Chapter 10 - Amphetamines Activate G-Protein Coupled Trace Amine-Associated Receptor 1 (TAAR1): Implications for Understanding and Treating Psychostimulant Abuse

Abstract

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 Gαs when exposed to molecules containing a phenylethylamine moiety. This pharmacophore is present in the endogenous noncatecholic biogenic “trace amines” β-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 β-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.