Alcohol Vapor Self-Administration in Rats

项目总结/摘要 酒精领域的一个主要问题是缺乏自愿诱导和维持酒精依赖的动物模型。 酒精依赖大鼠会很容易地自我管理酒精，但酒精消耗量非常低 并因此不产生临床上与酒精中毒相关的血液酒精水平（100-200 mg%， 每天几个小时）。在上一个资助期间，我们成功地开发了一种新的自愿模式， 慢性间歇性乙醇蒸汽自吸诱导和维持大鼠酒依赖 给药（EVSA）。在该模型中，动物表现出严重的成瘾样行为，包括成瘾的躯体体征。 戒断、焦虑样行为、痛觉过敏和尽管有不良后果仍有反应（在一个 渐进比例强化方案）。目前的建议旨在进一步 发展这种范式，识别酒精依赖自愿诱导的神经网络， 描述了一种自愿的“极端暴饮暴食”的新模式。极端酗酒是一个严重的社会问题 也是NIAAA 2017-2021战略计划的优先事项之一。暴饮暴食和极端暴饮暴食是 尤其令人不安的是，它们增加了停电、酒精中毒、性侵犯、性行为的风险。 传播疾病，学习成绩差，发展AUD。通过将酒精蒸汽自- 管理与国家的最先进的脑映射技术，我们将确定神经网络，驱动 饮酒和自愿诱导酒精依赖后复发。我们的数据显示， 酒精蒸汽的被动和主动给药导致饮酒的升级，增加了 获得酒精的动机，并增加复发，但自愿诱导依赖的特点是 背内侧纹状体（DMS）和背外侧纹状体（DLS）神经元的特异性募集， 戒断我们还建议进一步描述先前在动物中饮酒和复发的特征。 与被动暴露于酒精蒸汽而产生依赖性的动物相比。最后， 我们建议验证并充分描述一种新的极端酗酒模型，在这种模型中，动物自我- 给予酒精蒸汽，使血液酒精水平达到~400 mg%，失去意识 （“失去知觉”），并表现出短期记忆丧失。这些研究的结果将提供一个完整的 表征自愿产生依赖性的动物的饮酒和复发，并将揭示 神经回路的基础自愿诱导和酒精依赖的维持。结果从这个 该提案还将提供一种新的动物模型来研究和表征啮齿动物中的极端酗酒。 拟议中的研究有可能对成瘾领域产生持续而强大的影响 因为他们可以揭示在酒精自愿诱导过程中特别招募的神经元靶点， 依赖和极端暴食，可以用来开发新的治疗方法。

Project Summary / Abstract A major issue in the alcohol field is the lack of animal models of the voluntary induction and maintenance of alcohol dependence. Rats will readily self-administer alcohol, but the amount of alcohol consumed is very low and thus does not produce blood alcohol levels that are clinically relevant for alcoholism (100-200 mg% for several hours per day). In the previous funding period, we successfully developed a novel model of the voluntary induction and maintenance of alcohol dependence in rats using chronic intermittent ethanol vapor self- administration (EVSA). In this model, animals exhibit severe addiction-like behaviors, including somatic signs of withdrawal, anxiety-like behavior, hyperalgesia, and responding despite adverse consequences (on a progressive-ratio schedule of reinforcement) after 6 weeks of EVSA. The current proposal seeks to further develop this paradigm, identify the neuronal networks of the voluntary induction of alcohol dependence, and characterize a novel model of voluntary “extreme binging.” Extreme alcohol binging is a critical societal issue and one of the priorities of the NIAAA Strategic Plan 2017-2021. Binge and extreme binge drinking are particularly troubling because they increase the risks for blackouts, alcohol poisoning, sexual assault, sexually transmitted diseases, poor academic performance, and developing AUD. By combining alcohol vapor self- administration with state-of-the-art brain mapping techniques, we will identify neuronal networks that drive alcohol drinking and relapse after the voluntary induction of alcohol dependence. Our data show that both the passive and active administration of alcohol vapor produces the escalation of alcohol drinking, increases the motivation to obtain alcohol, and increases relapse, but the voluntary induction of dependence is characterized by the specific recruitment of dorsomedial striatum (DMS) and dorsolateral striatum (DLS) neurons during withdrawal. We also propose to further characterize alcohol drinking and relapse in animals that are previously made dependent by EVSA vs. animals that are made dependent by passive exposure to alcohol vapor. Finally, we propose to validate and fully characterize a novel model of extreme alcohol binging, in which animals self- administer alcohol vapor to the point of reaching blood alcohol levels of ~400 mg%, losing consciousness (“blacking out”), and exhibiting short-term memory loss. Results from these studies will provide a full characterization of alcohol drinking and relapse in animals that voluntarily develop dependence and will unveil neuronal circuits that underlie the voluntary induction and maintenance of alcohol dependence. Results from this proposal will also provide a novel animal model to study and characterize extreme alcohol binging in rodents. The proposed studies have the potential to have a sustained and powerful impact on the field of addiction because they could unveil neuronal targets that are specifically recruited during the voluntary induction of alcohol dependence and extreme binging that could be used to develop novel therapeutic approaches.