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NEUROPHARMACOLOGY

Primate Trace Amine Receptor 1 Modulation by the Dopamine Transporter

Division of Neurochemistry, New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts

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 -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.

Address correspondence to: Dr. Bertha K. Madras, Department of Psychiatry, New England Primate Research Center, Harvard Medical School, One Pine Hill Dr., Southborough, MA 01772. E-mail: bertha_madras{at}hms.harvard.edu

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