Abstinence and Extinction Drive Opposing Changes in Striatal Activity and Dopamine Signaling During Alcohol Relapse.

Relapse remains a major obstacle in the treatment of alcohol use disorder, often driven in part by enduring neuroadaptations. However, how different treatment strategies-such as abstinence versus extinction training-modulate the underlying neural circuits and synaptic mechanisms that shape relapse vulnerability remains poorly understood. In this study, we demonstrate that abstinence and extinction distinctly influence dorsomedial striatal (DMS) direct-pathway medium spiny neuron (dMSN) activity and dopamine signaling during cue-induced reinstatement of alcohol seeking. Using in vivo fiber photometry in D1-Cre rats expressing calcium or dopamine sensors, we found that abstinence enhanced dMSN calcium responses and dopamine release during reinstatement, whereas extinction normalized these neural signals and suppressed relapse-like behavior. Furthermore, bidirectional optogenetic modulation of medial prefrontal cortex (mPFC)-to-dMSN synapses revealed a causal role for corticostriatal plasticity in determining relapse propensity. Inducing long-term depression (LTD) in the abstinent state attenuated reinstatement, while inducing long-term potentiation (LTP) after extinction training reinstated alcohol seeking. Together, these findings identify distinct neural adaptations shaped by abstinence versus extinction and highlight corticostriatal plasticity as a potential target for relapse prevention. Highlight: Abstinence enhances striatal dMSN activity and dopamine signaling during cued relapse.Extinction training normalizes dMSN dynamics and reduces dopamine release during cued relapse.Optogenetic mPFC-to-dMSN long-term depression after abstinence reduces relapse.Optogenetic mPFC-to-dMSN long-term potentiation after extinction invigorates relapse.