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bioRxiv · 10.1101/2025.06.02.657507

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

Xie, X.·Cheng, R.·Wang, X.·Wang, J.
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Abstract

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. HighlightO_LIAbstinence enhances striatal dMSN activity and dopamine signaling during cued relapse. C_LIO_LIExtinction training normalizes dMSN dynamics and reduces dopamine release during cued relapse. C_LIO_LIOptogenetic mPFC-to-dMSN long-term depression after abstinence reduces relapse. C_LIO_LIOptogenetic mPFC-to-dMSN long-term potentiation after extinction invigorates relapse. C_LI

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Xie, X., Cheng, R., Wang, X., Wang, J.. 2025-06-06. bstinence and Extinction Drive Opposing Changes in Striatal Activity and Dopamine Signaling During Alcohol Relapse. https://doi.org/10.1101/2025.06.02.657507

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