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

Helen N. Panas, Laurie J. Lynch, Eric J. Vallender, Zhihua Xie, Guo Lin Chen, Spencer K. Lynn, Thomas S. Scanlan, Gregory M. Miller

Research output: Contribution to journalArticlepeer-review

64 Scopus citations

Abstract

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) cotransfected cells, and wild-type (WT) and TAAR1 knockout (KO) mice. The IC50 of T1AM competition for binding of the DAT-specific radio-ligand [3H]CFT was highly similar in DAT cells, WT striatal synaptosomes and KO striatal synaptosomes (0.72-0.81 μM). T1AM inhibition of 10 nM [3H]dopamine uptake (IC50: WT, 1.4 6 0.5 μM; KO, 1.2 ± 0.4 μM) or 50 nM [3H]serotonin uptake (IC50: WT, 4.5 ± 0.6 μM; KO, 4.7 ± 1.1 μM) 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 (β-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 [3H]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.

Original languageEnglish (US)
Pages (from-to)1962-1969
Number of pages8
JournalJournal of Neuroscience Research
Volume88
Issue number9
DOIs
StatePublished - Jul 2010

Keywords

  • Monoamine
  • Psychostimulant
  • TAAR1
  • Thermoregulation
  • Thyronamine

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

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