期刊
JOURNAL OF NEUROSCIENCE RESEARCH
卷 88, 期 9, 页码 1962-1969出版社
WILEY
DOI: 10.1002/jnr.22367
关键词
TAAR1; thyronamine; psychostimulant; thermoregulation; monoamine
资金
- National Institute on Drug Abuse
- National Institute of Diabetes and Digestive Kidney Diseases
- National Center for Research Resources [RR00168, DA022323, DA016606, DA025802, DA025697, DK52798]
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 knockout (KO) mice. The IC50 of T1AM competition for binding of the DAT-specific radio-ligand [H-3]CFT was highly similar in DAT cells, WT striatal synaptosomes and KO striatal synaptosomes (0.72-0.81 mu M). T1AM inhibition of 10 nM [H-3]dopamine uptake (IC50: WT, 1.4 +/- 0.5 mu M; KO, 1.2 +/- 0.4 mu M) or 50 nM [H-3]serotonin uptake (IC50: WT 4.5 +/- 0.6 mu M; KO, 4.7 +/- 1.1 mu M) 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 +/- 0.4, KO -5.6 +/- 1.0; and 25 mg/kg at 30 min: WT -2.7 +/- 0.4, KO -3.0 +/- 0.2). Other TAAR1 agonists including beta phenylethylamine (beta-PEA), MDMA (3,4-nnethylenedioxymethamphetamine) 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 [H-3]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. (C) 2010 Wiley-Liss, Inc.
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