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

神经肽 S 激活催产素系统产生抗焦虑和抑制饮酒

• 批准号: 10838740
• 负责人: Brendan Tunstall
• 金额: $ 6.75万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10838740
• 关键词: Acute; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Amygdaloid structure; Anniversary; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Arousal; Award; Basic Science; Behavior; Behavioral; Brain; Brain region; Cell Nucleus; Chronic; Data; Disease; Ethanol; Etiology; Exposure to; Fright; Functional disorder; Funding; Future; Genetic; Grant; Hypothalamic structure; Individual; Intervention; Knowledge; Laboratories; Lead; Measurement; Measures; Mediating; Mediator; Mentorship; Methods; Modeling; Monitor; Motivation; National Institute of Drug Abuse; National Research Service Awards; Neurobiology; Neurons; Neuropeptides; Neuropharmacology; Neurosciences; Oxytocin; Parents; Persons; Postdoctoral Fellow; Preparation; Public Health; Quality of life; Rattus; Relapse; Reporting; Research; Research Proposals; Rodent Model; Role; Self Administration; Signal Transduction; Stress; System; Testing; Therapeutic; Time; Training; United States; Virus; Work; alcohol abuse therapy; alcohol comorbidity; alcohol exposure; alcohol research; alcohol use disorder; anxiety reduction; anxiety-like behavior; anxious; biological adaptation to stress; career; career development; design; diagnostic criteria; drinking; effective therapy; experimental study; extracellular; graduate school; insight; interest; meetings; negative affect; novel; novel strategies; optogenetics; parent grant; pre-clinical; prevent; preventable death; programs; receptor; response; sensor; therapeutic development; tool; training opportunity; translational medicine; vapor; withdrawal-induced anxiety

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.

项目摘要 酒精依赖（AD）的特征是大脑应激信号加剧，导致焦虑状态， 酒精戒断，并有助于饮酒的强度，这可能有助于酒精的使用 疾病（AUD）。AUD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（Neuropeptide S）治疗可诱导抗焦虑作用， 在AUD的啮齿动物模型中观察到的增强的焦虑。有趣的是，最近的研究表明， 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是 R 00奖励的重点）。我们假设1。神经肽S治疗将产生治疗 在AD中的抗焦虑作用，从而减少饮酒的动机，以及2.马达加斯加生产 通过激活下丘脑内的催产素神经元产生抗焦虑和抗饮酒作用。 虽然酒精滥用系统被国家酒精滥用研究所列为AUD的重要目标， 酒精中毒，我们不知道任何研究，已报告的影响，对酒精饮用酒精 依赖在选择的高饮酒遗传系中测试酒精对焦虑和饮酒的影响 支持我们的假设，即酒精产生抗焦虑和抗饮酒作用，然而，我们渴望 进行实验，系统地证明酒精依赖中的作用 与非依赖性相比。此外，我们试图测试我们的假设，即， 通过激活大脑催产素系统的治疗作用。为了验证我们的假设，我们建议首先测试 在酒精戒断引起的焦虑的急性模型中， 中央杏仁核（下丘脑催产素投射神经元的终末区域，以及下丘脑催产素投射神经元的主要焦点）。 父母补助金）。接下来，我们将测试酒精对慢性酒精中毒患者自我管理酒精的动机的影响- 间歇性暴露于酒精依赖的蒸汽模型，同时还确定光遗传学是否 抑制下丘脑催产素神经元（参见父R 00奖项）可以防止这种NPS作用。 拟议的项目将作为一个培训机会，约翰马伦德斯小。我们的研究计划是 旨在让约翰在父母资助的范围内工作，在密切的合作下进行研究生培训。 导师，但同时，开始发展一个独立的研究利基。这个关键的方面， 这个建议将大大有利于约翰为将来独立的研究生涯做准备。 有了这种行为神经药理学方法，约翰完成拟议的项目预计将 揭示了酒精依赖中催产素和催产素信号作用的新信息。预计各国 这一数据将为酒精依赖的神经生物学研究开辟一条新的途径， 在基础神经科学和转化医学方面对酒精研究产生持续影响。

项目成果

Food-Seeking Behavior Is Mediated by Fos-Expressing Neuronal Ensembles Formed at First Learning in Rats.

寻找食物的行为是由大鼠首次学习时形成的表达 Fos 的神经元群介导的。

• DOI: 10.1523/eneuro.0373-20.2021
• 发表时间: 2021
• 期刊: eNeuro
• 影响因子: 3.4
• 作者: Quintana-Feliciano,Richard;Gobin,Christina;Kane,Louisa;Sortman,Bo;Rakela,Samantha;Genovese,Ariana;Tunstall,Brendan;Caprioli,Daniele;Iñiguez,SergioD;Warren,BrandonL
• 通讯作者: Warren,BrandonL

Spironolactone as a potential new pharmacotherapy for alcohol use disorder: convergent evidence from rodent and human studies.

• DOI: 10.1038/s41380-022-01736-y
• 发表时间: 2022-11
• 期刊: MOLECULAR PSYCHIATRY
• 影响因子: 11
• 作者: Farokhnia, Mehdi;Rentsch, Christopher T.;Chuong, Vicky;McGinn, M. Adrienne;Elvig, Sophie K.;Douglass, Eliza A.;Gonzalez, Luis A.;Sanfilippo, Jenna E.;Marchette, Renata C. N.;Tunstall, Brendan J.;Fiellin, David A.;Koob, George F.;Justice, Amy C.;Leggio, Lorenzo;Vendruscolo, Leandro F.
• 通讯作者: Vendruscolo, Leandro F.

κ-Opioid receptor antagonism reverses heroin withdrawal-induced hyperalgesia in male and female rats.

• DOI: 10.1016/j.ynstr.2021.100325
• 发表时间: 2021-05
• 期刊: Neurobiology of stress
• 影响因子: 5
• 作者: Marchette RCN;Gregory-Flores A;Tunstall BJ;Carlson ER;Jackson SN;Sulima A;Rice KC;Koob GF;Vendruscolo LF
• 通讯作者: Vendruscolo LF

Discriminative stimulus properties of the 5-HT1A receptor biased agonists NLX-101 and F13714, in rats trained to discriminate 8-OH-DPAT from saline.

• DOI: 10.1097/fbp.0000000000000659
• 发表时间: 2021-12-01
• 期刊: Behavioural pharmacology
• 影响因子: 1.6
• 作者: Broadbear JH;Depoortere RY;Vacy K;Ralph D;Tunstall BJ;Newman-Tancredi A
• 通讯作者: Newman-Tancredi A

Demand for fentanyl becomes inelastic following extended access to fentanyl vapor self-administration.

在扩展获得芬太尼蒸气自我管理后，对芬太尼的需求变得无弹性。

• DOI: 10.1016/j.neuropharm.2020.108355
• 发表时间: 2021-01
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: McConnell SA;Brandner AJ;Blank BA;Kearns DN;Koob GF;Vendruscolo LF;Tunstall BJ
• 通讯作者: Tunstall BJ