Primate trace amine receptor 1 modulation by the dopamine transporter.
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 (rhTA(1)) that was 96% homologous to human TA(1). The trace amines tyramine and beta-phenylethylamine (PEA) and the monoamine transporter substrates (+/-)-amphetamine and (+/-)-MDMA stimulated cAMP accumulation in rhTA(1)-expressing cell lines, as measured by a cAMP response element-luciferase assay. Cocaine did not stimulate cAMP accumulation in rhTA(1) cells, but it blocked [(3)H]PEA transport mediated by the dopamine transporter. Cotransfection with the human dopamine transporter enhanced PEA-, amphetamine-, and MDMA-mediated rhTA(1) receptor activation, but it diminished tyramine activation of rhTA(1). Because TA(1) (EGFP-rhTA(1) chimera) was largely intracellular, conceivably the dopamine transporter can facilitate access of specific agonists to intracellular TA(1). rhTA(1) mRNA expression was detected in rhesus monkey substantia nigra, implying that TA(1) may be colocalized with the dopamine transporter in dopamine neurons. In summary, primate TA(1) 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, rhTA(1) 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 TA(1) from rhesus monkey and demonstration that rhTA(1) receptors are activated by drugs of abuse, indicate that nonhuman primates may serve to model physiological and pharmacological TA(1)-mediated responses in humans.
Miller
Gregory M
GM
Division of Neurochemistry, New England Primate Research Center, Harvard Medical School, Southborough, MA 01772, USA.
Verrico
Christopher D
CD
Jassen
Amy
A
Konar
Martha
M
Yang
Hong
H
Panas
Helen
H
Bahn
Mary
M
Johnson
Ryan
R
Madras
Bertha K
BK
D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D003042:Cocaine / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D006801:Humans; D008253:Macaca mulatta; D008562:Membrane Glycoproteins / Q000502:physiology*; D026901:Membrane Transport Proteins / Q000502:physiology*; D008969:Molecular Sequence Data; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010627:Phenethylamines / Q000378:metabolism; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000502:physiology; D020218:Response Elements / Q000502:physiology; D013378:Substantia Nigra / Q000737:chemistry; D000095383:Trace Amine-Associated Receptors
D003042:Cocaine; D000242:Cyclic AMP; D004298:Dopamine; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D009419:Nerve Tissue Proteins; D010627:Phenethylamines; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors; C029261:phenethylamine