The Role of Kappa-Opioid Receptors in Alcohol Use Disorders

Kappa-阿片受体在酒精使用障碍中的作用

• 批准号: 10473825
• 负责人: Brendan M Walker
• 金额: $ 33.96万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10473825
• 关键词: Abstinence; Acute; Affect; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Animal Model; Animals; Anxiety Disorders; Attenuated; Behavior; Behavior Control; Behavioral; Cell Nucleus; Characteristics; Chronic; Cognitive; Cues; Data; Decision Making; Dependence; Development; Disease; Dynorphins; Excision; Foundations; Genetic; Goals; Heavy Drinking; Impaired cognition; Impulsivity; Knowledge; Medial; Mediating; Mediator of activation protein; Mental Depression; Molecular; Motivation; National Institute on Alcohol Abuse and Alcoholism; Opioid Antagonist; Organism; Outcome; Pathogenicity; Pattern; Performance; Pharmacology; Phenotype; Prefrontal Cortex; Principal Investigator; Public Health; Publishing; Receptor Activation; Recovery; Regulation; Relapse; Role; Self Administration; Self Medication; Short-Term Memory; Signal Transduction; Strategic Planning; System; Testing; Therapeutic; Withdrawal; Work; alcohol comorbidity; alcohol exposure; alcohol measurement; alcohol relapse; alcohol use disorder; chronic alcohol ingestion; cognitive control; conditioned fear; design; dysphoria; effective therapy; executive function; genetic approach; genetic manipulation; interdisciplinary approach; kappa opioid receptors; maladaptive behavior; medication compliance; negative affect; negative emotional state; neural circuit; neuroadaptation; novel; personalized medicine; personalized therapeutic; receptor function; response; success; therapeutic target; therapeutically effective; therapy design; therapy design/development; treatment adherence; treatment strategy; welfare

Project Summary. A fundamental characteristic of alcohol use disorders is the loss of control over alcohol consumption that results in progressively escalating levels of alcohol use and facilitates the progression to alcohol-dependence. Given the comorbidity of alcohol dependence and disorders of affect such as de-pression is extremely high, it has been posited that self-medication of negative affective states contributes to continued excessive alcohol use and relapse. Furthermore, negative affective states produced by chronic alcohol exposure can influence the neurocircuitry of cognitive control systems to perpetuate further excessive alcohol use. Once that degree of dysregulation is reached, components of the dependence cycle serve to facilitate each other in a manner that is extremely deleterious to personal, familial and societal welfare. The principal investigator’s long-term goal is to identify effective therapeutic targets and strategies for the treatment of AUDs. The objective of this renewal application, which is the next step in pursuit of that goal, is to understand the neuroadaptations in dynorphin (DYN) / kappa-opioid receptor (KOR) systems that occur in response to chronic alcohol exposure and contribute to maladaptive behavioral regulation in the form of maladaptive behavioral regulation. The central hypothesis is that the DYN / KOR system becomes progressively dysregulated in a manner that promotes the continued excessive consumption of alcohol and perpetuates the cycle of alcohol dependence. The rationale for the proposed studies is that identification of novel DYN / KOR- related treatment targets will enable the development of effective therapies designed to alleviate maladaptive behavioral regulation produced by dysphoria and alcohol dependence. This hypothesis will be tested by pursuing the following specific aims: Aim #1 evaluates kappa-opioid receptor dysregulation within cortical nuclei during acute withdrawal within working memory and impulse control domains. Aim #2 assesses the role of KORs in amygdalar nuclei in response to non-dependent dysphoria cues and alcohol-dependent withdrawal cue-induced maladaptive behavioral regulation using a combination of pharmacological and inducible genetic approaches. Animal models of self-administration, negative affective-like behavior, working memory and impulse control will serve as functional end-points to systematically investigate the mechanisms that contribute to maladaptive behavioral regulation in AUDs. These specific aims will collectively help to identify important neuroadaptations in DYN / KOR systems that can promote the transition to, and perpetuation of, AUDs and will provide much needed information regarding the influence of DYN / KORs on the neurocircuitry maladaptive behavioral regulation. Such a contribution is significant because it will help develop personalized therapeutic targets to treat AUDs that focus on the removal of maladaptive phenotypes; a strategy that should greatly increase medication compliance and decrease rates of relapse.

项目摘要。酒精使用障碍的一个基本特征是对酒精失去控制 消费，导致酒精使用水平逐步上升，并促进进展， 酒精依赖考虑到酒精依赖和情感障碍（如抑郁症）的合并症， 是非常高的，它已被假定，自我药疗的负面情感状态有助于继续 过度饮酒和复发。此外，长期饮酒所产生的负面情绪状态 暴露在酒精中会影响认知控制系统的神经回路，使过量的酒精持续存在 使用.一旦达到这种程度的失调，依赖循环的组成部分有助于促进每一个 对个人、家庭和社会福利极为有害的其他行为。校长 研究者的长期目标是确定有效的治疗靶点和治疗策略， AUD。此更新应用程序的目的是，这是追求这一目标的下一步，是了解 强啡肽（DYN）/κ-阿片受体（KOR）系统中的神经适应， 慢性酒精暴露，并有助于适应不良的行为调节的形式， 行为调节核心假设是DYN / KOR系统逐渐变得 以一种促进持续过量饮酒并使酒精永久化的方式失调。 酒精依赖的循环提出的研究的基本原理是，鉴定新的DYN / KOR- 相关的治疗目标将使有效的治疗方法，旨在减轻适应不良的发展 由烦躁和酒精依赖引起的行为调节。这一假设将由以下人员进行检验： 追求以下具体目标：目标#1评价皮质内κ-阿片受体失调 在工作记忆和冲动控制领域内的急性戒断期间的核。目标#2评估 杏仁核内KOR在非依赖性烦躁线索和酒精依赖性焦虑线索反应中的作用 撤药提示诱导的适应不良行为调节， 诱导遗传学方法。自我管理，负性情感样行为，工作的动物模型 记忆和冲动控制将作为系统研究机制的功能终点 导致AUD适应不良的行为调节。这些具体目标将共同有助于 确定DYN / KOR系统中重要的神经适应，可以促进向 永久化，AUD，并将提供有关DYN / KORs对 神经回路适应不良的行为调节。这样的贡献是重要的，因为它将有助于 开发个性化的治疗靶点，以治疗AUDs，重点是消除适应不良的表型; 这是一个可以大大提高药物依从性和降低复发率的策略。

项目成果

Plasticity associated with escalated operant ethanol self-administration during acute withdrawal in ethanol-dependent rats requires intact matrix metalloproteinase systems.

• DOI: 10.1016/j.nlm.2011.04.011
• 发表时间: 2011-09
• 期刊: NEUROBIOLOGY OF LEARNING AND MEMORY
• 影响因子: 2.7
• 作者: Smith, Alexander W.;Nealey, Kathryn A.;Wright, John W.;Walker, Brendan M.
• 通讯作者: Walker, Brendan M.

Dissociable effects of kappa-opioid receptor activation on impulsive phenotypes in wistar rats.

kappa-阿片受体激活对 Wistar 大鼠冲动表型的分离效应。

• DOI: 10.1038/npp.2013.129
• 发表时间: 2013
• 期刊: Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
• 作者: Walker,BrendanM;Kissler,JessicaL
• 通讯作者: Kissler,JessicaL

The one-two punch of alcoholism: role of central amygdala dynorphins/kappa-opioid receptors.

酒精中毒的一二拳：中央杏仁核的作用/kappa-阿片受体。

• DOI: 10.1016/j.biopsych.2013.03.014
• 发表时间: 2014-05-15
• 期刊: BIOLOGICAL PSYCHIATRY
• 影响因子: 10.6
• 作者: Kissler, Jessica L.;Sirohi, Sunil;Reis, Daniel J.;Jansen, Heiko T.;Quock, Raymond M.;Smith, Daniel G.;Walker, Brendan M.
• 通讯作者: Walker, Brendan M.

Dysregulated kappa-opioid receptors in the medial prefrontal cortex contribute to working memory deficits in alcohol dependence.

• DOI: 10.1111/adb.13138
• 发表时间: 2022-03
• 期刊: Addiction biology
• 影响因子: 3.4
• 作者: Wei G;Sirohi S;Walker BM
• 通讯作者: Walker BM

Maladaptive behavioral regulation in alcohol dependence: Role of kappa-opioid receptors in the bed nucleus of the stria terminalis.

• DOI: 10.1016/j.neuropharm.2018.07.034
• 发表时间: 2018-09-15
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Erikson CM;Wei G;Walker BM
• 通讯作者: Walker BM