Abstract
Recently identified trace amine receptors are potential direct targets for drugs of abuse, including amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). We cloned full-length rhesus monkey trace amine receptor 1 (rhTA1) that was 96% homologous to human TA1. The trace amines tyramine and β-phenylethylamine (PEA) and the monoamine transporter substrates (±)-amphetamine and (±)-MDMA stimulated cAMP accumulation in rhTA1-expressing cell lines, as measured by a cAMP response element-luciferase assay. Cocaine did not stimulate cAMP accumulation in rhTA1 cells, but it blocked [3H]PEA transport mediated by the dopamine transporter. Cotransfection with the human dopamine transporter enhanced PEA-, amphetamine-, and MDMA-mediated rhTA1 receptor activation, but it diminished tyramine activation of rhTA1. Because TA1 (EGFP-rhTA1 chimera) was largely intracellular, conceivably the dopamine transporter can facilitate access of specific agonists to intracellular TA1. rhTA1 mRNA expression was detected in rhesus monkey substantia nigra, implying that TA1 may be colocalized with the dopamine transporter in dopamine neurons. In summary, primate TA1 receptors are direct targets of trace amines, amphetamine, and MDMA. These receptors could also be indirect targets of amphetamine, MDMA, and cocaine through modification of monoamine transporter function. Conceivably, rhTA1 receptors may be located on pre- or postsynaptic membranes. Interference with the carrier function of monoamine transporters with a consequent rise of extracellular levels of trace amines could activate these receptors. The cloning of a highly homologous TA1 from rhesus monkey and demonstration that rhTA1 receptors are activated by drugs of abuse, indicate that nonhuman primates may serve to model physiological and pharmacological TA1-mediated responses in humans.
Footnotes
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This study was supported by Grants DA06303 (to B.K.M.), DA016606 (to G.M.M.), DA15305 (to B.K.M.), and RR00168. The research was presented in abstract form at Society for Neuroscience (2002, 2004), the annual meeting of the College on Problems of Drug Dependence (2004), and the American College of Neuropsychopharmacology (2004).
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doi:10.1124/jpet.105.084459.
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ABBREVIATIONS: DA, dopamine; NE, norepinephrine; 5-HT, 5-hydroxytryptamine (serotonin); PEA, β-phenylethylamine; TA, trace amine; rTA, rat trace amine; hTA, human trace amine; MDMA 3,4-methylenedioxymethamphetamine; TAR, trace amine receptor; PCR, polymerase chain reaction; gDNA, genomic DNA; hDAT, human dopamine transporter; CRE, cAMP response element; Luc, luciferase; HEK, human embryonic kidney; DMEM, Dulbecco's modified Eagle's medium; RLU, relative light unit; EGFP, enhanced green fluorescent protein; RT-PCR, reverse transcriptase-polymerase chain reaction; ANOVA, analysis of variance.
- Received February 3, 2005.
- Accepted March 8, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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