Miller Gregory M, Verrico Christopher D, Jassen Amy, Konar Martha, Yang Hong, Panas Helen, Bahn Mary, Johnson Ryan, Madras Bertha K
Division of Neurochemistry, New England Primate Research Center, Harvard Medical School, Southborough, MA 01772, USA.
J Pharmacol Exp Ther. 2005 Jun;313(3):983-94. doi: 10.1124/jpet.105.084459. Epub 2005 Mar 11.
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.
最近发现的痕量胺受体是包括苯丙胺和3,4-亚甲基二氧甲基苯丙胺（摇头丸）在内的滥用药物的潜在直接靶点。我们克隆了全长恒河猴痕量胺受体1（rhTA(1)），它与人类TA(1)的同源性为96%。通过cAMP反应元件-荧光素酶测定法检测，痕量胺酪胺和β-苯乙胺（PEA）以及单胺转运体底物（±）-苯丙胺和（±）-摇头丸刺激了表达rhTA(1)的细胞系中的cAMP积累。可卡因不会刺激rhTA(1)细胞中的cAMP积累，但它会阻断多巴胺转运体介导的[³H]PEA转运。与人多巴胺转运体共转染增强了PEA、苯丙胺和摇头丸介导的rhTA(1)受体激活，但减弱了酪胺对rhTA(1)的激活。由于TA(1)（EGFP-rhTA(1)嵌合体）主要位于细胞内，可以想象多巴胺转运体可以促进特定激动剂进入细胞内TA(1)。在恒河猴黑质中检测到了rhTA(1) mRNA表达，这意味着TA(1)可能与多巴胺神经元中的多巴胺转运体共定位。总之，灵长类动物TA(1)受体是痕量胺、苯丙胺和摇头丸的直接靶点。这些受体也可能是苯丙胺、摇头丸和可卡因通过改变单胺转运体功能的间接靶点。可以想象，rhTA(1)受体可能位于突触前或突触后膜上。干扰单胺转运体的载体功能，从而导致细胞外痕量胺水平升高，可能会激活这些受体。从恒河猴克隆出高度同源的TA(1)并证明rhTA(1)受体被滥用药物激活，表明非人灵长类动物可用于模拟人类中生理和药理TA(1)介导的反应。
