title: Rhesus monkey trace amine-associated receptor 1 signaling: enhancement by monoamine transporters and attenuation by the D2 autoreceptor in vitro.
abstract: Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that directly responds to endogenous monoamines as well as amphetamine-related psychostimulants, including methamphetamine. In the present study, we demonstrate TAAR1 mRNA and protein expression in rhesus monkey brain regions associated with monoaminergic systems, variable cellular distribution of TAAR1 in rhesus monkey brain, and TAAR1 coexpression with the dopamine transporter (DAT) in a subset of dopamine neurons in both rhesus monkey and mouse substantia nigra. On this basis, we evaluated rhesus monkey TAAR1 activation by different compounds and its functional relation with monoamine transporters and the dopamine D2 receptor (D2) short isoform (D2s) autoreceptor in vitro using a cAMP response element-luciferase assay. TAAR1 activation by monoamines and amphetamine-related compounds was greatly enhanced by coexpression of dopamine, norepinephrine, or serotonin transporters, and the activation enhancement was blocked by monoamine transporter inhibitors. This enhancement did not occur in control experiments in which the dopamine D1 receptor (D1) was substituted for TAAR1. Furthermore, activation of TAAR1 by dopamine was completely inhibited by D2s when coexpressed with TAAR1, and this inhibition was blocked by the D2 antagonist raclopride. Last, dopamine activation of TAAR1 could induce c-FOS-luciferase expression but only in the presence of DAT, whereas dopamine activation of D1 resulted in equivalent c-FOS expression in the presence or absence of DAT. Together, these data reveal a broad agonist spectrum for TAAR1, a functional relation of TAAR1 with monoamine transporters and D2s, and a mechanism by which D2 receptor drugs can influence brain monoaminergic function and have efficacy through affecting TAAR1 signaling.
authors.affiliation: Division of Neurochemistry, New England Primate Research Center, Harvard Medical School, One Pine Hill Dr., Southborough, MA 01772, USA.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Xie
authors.forename: Susan V
authors.initials: SV
authors.lastname: Westmoreland
authors.forename: Mary E
authors.initials: ME
authors.lastname: Bahn
authors.forename: Guo-Lin
authors.initials: GL
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Vallender
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Yao
authors.forename: Bertha K
authors.initials: BK
authors.lastname: Madras
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Miller
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D017660:Autoreceptors / Q000502:physiology*; D015153:Blotting, Western; D002478:Cells, Cultured; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000502:physiology*; D004591:Electrophoresis, Polyacrylamide Gel; D005455:Fluorescent Antibody Technique; D017930:Genes, Reporter / Q000502:physiology; D007150:Immunohistochemistry; D008156:Luciferases / Q000378:metabolism; D008253:Macaca mulatta; D009474:Neurons / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011869:Radioligand Assay; D017447:Receptors, Dopamine D1 / Q000502:physiology; D017448:Receptors, Dopamine D2 / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013378:Substantia Nigra / Q000166:cytology / Q000502:physiology; D014162:Transfection; D000095383:Trace Amine-Associated Receptors
chemical_list: D000661:Amphetamine; D017660:Autoreceptors; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D008156:Luciferases; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors