Discrete alcohol cues and contexts are relapse triggers for people with alcohol use disorder exerting particularly powerful control over behaviour when they co-occur. Here, we investigated the neural substrates subserving the capacity for alcohol-associated contexts to elevate responding to an alcohol-predictive conditioned stimulus (CS). Specifically, rats were trained in a distinct ‘alcohol context’ to respond by entering a fluid port during a discrete auditory CS that predicted the delivery of alcohol and were familiarized with a ‘neutral context’ wherein alcohol was never available. When conditioned CS responding was tested by presenting the CS without alcohol, we found that augmenting glutamatergic activity in the nucleus accumbens (NAc) shell by microinfusing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) reduced responding to an alcohol CS in an alcohol, but not neutral, context. Further, AMPA microinfusion robustly affected behaviour, attenuating the number, duration and latency of CS responses selectively in the alcohol context. Although dopaminergic inputs to the NAc shell were previously shown to be necessary for CS responding in an alcohol context, here, chemogenetic excitation of ventral tegmental area (VTA) dopamine neurons and their inputs to the NAc shell did not affect CS responding. Critically, chemogenetic excitation of VTA dopamine neurons affected feeding behaviour and elevated c-fos immunoreactivity in the VTA and NAc shell, validating the chemogenetic approach. These findings enrich our understanding of the substrates underlying Pavlovian responding for alcohol and reveal that the capacity for contexts to modulate responding to discrete alcohol cues is delicately underpinned by the NAc shell.

中文翻译：

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增强伏隔核壳中的谷氨酸能活性，但不增强多巴胺能活性，会扰乱酒精环境中对离散酒精提示的反应

离散的酒精暗示和环境是酒精使用障碍患者复发的诱因，当它们同时出现时，他们对行为施加特别强大的控制。在这里，我们研究了促进酒精相关环境增强对酒精预测性条件刺激（CS）反应能力的神经基质。具体来说，老鼠在不同的“酒精环境”中接受训练，在离散的听觉CS期间通过进入液体端口来做出反应，预测酒精的输送，并熟悉其中永远无法获得酒精的“中性环境”。当通过在不含酒精的情况下呈现 CS 来测试条件 CS 响应时，我们发现通过微量注入 α-氨基-3-羟基-5-甲基-4-异恶唑丙酸 (AMPA) 增强伏隔核 (NAc) 壳中的谷氨酸活性会降低响应酒精 CS 在酒精环境中，但不是中性环境。此外，AMPA 微量输注强烈影响行为，选择性地减弱酒精环境下 CS 反应的数量、持续时间和潜伏期。尽管先前已证明对 NAc 壳的多巴胺能输入对于酒精环境中的 CS 响应是必要的，但在此，腹侧被盖区 (VTA) 多巴胺神经元的化学遗传学激发及其对 NAc 壳的输入并不影响 CS 响应。至关重要的是，VTA 多巴胺神经元的化学遗传学激发影响了进食行为并提高了 VTA 和 NAc 壳中的 c-fos 免疫反应性，从而验证了化学遗传学方法。这些发现丰富了我们对巴甫洛夫酒精反应底物的理解，并揭示了环境调节对离散酒精线索的反应的能力是由 NAc 壳微妙地支撑的。