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: 9986995
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9986995
• 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; Treatment Efficacy; 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; medication compliance; negative affect; negative emotional state; neuroadaptation; novel; personalized medicine; personalized therapeutic; receptor function; response; success; therapeutic target; 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失去对酒精的控制。 导致酒精使用水平逐渐升高并促进进展的消费 考虑到酒精依赖和抑郁等情感障碍的共病。 非常高，据报道，消极情绪状态的自我治疗有助于持续 此外，长期饮酒造成的负面情绪状态。 暴露会影响认知控制系统的神经回路，从而使过量酒精持续存在 一旦达到这种程度的失调，依赖循环的各个组成部分就会促进每一个。 以对个人、家庭和社会福利极其有害的方式进行其他行为。 研究者的长期目标是确定有效的治疗靶点和治疗策略 此续订申请的目标是实现该目标的下一步，即了解情况。 强啡肽 (DYN) / kappa-阿片受体 (KOR) 系统中的神经适应是响应于 长期接触酒精并以适应不良的形式导致适应不良的行为调节 中心假设是 DYN / KOR 系统逐渐变得更强大。 失调的方式会促进持续过量饮酒并使酒精长期存在 所提出的研究的基本原理是识别新型 DYN / KOR-。 相关的治疗目标将有助于开发旨在缓解适应不良的有效疗法 烦躁不安和酒精依赖产生的行为调节将通过以下方法进行检验。 追求以下具体目标：目标#1评估皮质内的κ阿片受体失调 目标#2 评估工作记忆和冲动控制域内的急性撤退过程中的神经核。 KOR 在杏仁核中对非依赖性烦躁线索和酒精依赖性反应的作用 使用药物和药物相结合的戒断线索诱导的适应不良行为调节 诱导遗传方法的自我管理、消极情感行为、工作的动物模型。 记忆和冲动控制将作为功能终点来系统地研究其机制 这些具体目标将共同有助于 AUD 的适应不良行为调节。 确定 DYN/KOR 系统中可以促进过渡的重要神经适应，以及 AUD 的永久存在，并将提供有关 DYN / KOR 对的影响的急需信息 这种贡献很重要，因为它会有所帮助。 制定治疗 AUD 的个性化治疗目标，重点是消除适应不良表型； 这一策略将大大提高用药依从性并降低复发率。