Amphetamines Activate G-Protein Coupled Trace Amine-Associated Receptor 1 (TAAR1): Implications for Understanding and Treating Psychostimulant Abuse

Trace amine-associated receptor 1 (TAAR1) shares significant nucleotide and amino acid sequence identity with dopamine, adrenergic, and serotonergic receptors. Heterologously expressed in vitro, TAAR1 couples to cyclic adenosine monophosphate production via G s when exposed to molecules containing a phenylethylamine moiety. This pharmacophore is present in the endogenous noncatecholic biogenic "trace amines" phenylethylamine and p-tyramine, 3-iodothyronamine, the catecholamines dopamine, norepinephrine, and epinephrine, and the synthetic amines amphetamine, methamphetamine, parahydroxyamphetamine, and methylenedioxymethamphetamine (ecstasy). TAAR1 is expressed in glutamatergic neurons of the prefrontal cortex, dopamine-producing neurons of the ventral tegmental area, insulin-producing cells, discrete sections of the gastrointestinal tract, and immune cells. Due to its pharmacologic and anatomic profiles, TAAR1 is a target of commercial drug development with several TAAR1-selective compounds already reported. Behavioral studies involving TAAR1-selective ligands confirm modulating TAAR1-mediated signaling favorably alters rodent responses to amphetamines and cocaine. Consequently, TAAR1 must be considered an essential element of any comprehensive model of psychostimulant action.