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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 18, 2007; DOI: 10.1124/jpet.106.116863

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Received for publication November 9, 2006.
Revised December 15, 2006.
Accepted for publication December 15, 2006.

Rhesus monkey trace amine-associated receptor 1 signaling: enhancement by monoamine transporters and attenuation by the D2 autoreceptor in vitro

Zhihua Xie 1, Susan Westmoreland 1, Mary E Bahn 1, Guo-Lin Chen 1, Hong Yang 1, Eric Vallender 1, Wei-Dong Yao 1, Bertha K Madras 1, Gregory M. Miller 1*

1 Harvard Medical School, New England Primate Research Center

* Address correspondence to: E-mail: gregory_miller{at}hms.harvard.edu

Abstract

Trace Amine-Associated Receptor 1 (TAAR1) is a G-protein coupled receptor that directly responds to endogenous monoamines as well as amphetamine-related psychostimulants, including methamphetamine. In the present study, we demonstrate TAAR1 mRNA and protein expression in rhesus monkey brain regions associated with monoaminergic systems, variable cellular distribution of TAAR1 in rhesus monkey brain and TAAR1 co-expression with the dopamine transporter (DAT) in a subset of dopamine neurons in both rhesus monkey and mouse Substantia nigra. On this basis, we evaluated rhesus monkey TAAR1 activation by different compounds and its functional relation with monoamine transporters and the dopamine D2 autoreceptor (D2s) in vitro using a CRE-luciferase assay. TAAR1 activation by monoamines and amphetamine- related compounds was greatly enhanced by co-expression of dopamine, norepinephrine or serotonin transporters, and the activation enhancement was blocked by monoamine transporter inhibitors. This enhancement did not occur in control experiments in which the D1 dopamine receptor was substituted for TAAR1. Furthermore, activation of TAAR1 by dopamine was completely inhibited by D2s when co- expressed with TAAR1, and this inhibition was blocked by the D2 antagonist raclopride. Lastly, dopamine activation of TAAR1 could induce c-FOS-luciferase expression but only in the presence of DAT, whereas dopamine activation of D1 resulted in equivalent c-FOS expression in the presence or absence of DAT. Together, these data reveal a broad agonist spectrum for TAAR1, a functional relation of TAAR1 with monoamine transporters and D2s, and a mechanism by which D2 receptor drugs can influence brain monoaminergic function and have efficacy through affecting TAAR1 signaling.


Key words: Dopamine, Luciferase, Methamphetamine, Norepinephrine, Serotonin, cAMP


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