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 dopa...
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creator | Panas, Helen N. Lynch, Laurie J. Vallender, Eric J. Xie, Zhihua Chen, Guo-lin Lynn, Spencer K. Scanlan, Thomas S. Miller, Gregory M. |
description | 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 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 ± 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. © 2010 Wiley‐Liss, Inc. |
doi_str_mv | 10.1002/jnr.22367 |
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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 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 ± 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. © 2010 Wiley‐Liss, Inc.</description><identifier>ISSN: 0360-4012</identifier><identifier>ISSN: 1097-4547</identifier><identifier>EISSN: 1097-4547</identifier><identifier>DOI: 10.1002/jnr.22367</identifier><identifier>PMID: 20155805</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Animals ; Body Temperature Regulation - drug effects ; Body Temperature Regulation - physiology ; Cell Line ; Central Nervous System Stimulants - pharmacology ; Corpus Striatum - drug effects ; Corpus Striatum - metabolism ; Dopamine - metabolism ; Dopamine Plasma Membrane Transport Proteins - genetics ; Dopamine Plasma Membrane Transport Proteins - metabolism ; Humans ; Macaca mulatta ; Male ; Methamphetamine - pharmacology ; Mice ; Mice, Knockout ; monoamine ; N-Methyl-3,4-methylenedioxyamphetamine - pharmacology ; Phenethylamines - pharmacology ; psychostimulant ; Receptors, G-Protein-Coupled - agonists ; Receptors, G-Protein-Coupled - genetics ; Receptors, G-Protein-Coupled - metabolism ; Serotonin - metabolism ; Synaptosomes - drug effects ; Synaptosomes - metabolism ; TAAR1 ; thermoregulation ; Thyroid Hormones - administration & dosage ; Thyroid Hormones - pharmacology ; thyronamine ; Thyronines - administration & dosage ; Thyronines - pharmacology</subject><ispartof>Journal of neuroscience research, 2010-07, Vol.88 (9), p.1962-1969</ispartof><rights>Copyright © 2010 Wiley‐Liss, Inc.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5167-e797fa4e6b9bb9a92975528ec42cfeb9b7f650c11fc9be71a5a27f3b49e3d8c73</citedby><cites>FETCH-LOGICAL-c5167-e797fa4e6b9bb9a92975528ec42cfeb9b7f650c11fc9be71a5a27f3b49e3d8c73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fjnr.22367$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fjnr.22367$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>230,314,780,784,885,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/20155805$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Panas, Helen N.</creatorcontrib><creatorcontrib>Lynch, Laurie J.</creatorcontrib><creatorcontrib>Vallender, Eric J.</creatorcontrib><creatorcontrib>Xie, Zhihua</creatorcontrib><creatorcontrib>Chen, Guo-lin</creatorcontrib><creatorcontrib>Lynn, Spencer K.</creatorcontrib><creatorcontrib>Scanlan, Thomas S.</creatorcontrib><creatorcontrib>Miller, Gregory M.</creatorcontrib><title>Normal thermoregulatory responses to 3-iodothyronamine, trace amines and amphetamine-like psychostimulants in trace amine associated receptor 1 knockout mice</title><title>Journal of neuroscience research</title><addtitle>J. Neurosci. Res</addtitle><description>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 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 ± 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. © 2010 Wiley‐Liss, Inc.</description><subject>Animals</subject><subject>Body Temperature Regulation - drug effects</subject><subject>Body Temperature Regulation - physiology</subject><subject>Cell Line</subject><subject>Central Nervous System Stimulants - pharmacology</subject><subject>Corpus Striatum - drug effects</subject><subject>Corpus Striatum - metabolism</subject><subject>Dopamine - metabolism</subject><subject>Dopamine Plasma Membrane Transport Proteins - genetics</subject><subject>Dopamine Plasma Membrane Transport Proteins - metabolism</subject><subject>Humans</subject><subject>Macaca mulatta</subject><subject>Male</subject><subject>Methamphetamine - pharmacology</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>monoamine</subject><subject>N-Methyl-3,4-methylenedioxyamphetamine - pharmacology</subject><subject>Phenethylamines - pharmacology</subject><subject>psychostimulant</subject><subject>Receptors, G-Protein-Coupled - agonists</subject><subject>Receptors, G-Protein-Coupled - genetics</subject><subject>Receptors, G-Protein-Coupled - metabolism</subject><subject>Serotonin - metabolism</subject><subject>Synaptosomes - drug effects</subject><subject>Synaptosomes - metabolism</subject><subject>TAAR1</subject><subject>thermoregulation</subject><subject>Thyroid Hormones - administration & dosage</subject><subject>Thyroid Hormones - pharmacology</subject><subject>thyronamine</subject><subject>Thyronines - administration & dosage</subject><subject>Thyronines - pharmacology</subject><issn>0360-4012</issn><issn>1097-4547</issn><issn>1097-4547</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2010</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFks9u1DAQxiMEokvhwAsg3xASaf0njuMLUlmgBVWLVIGQuFiOM2ncTeJge4E8DO-Ku9uuygH15PHMN7-Zkb4se07wEcGYHl-N_ohSVooH2YJgKfKCF-JhtsCsxHmBCT3InoRwhTGWkrPH2QHFhPMK80X2Z-X8oHsUO_CD83C56XV0fkYewuTGAAFFh1huXeNiN3s36sGO8BpFrw2g7ScgPTYpnDqI20Te2zWgKcymcyHaITHHGJAd73YhHYIzVkdo0jADUxqLCFqPzqzdJqLBGniaPWp1H-DZzXuYff3w_svyLD__fPpxeXKeG05KkYOQotUFlLWsa6kllYJzWoEpqGkhJUVbcmwIaY2sQRDNNRUtqwsJrKmMYIfZmx132tQDNAbGtGivJm8H7WfltFX_VkbbqUv3UzFeiaooE-DlDcC7HxsIUQ02GOjT4eA2QVUVwwUpCLlfWUpelay8nykYS0eS6pr5aqc03oXgod1vTrC6dohKDlFbhyTti7un7pW3lkiC453gl-1h_j9JfVpd3CLzXYcNEX7vO7Rfq1QVXH1bnap3b1cXy7PvUlH2F1zb2kw</recordid><startdate>201007</startdate><enddate>201007</enddate><creator>Panas, Helen N.