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Vol. 60, Issue 6, 1181-1188, December 2001
Departments of Physiology & Pharmacology (J.R.B., S.A., L.M.H.,
G.Z., D.I.Q., T.D., K.L.S., S.P., S.B.O., R.E.M., D.K.G.) and Molecular
and Medical Genetics (S.B.O., R.E.M), School of Medicine, the Vollum
Institute (M.S.S., S.G.A.), and the Howard Hughes Medical Institute
(S.G.A.), Oregon Health & Science University, Portland, Oregon; and
Centre for Addiction and Mental Health, University of Toronto, Canada
(J.L.K.)
The trace amine para-tyramine is structurally and
functionally related to the amphetamines and the biogenic amine
neurotransmitters. It is currently thought that the biological
activities elicited by trace amines such as p-tyramine
and the psychostimulant amphetamines are manifestations of their
ability to inhibit the clearance of extracellular transmitter and/or
stimulate the efflux of transmitter from intracellular stores. Here we
report the discovery and pharmacological characterization of a rat G
protein-coupled receptor that stimulates the production of cAMP when
exposed to the trace amines p-tyramine, 
-phenethylamine, tryptamine, and octopamine. An extensive
pharmacological survey revealed that psychostimulant and hallucinogenic
amphetamines, numerous ergoline derivatives, adrenergic ligands, and
3-methylated metabolites of the catecholamine neurotransmitters are
also good agonists at the rat trace amine receptor 1 (rTAR1). These
results suggest that the trace amines and catecholamine metabolites may serve as the endogenous ligands of a novel intercellular signaling system found widely throughout the vertebrate brain and periphery. Furthermore, the discovery that amphetamines, including
3,4-methylenedioxymethamphetamine (MDMA; "ecstasy"), are potent
rTAR1 agonists suggests that the effects of these widely used drugs may
be mediated in part by this receptor as well as their previously
characterized targets, the neurotransmitter transporter proteins.
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