Trace Amine-associated Receptor 1 Agonists for Treatment of Substance use Disorder: Evidence from Rodent Behavioral Studies.

Abstract

This narrative review provides evidence regarding the impact of trace amine-associated receptor 1 (TAAR1) agonists on rodent models of substance use disorders (SUDs). We delineated the fundamental aspects of the pharmacodynamics and pharmacokinetics of TAAR1 agonists and collected in vivo studies that investigated TAAR1 activation in behavioral sensitization, conditioned behaviors, or self-administration models. TAAR1 agonists have demonstrated efficacy in suppressing addiction-relevant behaviors associated with cocaine. Their effectiveness is largely consistent across intrinsic activity levels, routes of administration, and experimental protocols. TAAR1 agonists also show certain preliminary promise as amphetamine psychostimulants, nicotine, alcohol, and opioids, but the number of studies remains very small. The reported effects occurred at doses that did not impair natural reward behavior. Moreover, the findings for alcohol use disorder demonstrated efficacy in both male and female subjects. Conversely, opioid studies have presented mixed results, highlighting the need for further investigation. There is a lack of studies examining the effects of TAAR1 agonists in female subjects, which is crucial for understanding potential sex differences in treatment responses. The limited number of research groups working on this topic raises concerns regarding bias and reproducibility. Future research should address these gaps, expand investigations to diverse populations, and replicate findings across laboratories to strengthen evidence for TAAR1 agonists as potential therapeutic agents for cocaine-use disorder.