</creator><creator>Lynch, Laurie J.</creator><creator>Vallender, Eric J.</creator><creator>Xie, Zhihua</creator><creator>Chen, Guo-lin</creator><creator>Lynn, Spencer K.</creator><creator>Scanlan, Thomas S.</creator><creator>Miller, Gregory M.</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7TK</scope><scope>5PM</scope></search><sort><creationdate>201007</creationdate><title>Normal thermoregulatory responses to 3-iodothyronamine, trace amines and amphetamine-like psychostimulants in trace amine associated receptor 1 knockout mice</title><author>Panas, Helen N. ; Lynch, Laurie J. ; Vallender, Eric J. ; Xie, Zhihua ; Chen, Guo-lin ; Lynn, Spencer K. ; Scanlan, Thomas S. ; Miller, Gregory M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5167-e797fa4e6b9bb9a92975528ec42cfeb9b7f650c11fc9be71a5a27f3b49e3d8c73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2010</creationdate><topic>Animals</topic><topic>Body Temperature Regulation - drug effects</topic><topic>Body Temperature Regulation - physiology</topic><topic>Cell Line</topic><topic>Central Nervous System Stimulants - pharmacology</topic><topic>Corpus Striatum - drug effects</topic><topic>Corpus Striatum - metabolism</topic><topic>Dopamine - metabolism</topic><topic>Dopamine Plasma Membrane Transport Proteins - genetics</topic><topic>Dopamine Plasma Membrane Transport Proteins - metabolism</topic><topic>Humans</topic><topic>Macaca mulatta</topic><topic>Male</topic><topic>Methamphetamine - pharmacology</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>monoamine</topic><topic>N-Methyl-3,4-methylenedioxyamphetamine - pharmacology</topic><topic>Phenethylamines - pharmacology</topic><topic>psychostimulant</topic><topic>Receptors, G-Protein-Coupled - agonists</topic><topic>Receptors, G-Protein-Coupled - genetics</topic><topic>Receptors, G-Protein-Coupled - metabolism</topic><topic>Serotonin - metabolism</topic><topic>Synaptosomes - drug effects</topic><topic>Synaptosomes - metabolism</topic><topic>TAAR1</topic><topic>thermoregulation</topic><topic>Thyroid Hormones - administration & dosage</topic><topic>Thyroid Hormones - pharmacology</topic><topic>thyronamine</topic><topic>Thyronines - administration & dosage</topic><topic>Thyronines - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Panas, Helen N.</creatorcontrib><creatorcontrib>Lynch, Laurie J.</creatorcontrib><creatorcontrib>Vallender, Eric J.</creatorcontrib><creatorcontrib>Xie, Zhihua</creatorcontrib><creatorcontrib>Chen, Guo-lin</creatorcontrib><creatorcontrib>Lynn, Spencer K.</creatorcontrib><creatorcontrib>Scanlan, Thomas S.</creatorcontrib><creatorcontrib>Miller, Gregory M.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Neurosciences Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of neuroscience research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Panas, Helen N.</au><au>Lynch, Laurie J.</au><au>Vallender, Eric J.</au><au>Xie, Zhihua</au><au>Chen, Guo-lin</au><au>Lynn, Spencer K.</au><au>Scanlan, Thomas S.</au><au>Miller, Gregory M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Normal thermoregulatory responses to 3-iodothyronamine, trace amines and amphetamine-like psychostimulants in trace amine associated receptor 1 knockout mice</atitle><jtitle>Journal of neuroscience research</jtitle><addtitle>J. Neurosci. Res</addtitle><date>2010-07</date><risdate>2010</risdate><volume>88</volume><issue>9</issue><spage>1962</spage><epage>1969</epage><pages>1962-1969</pages><issn>0360-4012</issn><issn>1097-4547</issn><eissn>1097-4547</eissn><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) co‐transfected cells, and wild‐type (WT) and TAAR1 knock‐out (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 ± 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. © 2010 Wiley‐Liss, Inc.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>20155805</pmid><doi>10.1002/jnr.22367</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Body Temperature Regulation - drug effects Body Temperature Regulation - physiology Cell Line Central Nervous System Stimulants - pharmacology Corpus Striatum - drug effects Corpus Striatum - metabolism Dopamine - metabolism Dopamine Plasma Membrane Transport Proteins - genetics Dopamine Plasma Membrane Transport Proteins - metabolism Humans Macaca mulatta Male Methamphetamine - pharmacology Mice Mice, Knockout monoamine N-Methyl-3,4-methylenedioxyamphetamine - pharmacology Phenethylamines - pharmacology psychostimulant Receptors, G-Protein-Coupled - agonists Receptors, G-Protein-Coupled - genetics Receptors, G-Protein-Coupled - metabolism Serotonin - metabolism Synaptosomes - drug effects Synaptosomes - metabolism TAAR1 thermoregulation Thyroid Hormones - administration & dosage Thyroid Hormones - pharmacology thyronamine Thyronines - administration & dosage Thyronines - pharmacology |
title | Normal thermoregulatory responses to 3-iodothyronamine, trace amines and amphetamine-like psychostimulants in trace amine associated receptor 1 knockout mice |
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