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

• 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
• 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

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）：酒精依赖是一种广泛存在的公共健康问题，治疗方法有限。这种慢性、复发性疾病的特征是一段时间的戒断，随后又恢复大量使用，可以在啮齿类动物中使用成熟的慢性间歇性乙醇（CIE）暴露程序进行建模。虽然已知压力会促进酒精消费，特别是引发复发，但压力暴露对过渡到与依赖相关的过度饮酒水平的影响尚不清楚。我们的实验室已经表明，在CIE乙醇依赖模型中，强迫游泳应激暴露加速了过度饮酒的出现速度，并增强了依赖而非依赖受试者的升级消费幅度。dynorphin/kappa阿片受体（KOR）系统参与调节与依赖相关的应激反应和乙醇消耗。因此，我们有理由认为，dynorphin/KOR系统可能在这种与cie饮酒模型的应激相互作用中发挥作用。本研究项目的重点是检查dynorphin/KOR活性在介导应激暴露能力中的作用，以促进和增强乙醇依赖小鼠CIE模型中的饮酒升级。拟议的研究将采用系统药理学和部位特异性药物合成方法。在目的1中，我将使用我们的强迫游泳应激(FSS)-CIE饮酒模式来(1)评估使用新型的、短效的、选择性的KOR拮抗剂FP3FBZ是否能减轻CIE诱导的饮酒升级的应激促进作用；(2)确定与非依赖对照相比，在CIE暴露小鼠中，全身使用KOR激动剂U50,488是否可以替代和模拟FSS暴露对乙醇饮酒增加的影响。对于目标2，我将在相同的FSS- cie饮酒模型中使用设计受体技术（病毒注射cre依赖性的脏脏蛋白）和原肌啡- ires - cre转基因小鼠，以(1)确定中央杏仁核中的“沉默”肌啡神经元（通过激活抑制性脏脏蛋白）是否阻断了cie诱导的升级饮酒的应激促进；(2)评估中央杏仁核中的肌啡神经元（通过兴奋性脏脏蛋白）的激活是否可以替代和模拟咖啡因的作用与非依赖对照相比，应激暴露增加了cie暴露小鼠的乙醇摄入量。这个项目的结果将促进我们对压力能力的神经机制的理解，以促进过渡到