Amphetamine, 3,4-Methylenedioxymethamphetamine, Lysergic Acid Diethylamide, and Metabolites of the Catecholamine Neurotransmitters Are Agonists of a Rat Trace Amine Receptor

A rat G protein-coupled receptor (rTAR1) stimulates cAMP production when exposed to trace amines such as p-tyramine, beta-phenethylamine, tryptamine, and octopamine. Psychostimulant and hallucinogenic amphetamines, ergoline derivatives, adrenergic ligands, and 3-methylated metabolites of catecholamine neurotransmitters also act as potent agonists at this receptor. These findings indicate that trace amines and catecholamine metabolites may be endogenous ligands for a novel intercellular signaling system in the vertebrate brain and periphery. The potency of amphetamines, including MDMA (ecstasy), as rTAR1 agonists suggests that some effects of these drugs may be mediated through this receptor in addition to neurotransmitter transporter proteins.

Study at a glance

Abstract

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, beta-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.