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

IF 4.6 2区医学 Q1 NEUROSCIENCES

Neuropharmacology Pub Date : 2025-08-21 DOI:10.1016/j.neuropharm.2025.110646

Xueyi Xie, Ruifeng Chen, Yufei Huang, Xuehua Wang, Jun Wang

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Abstract

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.

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戒酒和戒酒在酒精复发期间驱动纹状体活动和多巴胺信号的相反变化

复发仍然是治疗酒精使用障碍的主要挑战，部分原因是持续的神经适应。然而，不同的酒精后经历，如被动戒断（戒酒）与主动戒酒训练，如何不同地塑造影响复发脆弱性的神经回路和突触机制仍不清楚。本研究表明，在线索诱导的酒精寻求恢复过程中，这些经历对背内侧纹状体（DMS）直接通路中棘神经元（dmsn）和多巴胺动力学具有相反的影响。使用D1-Cre大鼠体内纤维光度法，我们发现戒断在恢复过程中增加了多巴胺释放和dMSN钙活性，而消失训练减少了多巴胺释放并阻止了戒断相关的dMSN活性升高。考虑到多巴胺调节皮质纹状体对dmsn的可塑性，并且这种可塑性在寻求酒精的行为中起着关键作用，这些相反的多巴胺信号表明内侧前额叶皮层（mPFC）与dmsn突触强度的经验依赖性变化可能有助于复发易感。为了验证这一点，我们使用了特定途径的光遗传可塑性方案，发现在戒酒后诱导长期抑郁（LTD）会减弱酒精的恢复，而在戒酒后诱导长期增强（LTP）会恢复酒精的寻求。这些发现表明，多巴胺依赖的皮质纹状体可塑性双向介导复发，并由先前的酒精相关经历塑造，将其确定为预防复发的潜在目标。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Neuropharmacology 医学-神经科学

CiteScore

10.00

自引率

4.30%

发文量

288

审稿时长

45 days

期刊介绍： Neuropharmacology publishes high quality, original research and review articles within the discipline of neuroscience, especially articles with a neuropharmacological component. However, papers within any area of neuroscience will be considered. The journal does not usually accept clinical research, although preclinical neuropharmacological studies in humans may be considered. The journal only considers submissions in which the chemical structures and compositions of experimental agents are readily available in the literature or disclosed by the authors in the submitted manuscript. Only in exceptional circumstances will natural products be considered, and then only if the preparation is well defined by scientific means. Neuropharmacology publishes articles of any length (original research and reviews).