The Role of Kappa-Opioid Receptors in Alcohol Use Disorders

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 导致酒精使用水平逐步上升的消费，并促进进展到 酒精依赖。考虑到酒精依赖和抑郁等情感障碍的共病 是非常高的，有人认为负面情绪状态的自我治疗有助于持续 过量饮酒和复发。此外，长期饮酒产生的负面情绪状态 暴露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就会促进每一个 另一种方式对个人、家庭和社会福利极其有害。校长 研究人员的长期目标是确定有效的治疗靶点和治疗策略 AUDS。续签申请的目标是理解，这是追求这一目标的下一步 强啡肽(Dyn)/kappa阿片受体(KOR)系统的神经适应 慢性酒精暴露并以适应不良的形式促进适应不良的行为调节 行为规范。中心假设是Dyn/KOR系统逐渐变得 以一种不受监管的方式促进持续过度饮酒并使 酒精依赖的循环。拟议研究的基本原理是识别新的Dyn/KOR- 相关的治疗目标将使旨在缓解适应不良的有效疗法的开发成为可能 由烦躁不安和酒精依赖所产生的行为调节。这一假设将通过以下方式检验 追求以下特定目标：目标1评估大脑皮层kappa-阿片受体失调 工作记忆和冲动控制领域内急性撤退时的核团。AIM#2评估 杏仁核内Kors在非依赖型焦虑症和酒精依赖型反应中的作用 联合应用药物和药物诱导戒断线索诱导的适应不良行为调节 可诱导的遗传方法。自我管理、负面情绪化行为、工作的动物模型 记忆和冲动控制将作为功能终点，系统地研究这种机制 这导致了AUDS患者的不适应行为调节。这些具体目标将共同帮助 确定Dyn/KOR系统中的重要神经适应，可以促进向 ，AUDS的永久化，并将提供关于Dyn/Kors对 神经回路失调的行为调节。这样的贡献意义重大，因为它将有所帮助。 开发个人化的治疗靶点，以治疗侧重于去除不适应表型的AUD； 这一策略应该会极大地提高服药依从性并降低复发率。

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.