Trace amine-associated receptor 1: a novel target of methamphetamine

Trace amine–associated receptor 1 (TAAR1) is a G‑protein–coupled receptor activated by endogenous trace amines such as β‑phenylethylamine and p‑tyramine. Although altered trace‑amine signaling has been linked to mood disorders, the physiological role of TAAR1 remains unclear. This dissertation tests the hypothesis that TAAR1 is a direct target of amphetamine (AMPH) and methamphetamine (METH). Using cAMP assays, I show that AMPH and METH activate TAAR1 across multiple mammalian species with species‑specific stereoselectivity. Mutagenesis studies identified transmembrane residues responsible for these differences. Human TAAR1 was activated by physiologically relevant concentrations of AMPH and METH, and preliminary imaging studies suggest partial co‑localization of TAAR1 with the dopamine transporter. These findings support TAAR1 as a novel mediator of psychostimulant action and a potential therapeutic target for METH use disorders and mood‑related conditions.