Department of Neuroscience, Medical University of South Carolina, Charleston, South Carolina, USA.
Addict Biol. 2023 Oct;28(10):e13335. doi: 10.1111/adb.13335.
Use of addictive substances like cocaine produces enduring associations between the drug experience and cues in the drug-taking environment. In individuals with a substance use disorder (SUD) and attempting to remain abstinent, these powerful drug-cue associations can trigger a return to active drug use, but the molecular mechanisms regulating drug-cue associations remain poorly understood. The activity-regulated cytoskeleton-associated protein (Arc) is induced by cocaine in the nucleus accumbens (NAc), an important brain reward region, but Arc's NAc function in SUD-related behaviour remains unclear. We show here that cocaine self-administration (SA) in rats produced a significant upregulation of Arc protein in both the core and shell subregions of the NAc. Subregion-specific Arc reduction (shRNA) in the medial NAc Shell enhanced both context-associated and cue-reinstated cocaine seeking, but without altering the motivation to work for cocaine, the sensitivity to the reinforcing effects of cocaine or the ability of cocaine priming to reinstate drug seeking. In contrast, we observed no effects of Arc knockdown in the NAc core on any aspect of cocaine SA, extinction or reinstated cocaine seeking, suggesting that Arc functions within the medial NAc shell, but not NAc core, to limit the strength of drug-context and drug-cue associations that promote cocaine-seeking behaviour.
使用可卡因等成瘾物质会在药物体验和药物使用环境中的线索之间产生持久的关联。在有物质使用障碍（SUD）并试图保持戒断的个体中，这些强大的药物线索关联会引发重新开始使用药物，但调节药物线索关联的分子机制仍知之甚少。活性调节细胞骨架相关蛋白（Arc）在可卡因作用下在伏隔核（NAc）中被诱导，伏隔核是一个重要的大脑奖励区域，但 Arc 在 SUD 相关行为中的 NAc 功能仍不清楚。我们在这里表明，大鼠可卡因自我给药（SA）导致 NAc 的核心和壳区 Arc 蛋白显著上调。内侧 NAc 壳区的 Arc 特异性减少（shRNA）增强了与环境相关的和线索再引发的可卡因寻求，但不改变对可卡因的工作动机、可卡因强化作用的敏感性或可卡因引发对药物寻求的再引发能力。相比之下，我们没有观察到 NAc 核心的 Arc 敲低对可卡因 SA、消退或再引发可卡因寻求的任何方面有影响，这表明 Arc 在 NAc 壳区的内侧起作用，而不是 NAc 核心，以限制促进可卡因寻求行为的药物-环境和药物-线索关联的强度。
