Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor

The trace amine para-tyramine is structurally and functionally related to t he amphetamines and the biogenic amine neurotransmitters. It is currently t hought that the biological activities elicited by trace amines such as p-ty ramine and the psychostimulant amphetamines are manifestations of their abi lity to inhibit the clearance of extracellular transmitter and/or stimulate the efflux of transmitter from intracellular stores. Here we report the di scovery and pharmacological characterization of a rat G protein-coupled rec eptor that stimulates the production of cAMP when exposed to the trace amin es p-tyramine, beta -phenethylamine, tryptamine, and octopamine. An extensi ve pharmacological survey revealed that psychostimulant and hallucinogenic amphetamines, numerous ergoline derivatives, adrenergic ligands, and 3-meth ylated metabolites of the catecholamine neurotransmitters are also good ago nists 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 ampheta mines, including 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy"), are p otent rTAR1 agonists suggests that the effects of these widely used drugs m ay be mediated in part by this receptor as well as their previously charact erized targets, the neurotransmitter transporter proteins.