Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.
Neuropharmacology. 2023 Jan 1;222:109309. doi: 10.1016/j.neuropharm.2022.109309. Epub 2022 Nov 2.
A major limitation of the most widely used current animal models of alcohol dependence is that they use forced exposure to ethanol including ethanol-containing liquid diet and chronic intermittent ethanol (CIE) vapor to produce clinically relevant blood alcohol levels (BAL) and addiction-like behaviors. We recently developed a novel animal model of voluntary induction of alcohol dependence using ethanol vapor self-administration (EVSA). However, it is unknown whether EVSA leads to an escalation of alcohol drinking per se, and whether such escalation is associated with neuroadaptations in brain regions related to stress, reward, and habit. To address these issues, we compared the levels of alcohol drinking during withdrawal between rats passively exposed to alcohol (CIE) or voluntarily exposed to EVSA and measured the number of Fos+ neurons during acute withdrawal (16 h) in key brain regions important for stress, reward, and habit-related processes. CIE and EVSA rats exhibited similar BAL and similar escalation of alcohol drinking and motivation for alcohol during withdrawal. Acute withdrawal from EVSA and CIE recruited a similar number of Fos+ neurons in the Central Amygdala (CeA), however, acute withdrawal from EVSA recruited a higher number of Fos+ neurons in every other brain region analyzed compared to acute withdrawal from CIE. In summary, while the behavioral measures of alcohol dependence between the voluntary (EVSA) and passive (CIE) model were similar, the recruitment of neuronal ensembles during acute withdrawal was very different. The EVSA model may be particularly useful to unveil the neuronal networks and pharmacology responsible for the voluntary induction and maintenance of alcohol dependence and may improve translational studies by providing preclinical researchers with an animal model that highlights the volitional aspects of alcohol use disorder.
目前最广泛使用的酒精依赖动物模型的一个主要局限性是，它们使用强制暴露于乙醇，包括含乙醇的液体饮食和慢性间歇性乙醇（CIE）蒸气，以产生与临床相关的血液酒精水平（BAL）和类似成瘾的行为。我们最近开发了一种使用乙醇蒸气自我给药（EVSA）的自愿诱导酒精依赖的新型动物模型。然而，尚不清楚 EVSA 是否会导致酒精摄入本身的增加，以及这种增加是否与与应激、奖励和习惯相关的大脑区域的神经适应有关。为了解决这些问题，我们比较了被动暴露于酒精（CIE）或自愿暴露于 EVSA 的大鼠在戒断期间的饮酒水平，并测量了在与应激、奖励和习惯相关的过程相关的关键大脑区域中急性戒断（16 小时）时 Fos+神经元的数量。CIE 和 EVSA 大鼠表现出相似的 BAL 和相似的酒精摄入和戒断期间对酒精的动机增加。EVSA 和 CIE 的急性戒断在中央杏仁核（CeA）中招募了相似数量的 Fos+神经元，但与 CIE 的急性戒断相比，EVSA 的急性戒断在分析的每个其他大脑区域中招募了更多的 Fos+神经元。总之，虽然自愿（EVSA）和被动（CIE）模型之间的酒精依赖行为测量相似，但急性戒断期间神经元集合的募集非常不同。EVSA 模型可能特别有助于揭示自愿诱导和维持酒精依赖的神经元网络和药理学，并且可以通过为临床前研究人员提供突出酒精使用障碍自愿方面的动物模型来改善转化研究。
