Role of Dynorphin and Kappa Opioid Receptors in Stress Effects on Ethanol Dependence-Related Escalated Drinking

强啡肽和卡帕阿片受体在乙醇依赖相关逐步饮酒的压力影响中的作用

基本信息

批准号：
8835790
负责人：
Rachel Ivy Anderson
金额：
$ 5.15万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-05 至 2016-02-04
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8835790
关键词：
Abstinence Agonist Air Alcohol consumption Alcohol dependence Alcohols Amygdaloid structure Attention Attenuated Binding Cell Nucleus Chemosensitization Chronic Chronic stress Clozapine Consumption Coupled Data Dependence Designer Drugs Development Disease Dynorphins Ethanol Ethanol dependence Exposure to Goals Heavy Drinking Injection of therapeutic agent Intake Internal Ribosome Entry Site Laboratories Mediating Modeling Mus National Research Service Awards Neurons Neuropeptides Opioid Receptor Oxides Play Procedures Public Health Receptor Signaling Relapse Research Research Project Grants Research Training Rodent Role Site Stress Swimming System Technology Testing Transgenic Mice Viral Viral Vector Work alcohol effect alcohol exposure alcohol reward biological adaptation to stress career design drinking mouse model neuromechanism novel prevent prodynorphin public health relevance receptor skills social therapeutic target treatment strategy vapor

项目摘要

DESCRIPTION (provided by applicant): Alcohol dependence is a widespread public health concern with limited treatment options available. This chronic, relapsing disorder is characterized by periods of abstinence followed by a return to heavy use and can be modeled in rodents using a well-established chronic intermittent ethanol (CIE) exposure procedure. While stress is known to promote alcohol consumption and, in particular, trigger relapse, the influence of stress exposure on transition to excessive levels of drinking associated with dependence is less well understood. Our lab has shown that forced swim stress exposure accelerates the rate at which excessive drinking emerges in the CIE model of ethanol dependence and enhances the magnitude of escalated consumption in dependent but not nondependent subjects. The dynorphin/kappa opioid receptor (KOR) system is implicated in modulating both stress responses and ethanol consumption associated with dependence. Thus, it is plausible to suggest that the dynorphin/KOR system may play a role in this stress interaction with the CIE-drinking model. This research project is focused on examining the role of dynorphin/KOR activity in mediating the ability of stress exposure to facilitate and enhance escalation of drinkig in the mouse CIE model of ethanol dependence. The proposed studies will employ both systemic pharmacological and site-specific pharmacosynthetic approaches. For Aim 1, I will use our forced swim stress (FSS)-CIE-drinking paradigm to (1) assess whether administration of the novel, short-acting, selective KOR antagonist FP3FBZ attenuates stress facilitation of CIE-induced escalated drinking and (2) determine whether systemic administration of the KOR agonist U50,488 can substitute for and mimic the effects of FSS exposure in increasing ethanol drinking in CIE- exposed mice compared to nondependent controls. For Aim 2, I will use designer receptor technology (viral injection of Cre-dependent DREADDs) along with prodynorphin-IRES-Cre transgenic mice in the same FSS- CIE-drinking model to (1) determine whether 'silencing' dynorphin neurons (via activation of inhibitory DREADDs) in the central amygdala blocks stress facilitation of CIE-induced escalated drinking and (2) assess whether activation of dynorphin neurons (via excitatory DREADDs) in the central amygdala can substitute for and mimic the effects of stress exposure in enhancing ethanol intake in CIE-exposed mice compared to nondependent controls. Results from this project will advance our understanding of the neural mechanisms underlying the ability of stress to facilitate transition to excessive ethanol drinking associated with dependence, as well as characterize the potential for the KOR system to serve as a therapeutic target for treatment strategies for alcohol dependence.

描述（由申请人提供）：酒精依赖是一个广泛的公共卫生问题，可用的治疗选择有限。这种慢性、复发性疾病的特点是一段时间的禁欲，然后又重新大量使用，可以使用成熟的慢性间歇性乙醇（CIE）暴露程序在啮齿动物中进行建模。虽然已知压力会促进饮酒，特别是引发旧病复发，但压力暴露对过度饮酒（与依赖性相关）的影响尚不清楚。我们的实验室表明，强迫游泳压力暴露会加速乙醇依赖的 CIE 模型中出现过度饮酒的速度，并增加依赖者而非非依赖者的饮酒量增加的程度。强啡肽/卡帕阿片受体 (KOR) 系统参与调节应激反应和与依赖性相关的乙醇消耗。因此，强啡肽/KOR 系统可能在与 CIE 饮酒模型的应激相互作用中发挥作用是合理的。该研究项目的重点是研究强啡肽/KOR 活性在介导压力暴露能力中的作用，以促进和增强小鼠 CIE 乙醇依赖模型中饮酒的升级。拟议的研究将采用系统药理学和位点特异性药物合成方法。对于目标 1，我将使用我们的强迫游泳应激 (FSS)-CIE 饮酒范例来 (1) 评估新型、短效、选择性 KOR 拮抗剂 FP3FBZ 的给药是否会减弱 CIE 诱导的饮酒增加的应激促进作用，以及 (2 ）确定与非依赖性对照相比，全身施用 KOR 激动剂 U50,488 是否可以替代和模拟 FSS 暴露对 CIE 暴露小鼠乙醇饮酒量增加的影响。对于目标 2，我将使用设计受体技术（病毒注射 Cre 依赖性 DREADD）以及同一 FSS-CIE 饮酒模型中的前强啡肽-IRES-Cre 转基因小鼠来 (1) 确定是否“沉默”强啡肽神经元（通过中央杏仁核中抑制性 DREADD 的激活会阻止 CIE 诱导的饮酒增加的应激促进作用，并且 (2) 评估是否激活与非依赖性对照组相比，中央杏仁核中的强啡肽神经元（通过兴奋性 DREADD）可以替代和模拟压力暴露的效果，从而增强 CIE 暴露小鼠的乙醇摄入量。该项目的结果将加深我们对压力促进过渡的神经机制的理解。过量饮酒与酒精依赖相关，并描述了 KOR 系统作为酒精依赖治疗策略的治疗目标的潜力。