Trace amine-associated receptor 1 agonists reduce alcohol drinking and differentially modulate dopamine release in the nucleus accumbens of alcohol preferring mice.

Current treatments for alcohol use disorder have limited efficacy underscoring the need for novel therapeutic targets. Trace amine-associated receptor 1 (TAAR1) is a promising candidate due to its ability to act as a brake on dopaminergic transmission and alcohol consumption. However, both the relative efficacy of full and partial TAAR1 agonists in reducing alcohol-related behaviors and their underlying mechanisms of action remain unclear. In this study, we evaluated the effects of the full agonist RO5166017 and the partial agonist RO5263397 on alcohol consumption using an intermittent access protocol in alcohol-preferring male C57BL/6JRj mice. Given their distinct pharmacological and electrophysiological properties, we also investigated the effects of these agonists on presynaptic dopaminergic transmission using fast-scan cyclic voltammetry in the nucleus accumbens, a key structure involved in alcohol reinforcement. Full and partial TAAR1 agonists reduced alcohol intake by 25 % and 43 %, respectively. We further report that these agonists exhibit opposite effects on dopamine release under basal conditions, but that these effects are reversed in animals chronically exposed to alcohol. The reversal in dopamine release did not result from alcohol-induced modifications of TAAR1 or D2 receptor expression. Our findings highlight the therapeutic potential of TAAR1 agonists for alcohol addiction and reveal important functional differences between full and partial agonists. Further research is needed to determine the clinical relevance of these distinct pharmacodynamic profiles and optimize TAAR1-targeting pharmacotherapies.