Abstract
The synthetic amines methamphetamine (METH), amphetamine (AMPH), and their metabolite para-hydroxyamphetamine (POHA) are chemically and structurally related to the catecholamine neurotransmitters and a small group of endogenous biogenic amines collectively referred to as the trace amines (TAs). Recently, it was reported that METH, AMPH, POHA, and the TAs para-tyramine (TYR) and β-phenylethylamine (PEA) stimulate cAMP production in human embryonic kidney (HEK)-293 cells expressing rat trace amine-associated receptor 1 (rTAAR1). The discovery that METH and AMPH activate the rTAAR1 motivated us to study the effect of these drugs on the mouse TAAR1 (mTAAR1) and a human-rat chimera (hrChTAAR1). Furthermore, because S-(+)-isomers of METH and AMPH are reported to be more potent and efficacious in vivo than R-(–), we determined the enantiomeric selectivity of all three species of TAAR1. In response to METH, AMPH, or POHA exposure, the accumulation of cAMP by HEK-293 cells stably expressing different species of TAAR1 was concentration- and isomer-dependent. EC50 values for S-(+)-METH were 0.89, 0.92, and 4.44 μM for rTAAR1, mTAAR1, and h-rChTAAR1, respectively. PEA was a potent and full agonist at each species of TAAR1, whereas TYR was a full agonist for the rodent TAAR1s but was a partial agonist at h-rChTAAR1. Interestingly, both isomers of METH were full agonists at mTAAR1 and h-rChTAAR1, whereas both were partial agonists at rTAAR1. Taken together, these in vitro results suggest that, in vivo, TAAR1 could be a novel mediator of the effects of these drugs.
Footnotes
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This work was supported in part by grants (to D.K.G.) from National Institute on Drug Abuse and National Institute of Mental Health.
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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.106.115402.
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ABBREVIATIONS: METH, methamphetamine; AMPH, amphetamine; DA, dopamine; NE, norepinephrine; TA, trace amine; PEA β-phenylethylamine; TYR, para-tyramine; OCT octopamine; ADHD, attention deficit hyperactivity disorder; 5HT. 5-hydroxytryptamine (serotonin); CNS, central nervous system; GPCR, G protein-coupled receptor; TAAR, trace amine-associated receptor; r, rat; h, human; m, mouse; POHA, para-hydroxyamphetamine; HEK, human embryonic kidney; PEAmax, maximal cAMP produced in response to PEA; KRH, Krebs-Ringer-HEPES; DAT, plasma membrane dopamine transporter; CI, confidence interval.
- Received October 18, 2006.
- Accepted January 10, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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