 2.5 g/kg, intraperitoneal [i.p.]) manifested as LORR observed at a lower dose and for longer time, with similar BELs and rates of ethanol clearance; and (3) lower cumulative locomotor activity over 60 minutes in response to an acute ethanol challenge (1.0-2.5 g/kg, i.p.). CONCLUSIONS: The present findings are the first to implicate TAAR1 in the behavioral and reinforcement-related effects of ethanol and raise the question of whether specific drugs that target TAAR1 could potentially reduce alcohol consumption in humans with AUDs.

Augmentation of methamphetamine-induced behaviors in transgenic mice lacking the trace amine-associated receptor 1.

The trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that is functionally activated by amphetamine-based psychostimulants, including amphetamine, methamphetamine and MDMA. Previous studies have shown that in transgenic mice lacking the TAAR1 gene (TAAR1 knockout; KO) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild-type (WT) mice. Further, the psychostimulant effects of cocaine can be diminished by selective activation of TAAR1. These findings suggest that TAAR1 might be implicated in the rewarding properties of psychostimulants. To investigate the role of TAAR1 in the rewarding effects of drugs of abuse, the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and TAAR1 KO mice. In locomotor activity studies, both single and repeated exposure to d-amphetamine or methamphetamine generated significantly higher levels of total distance traveled in TAAR1 KO mice compared to WT mice. In conditioned place preference (CPP) studies, TAAR1 KO mice acquired methamphetamine-induced CPP earlier than WT mice and retained CPP longer during extinction training. In morphine-induced CPP, both WT and KO genotypes displayed similar levels of CPP. Results from locomotor activity studies suggest that TAAR1 may have a modulatory role in the behavioral sensitization to amphetamine-based psychostimulants. That methamphetamine-but not morphine-induced CPP was augmented in TAAR1 KO mice suggests a selective role of TAAR1 in the conditioned reinforcing effects of methamphetamine. Collectively, these findings provide support for a regulatory role of TAAR1 in methamphetamine signaling.

Normal thermoregulatory responses to 3-iodothyronamine, trace amines and amphetamine-like psychostimulants in trace amine associated receptor 1 knockout mice.

3-Iodothyronamine (T1AM) is a metabolite of thyroid hormone. It is an agonist at trace amine-associated receptor 1 (TAAR1), a recently identified receptor involved in monoaminergic regulation and a potential novel therapeutic target. Here, T1AM was studied using rhesus monkey TAAR1 and/or human dopamine transporter (DAT) co-transfected cells, and wild-type (WT) and TAAR1 knock-out (KO) mice. The IC(50) of T1AM competition for binding of the DAT-specific radio-ligand [(3)H]CFT was highly similar in DAT cells, WT striatal synaptosomes and KO striatal synaptosomes (0.72-0.81 microM). T1AM inhibition of 10 nM [(3)H]dopamine uptake (IC(50): WT, 1.4 + or - 0.5 microM; KO, 1.2 + or - 0.4 microM) or 50 nM [(3)H]serotonin uptake (IC(50): WT, 4.5 + or - 0.6 microM; KO, 4.7 + or - 1.1 microM) in WT and KO synaptosomes was also highly similar. Unlike other TAAR1 agonists that are DAT substrates, TAAR1 signaling in response to T1AM was not enhanced in the presence of DAT as determined by CRE-luciferase assay. In vivo, T1AM induced robust hypothermia in WT and KO mice equivalently and dose dependently (maximum change degrees Celsius: 50 mg/kg at 60 min: WT -6.0 + or - 0.4, KO -5.6 + or - 1.0; and 25 mg/kg at 30 min: WT -2.7 + or - 0.4, KO -3.0 + or - 0.2). Other TAAR1 agonists including beta-phenylethylamine (beta-PEA), MDMA (3,4-methylenedioxymethamphetamine) and methamphetamine also induced significant, time-dependent thermoregulatory responses that were alike in WT and KO mice. Therefore, TAAR1 co-expression does not alter T1AM binding to DAT in vitro nor T1AM inhibition of [(3)H]monoamine uptake ex vivo, and TAAR1 agonist-induced thermoregulatory responses are TAAR1-independent. Accordingly, TAAR1-directed compounds will likely not affect thermoregulation nor are they likely to be cryogens.