TAAR1 as a Target for Addiction Therapy.

The trace amine-associated receptor 1 (TAAR1) has emerged as a target for therapeutic consideration from outcomes in preclinical models of substance use disorders. As an intracellular G protein-coupled receptor prominently expressed within monoaminergic nuclei, TAAR1 acts as a key modulator of biogenic amine transmission. Extensive preclinical studies using selective agonists and genetic models, including knock-out mice and rats, selected mouse lines, recombinant inbred mouse strains, and Taar1 gene-edited mice, demonstrate that TAAR1 activation serves a protective role against addiction-like behaviors. TAAR1 agonists inhibit the rewarding, reinforcing, and reinstatement-inducing effects of multiple drug classes, including amphetamines, cocaine, opioids, and others. Genetic rodent models reveal that a lack of functional TAAR1 elevates vulnerability to voluntary psychostimulant intake and blunts sensitivity to drug-induced aversive and potentially adverse physiological effects. The precise molecular mechanisms underlying these TAAR1-mediated behaviors continue to be explored, involving complex ligand-specific TAAR1 signaling that regulates transporter internalization, neurotransmitter levels, and neuronal activity. Overall, the existing findings support TAAR1 as a therapeutic target for treatment of substance use disorders. However, translating these findings into effective human pharmacotherapies requires navigating ligand-specific effects and pharmacokinetic demands and defining the role of human TAAR1 genetic diversity in therapeutic response.