TAAR1 activation normalizes dopamine signaling and decreases alcohol intake in SRKO mice after adolescent ethanol exposure.

Glutamatergic and dopaminergic dysregulations are major features of alcohol use disorder (AUD). The trace amine-associated receptor 1 (TAAR1), which modulates both systems, has emerged as a promising therapeutic target, although the underlying mechanisms remain unclear. Here, we used male serine racemase knockout (SRKO) mice, a model of chronic NMDA receptor hypofunction and mesolimbic hyperdopaminergia, to investigate how TAAR1 activation shapes alcohol consumption and ethanol-induced dopamine release. Ethanol intake was measured during adolescence and adulthood, and ex vivo fast-scan cyclic voltammetry was used to examine dopamine release in the nucleus accumbens (NAc) core. SRKO mice consumed less alcohol than wild-type controls during adolescence, an effect amplified in adulthood and associated with a blunted dopaminergic response to acute ethanol. Adult SRKO mice previously exposed to alcohol during adolescence displayed an enhanced sensitivity to the TAAR1 full agonist RO5166017, which markedly reduced alcohol consumption and normalized dopamine signaling across groups, leading to similar ethanol-evoked decreases in NAc dopamine release. These findings show that NMDA receptor hypofunction and adolescent alcohol exposure increase TAAR1 signaling sensitivity, making TAAR1 activation particularly effective at reducing alcohol consumption and normalizing dopamine function. This work supports TAAR1 as a relevant molecular target for AUD, especially in conditions involving glutamatergic dysfunction and a history of adolescent alcohol exposure.