Alcohol Vapor Self-Administration in Rats

项目摘要/摘要 酒精领域的一个主要问题是缺乏自愿诱导和维持的动物模型。 酒精依赖。大鼠很容易自我管理酒精，但饮酒量很低。 因此不会产生临床上与酒精中毒相关的血液酒精水平(100-200毫克 每天几个小时)。在之前的资助期间，我们成功地开发了一种新型的志愿服务模式 慢性间歇性乙醇蒸气自身注射诱导和维持大鼠酒依赖 管理(EVSA)。在这个模型中，动物表现出严重的成瘾行为，包括 戒断、焦虑样行为、痛觉过敏和不顾不良后果的反应(在 增强的累进比率计划)在EVSA后6周。目前的提案旨在进一步 发展这一范式，确定自愿诱导酒精依赖的神经元网络，以及 描述了一种自愿的“极端狂欢”的新模式。极端酗酒是一个关键的社会问题 也是NIAAA 2017-2021年战略计划的优先事项之一。狂欢和极端狂饮是 尤其令人不安，因为它们增加了昏迷、酒精中毒、性侵犯、性侵犯、 传播疾病，学习成绩差，以及发展中的AUD。通过将酒精蒸气自身结合 管理使用最先进的大脑映射技术，我们将识别驱动 饮酒和自愿诱导后复发的酒精依赖。我们的数据显示， 被动和主动使用酒精蒸气会导致饮酒行为升级，增加 获得酒精的动机，并增加复发，但自愿诱导的依赖是特点 背内侧纹状体(DMS)和背外侧纹状体(DLS)神经元的特异性募集 戒烟。我们还建议进一步确定饮酒和复发的动物的特征 通过EVSA与被动暴露在酒精蒸气中而使其依赖的动物。最后， 我们建议验证并充分描述一种新的极端酗酒模型，在该模型中，动物自我 使用酒精蒸气达到血液酒精含量约400毫克，失去知觉 (“昏迷”)，并表现出短期记忆丧失。这些研究的结果将提供完整的 自愿形成依赖并将揭示饮酒和复发的动物的特征 神经回路是自愿诱导和维持酒精依赖的基础。由此产生的结果 该提案还将提供一种新的动物模型来研究和表征啮齿类动物的极端酗酒行为。 拟议的研究有可能对成瘾领域产生持续而有力的影响。 因为他们可以揭示在自愿酒精诱导过程中专门招募的神经元靶点 依赖和极端狂欢，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.