Abstinence and extinction drive opposing changes in striatal activity and dopamine signaling during alcohol relapse.

Relapse remains a major challenge in the treatment of alcohol use disorder, driven in part by persistent neuroadaptations. However, how different post-alcohol experiences, such as passive withdrawal (abstinence) versus active extinction training, differentially shape the neural circuits and synaptic mechanisms that influence relapse vulnerability remains unclear. Here, we show that these experiences have opposing effects on dorsomedial striatal (DMS) direct-pathway medium spiny neurons (dMSNs) and dopamine dynamics during cue-induced reinstatement of alcohol seeking. Using in vivo fiber photometry in D1-Cre rats, we found that abstinence increased both dopamine release and dMSN calcium activity during reinstatement, whereas extinction training reduced dopamine release and prevented abstinence-related elevation in dMSN activity. Given that dopamine regulates corticostriatal plasticity onto dMSNs, and that such plasticity plays a critical role in alcohol-seeking behavior, these opposing dopamine signals suggest experience-dependent changes in medial prefrontal cortex (mPFC)-to-dMSN synaptic strength that may contribute to relapse vulnerability. To test this, we used pathway-specific optogenetic plasticity protocols and found that inducing long-term depression (LTD) after abstinence attenuated reinstatement, whereas inducing long-term potentiation (LTP) after extinction reinstated alcohol seeking. These findings suggest that dopamine-dependent corticostriatal plasticity bidirectionally mediates relapse and is shaped by prior alcohol-related experience, identifying it as a potential target for relapse prevention.