The Florey Institute of Neuroscience and Mental Health, Parkville, Victoria 3052, Australia,
Florey Department of Neuroscience and Mental Health, The University of Melbourne, Victoria 3010, Australia, and.
J Neurosci. 2019 Feb 6;39(6):1077-1087. doi: 10.1523/JNEUROSCI.1596-18.2018. Epub 2018 Dec 3.
Humans with alcohol use disorder typically abstain because of the negative consequences associated with excessive drinking, and exposure to contexts previously associated with alcohol use can trigger relapse. We used a rat model that captures a characteristic of this human condition: namely voluntary abstinence from alcohol use because of contingent punishment. There is substantial variability in the propensity to relapse following extended periods of abstinence, and this is a critical feature preventing the successful treatment of alcohol use disorder. Here we examined relapse following acute or prolonged abstinence. In male alcohol preferring P rats, we found an increased propensity to relapse in Context B, the punishment context after prolonged abstinence. Next, we found that neither alcohol intake history nor the motivational strength of alcohol predicted the propensity to relapse. We next examined the putative circuitry of context-induced relapse to alcohol seeking following prolonged abstinence using Fos as a marker of neuronal activation. The anterior insular cortex (AI) was the only brain region examined where Fos expression correlated with alcohol seeking behavior in Context B after prolonged abstinence. Finally, we used local infusion of GABA and GABA receptor agonists (muscimol + baclofen) to show a causal role of the AI in context-induced relapse in Context B, the punishment context after prolonged abstinence. Our results show that there is substantial individual variability in the propensity to relapse in the punishment-associated context after prolonged abstinence, and this is mediated by activity in the AI. A key feature of alcohol use disorder is that sufferers show an enduring propensity to relapse throughout their lifetime. Relapse typically occurs despite the knowledge of adverse consequences including health complications or relationship breakdowns. Here we use a recently developed rodent model that recapitulates this behavior. After an extended period of abstinence, relapse propensity is markedly increased in the "adverse consequence" environment, akin to humans with alcohol use disorder relapsing in the face of adversity. From a circuitry perspective, we demonstrate a causal role of the anterior insular cortex in relapse to alcohol seeking after extended abstinence following punishment imposed voluntary cessation of alcohol use.
患有酒精使用障碍的人通常会因为过度饮酒带来的负面影响而戒酒，而接触到以前与饮酒相关的环境会引发复发。我们使用了一种大鼠模型，该模型捕捉到了人类这种状况的一个特征：即由于偶然的惩罚而自愿停止饮酒。在长时间的戒酒之后，复发的倾向存在很大的差异，这是阻止酒精使用障碍成功治疗的一个关键特征。在这里，我们研究了急性或长期戒酒之后的复发情况。在雄性酒精偏好 P 大鼠中，我们发现，在长时间戒酒之后的惩罚环境 B 中，复发的倾向增加了。接下来，我们发现，饮酒史或酒精的动机强度都不能预测复发的倾向。接下来，我们使用 Fos 作为神经元激活的标志物，研究了长时间戒酒之后，由环境引发的对酒精寻求的复发的潜在回路。在大脑中，只有前脑岛皮层（anterior insular cortex，AI）被检查到，在长时间戒酒之后，Fos 的表达与环境 B 中的酒精寻求行为相关。最后，我们使用 GABA 和 GABA 受体激动剂（muscimol + baclofen）的局部输注，证明了 AI 在长时间戒酒之后的惩罚相关环境 B 中，对环境诱导的复发起着因果作用。我们的结果表明，在长时间戒酒之后，在与惩罚相关的环境中，复发的倾向存在很大的个体差异，而这种差异是由 AI 的活动介导的。酒精使用障碍的一个关键特征是，患者在其一生中都会持续表现出复发的倾向。复发通常发生在患者知道会带来不良后果，包括健康并发症或关系破裂的情况下。在这里，我们使用一种新开发的啮齿动物模型，该模型再现了这种行为。在长时间的戒酒之后，在“不利后果”环境中，复发的倾向显著增加，这类似于患有酒精使用障碍的人在面对逆境时会复发。从回路的角度来看，我们证明了前脑岛皮层在惩罚引起的自愿停止饮酒之后，对长时间戒酒之后的酒精寻求复发起着因果作用。
