Activation of the Oxytocin System by Neuropeptide S to Generate Anxiolysis and Curb Alcohol Drinking

项目摘要 酒精依赖(AD)的特点是大脑应激信号加剧，导致焦虑状态。 戒酒并导致饮酒强度增加，从而导致饮酒 精神障碍(澳元)。澳门氏症是一个全球公共卫生问题，迫切需要更有效的治疗方法。 临床前数据表明，神经肽S(NPS)治疗具有抗焦虑作用 在AUD啮齿动物模型中观察到的增强的焦虑。有趣的是，最近有证据表明核动力源 治疗激活下丘脑催产素神经元(酒精依赖中的催产素系统激活 家长R00奖的焦点)。我们假设：1.神经肽S治疗会产生一种治疗作用 在阿尔茨海默病中缓解焦虑的作用，从而减少饮酒的动机，并使2。NPS可以产生 抗焦虑和戒酒作用是通过激活下丘脑内的催产素神经元实现的。 虽然NPS系统被美国国家酒精滥用研究所和美国农业部列为重要目标 酒精中毒，我们不知道有任何研究报道了NPS对酒精饮酒的影响 依赖。NPS对高饮酒人群焦虑和饮酒影响的检测 支持我们的假设，即NPS产生缓解焦虑和戒酒的效果，然而，我们渴望 进行能够系统地展示NPS在酒精依赖中的作用的实验 与非依赖形成对比。此外，我们试图测试我们的假设，即NPS可以产生这些假定 通过激活大脑催产素系统的治疗作用。为了检验我们的假设，我们建议首先测试 NPS在急性酒精戒断焦虑模型中的作用，同时监测催产素释放 中央杏仁核(下丘脑催产素投射神经元的终末区域，也是 家长补助金)。接下来，我们将测试NPS对慢性酒精中毒患者自我饮酒动机的影响。 间歇性暴露于蒸气中的酒精依赖模型，同时也决定了是否有光遗传 抑制下丘脑催产素神经元(见父母R00奖)可以阻止NPS的这种作用。 拟议的项目将成为小约翰·马伦德斯的培训机会。我们的研究计划是 旨在允许约翰在父母资助的范围内工作，近距离进行他的研究生培训 指导，但同时，开始发展一个独立的研究利基。这一关键方面是 这项提议将极大地有利于约翰为未来的独立研究生涯做准备。 通过这种行为神经药理学方法，约翰完成了拟议的项目，预计将 揭示NPS和催产素信号在酒精依赖中的作用的新信息。预计 这些数据将为研究酒精依赖的神经生物学开辟一条新的途径，从而 在基础神经科学和转化医学方面对酒精研究的持续影响。

Project Summary Alcohol dependence (AD) is characterized by exacerbated brain stress signaling that drives an anxious state in alcohol withdrawal and contributes to the intensity of alcohol drinking, which can contribute to alcohol use disorder (AUD). AUD is a global public health issue for which more effective treatments are urgently needed. Preclinical data suggest that Neuropeptide S (NPS) treatment induces an anxiolytic effect that can counter the enhanced anxiety observed in rodent models of AUD. Interestingly, it has been recently demonstrated that NPS treatment activates hypothalamic oxytocin neurons (oxytocin system activation in alcohol dependence is the focus of the parent R00 award). We hypothesize that 1. Neuropeptide S treatment will produce a therapeutic action of anxiolysis in AD, thereby lessening the motivation to consume alcohol and that 2. NPS can produce anxiolytic and anti-drinking effects through activation of oxytocin neurons within the hypothalamus. While the NPS system is listed as an important target in AUD by the National Institutes of Alcohol Abuse and Alcoholism, we are not aware of any study that has reported the effect of NPS on alcohol drinking in alcohol dependence. Tests of NPS’s effects on anxiety and alcohol drinking in genetic lines selected for high drinking support our hypothesis that NPS produces an anxiolytic and anti-drinking effect, however, we are eager to conduct the experiments which can systematically demonstrate a role for NPS in alcohol dependence contrasted with non-dependence. Further, we seek to test our hypothesis that NPS can produce these putative therapeutic actions via activation of the brain oxytocin system. To test our hypotheses, we propose to first test the effect of NPS in an acute model of alcohol-withdrawal-induced anxiety, while monitoring oxytocin release in the central amygdala (a terminal region for hypothalamic oxytocin projection neurons, and a major focus of the parent grant). Next, we will test the effect of NPS on the motivation to self-administer alcohol in the chronic- intermittent exposure to vapor model of alcohol dependence, while also determining whether optogenetic inhibition of hypothalamic oxytocin neurons (see parent R00 award) can prevent this NPS action. The proposed project will serve as a training opportunity for John Marendes Jr. Our Research Plan is designed to allow John to work within the scope of the parent grant, undertaking his graduate training with close mentorship, but at the same time, to begin developing an independent research niche. This critical aspect of the proposal will greatly benefit John in preparing for an independent research career in the future. With this behavioral neuropharmacology approach, John’s completion of the proposed project is expected to reveal new information about the role of NPS and oxytocin signaling in alcohol dependence. It is anticipated that this data will open a new avenue for research into the neurobiology of alcohol dependence, and thereby have a sustained impact on alcohol research in terms of both basic neuroscience and translational medicine.