Abstract
Brain monoamines include common biogenic amines (dopamine, norepinephrine, and serotonin) and trace amines [β-phenylethylamine (β-PEA), tyramine, tryptamine, and octopamine]. Common biogenic amines are well established as neurotransmitters, but the roles and functional importance of trace amines remain elusive. Here, we re-evaluated the interaction of trace amines with trace amine-associated receptor 1 (TAAR1) and investigated effects of β-PEA on monoamine transporter function and influence of monoamine autoreceptors on TAAR1 signaling. We confirmed that TAAR1 was activated by trace amines and demonstrated that TAAR1 activation by β-PEA significantly inhibited uptake and induced efflux of [3H]dopamine, [3H]norepinephrine, and [3H]serotonin in transfected cells. In brain synaptosomes, β-PEA significantly inhibited uptake and induced efflux of [3H]dopamine and [3H]serotonin in striatal and [3H]norepinephrine in thalamic synaptosomes of rhesus monkeys and wild-type mice, but it lacked the same effects in synaptosomes of TAAR1 knockout mice. The effect of β-PEA on efflux was blocked by transporter inhibitors in either the transfected cells or wild-type mouse synaptosomes. We also demonstrated that TAAR1 signaling was not affected by monoamine autoreceptors at exposure to trace amines that we show to have poor binding affinity for the autoreceptors relative to common biogenic amines. These results reveal that β-PEA alters monoamine transporter function via interacting with TAAR1 but not monoamine autoreceptors. The functional profile of β-PEA may reveal a common mechanism by which trace amines exert modulatory effects on monoamine transporters in brain.
Footnotes
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This work was supported by grants from The National Institute on Drug Abuse and The National Center for Research Resources: DA022323 (to G.M.M.), DA016606 (to G.M.M.), DA06303 (to G.M.M.), DA021180 (to G.M.M.), and RR00168.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.134247.
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ABBREVIATIONS: β-PEA, β-phenylethylamine; 5HT1A and 5HT1B, subtype A and B of serotonin receptor 1; α2A and α2B, subtype A and B of α-adrenal receptor 2; CRE-Luc, cAMP-response element-driven luciferase reporter; DAT, dopamine transporter; D2s, dopamine D2 receptor short isoform; DMEM, Dulbecco's modified Eagle's medium; NET, norepinephrine transporter; SERT, serotonin transporter; TAAR1, trace amine-associated receptor 1; HEK, human embryonic kidney; PLB, Passive lysis buffer; RLU, relative light units; SKF86466, 6-chloro-2,3,4,5-tetrahydo-3-methyl-1H-3-benzazepine.
- Received November 13, 2007.
- Accepted January 7, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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