Role of Oxytocin in a Mouse Model of PTSD-AUD Comorbidity

催产素在 PTSD-AUD 合并症小鼠模型中的作用

• 批准号: 9756258
• 负责人: HOWARD C. BECKER
• 金额: $ 37.38万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756258
• 关键词: Adult; Alcohol consumption; Alcoholism; Alcohols; Amygdaloid structure; Animal Model; Animals; Anxiety; Behavior; Behavioral; Brain region; Chronic; Chronic Post Traumatic Stress Disorder; Chronic stress; Clinical; Cognitive; Comorbidity; Consumption; Cues; Data; Development; Disease; Emotional; Environmental Risk Factor; Epidemiology; Exposure to; Female; Goals; Heavy Drinking; High Prevalence; Hypothalamic structure; Impairment; Individual Differences; Link; Literature; Messenger RNA; Modeling; Motivation; Mus; Neurohormones; Odors; Oxytocin; Oxytocin Receptor; Pilot Projects; Post-Traumatic Stress Disorders; Pre-Clinical Model; Procedures; Public Health; Recording of previous events; Relapse; Research Project Grants; Rewards; Role; Self Administration; Series; Specificity; Stimulus; Stress; Structure of terminal stria nuclei of preoptic region; Sucrose; System; Testing; Training; Treatment Efficacy; Work; acute stress; addiction; alcohol abuse therapy; alcohol effect; alcohol relapse; alcohol seeking behavior; alcohol use disorder; biological adaptation to stress; clinically relevant; design; drinking; drinking behavior; dual diagnosis; early life stress; effective therapy; experience; mRNA Expression; male; mouse model; neurobiological mechanism; novel; novel therapeutics; prevent; response; stressor; traumatic event

PROJECT SUMMARY While there is a high prevalence for the co-occurrence of alcohol use disorders (AUD) and post-traumatic stress disorder (PTSD), the mechanisms underlying these disorders are not fully understood. Further, few treatments are effective for those suffering with PTSD-AUD comorbidity. Animal models that closely mimic the key clinical features of these disorders are critical for elucidating mechanisms and factors that underlie the co-occurrence of these illnesses and facilitate development of new and more effective therapeutics. We have recently conducted a series of pilot studies with the goal of developing such a model. Specifically, we have demonstrated that chronic predator odor (TMT) exposure sensitizes male and female mice to later acute stress (TMT)-induced reinstatement of alcohol relapse-like behavior. This effect is long lasting (>60 days) and the sensitized effect generalizes to exposure to context cues associated with prior chronic TMT exposure. We have also demonstrated that a novel model of chronic early-life stress (CES) has long-lasting effects on anxiety behavior and stress responsiveness, as well as increased stress-related alcohol consumption. Finally, our pilot work shows that chronic TMT exposure produces long-last alterations in oxytocin (OT) expression in hypothalamus (PVN) as well as oxytocin receptor mRNA expression in stress-relevant projection brain regions (central amygdala; CeA, bed nucleus of stria terminalis; BNST). Further, systemic administration of OT blocked stress (TMT)-induced alcohol relapse in mice with and without a history of chronic stress exposure. Proposed studies in this application are designed to build on and expand these compelling and supportive pilot findings. The overall objective of this proposal is to optimize and further characterize our model of PTSD that captures many key clinical features of the disorder, link consequences of the model to alcohol self- administration and relapse behavior, and examine the role of the neurohormone oxytocin in this mouse model of PTSD-AUD comorbidity. Specifically, after more fully characterizing the chronic predator odor (TMT) model, we will examine whether CES similarly sensitizes mice to stress-induced alcohol relapse and then use these procedures in combination to examine whether CES experience further augments the ability of chronic TMT exposure to subsequently sensitize mice to acute stress challenge provoking alcohol relapse-like behavior. This unique mouse model of PTSD-AUD will then be used to probe involvement of the oxytocin system, with studies also examining the capacity of exogenous OT treatment to block and/or prevent sensitized stress-induced alcohol relapse in the CES-TMT model. The overall goal is to establish and utilize a clinically relevant mouse model of PTSD-AUD that will advance our understanding of these co- occurring disorders and facilitate development of more effective treatments for PTSD-AUD comorbidity.

项目摘要 虽然酒精使用障碍（AUD）和创伤后的同时存在较高的患病率 应激障碍（PTSD），这些疾病的基础机制尚未完全了解。此外，很少 治疗对患有PTSD审计合并症的人有效。紧密模仿的动物模型 这些疾病的关键临床特征对于阐明机制和因素至关重要 这些疾病的同时出现，并促进了新的，更有效的治疗剂的发展。我们有 最近进行了一系列试点研究，目的是开发这种模型。具体来说，我们有 证明慢性捕食者气味（TMT）暴露使雄性和雌性小鼠敏感到以后的急性 应力（TMT）诱导的恢复酒精复发样行为。这种效果持久（> 60天），并且 敏化效应概括地暴露于与先前的慢性TMT暴露相关的上下文提示。我们 还证明了一种新型的慢性早期应力（CES）的新型模型对 焦虑行为和压力反应能力，并增加与压力相关的酒精消耗。最后， 我们的试验工作表明，慢性TMT暴露会在催产素（OT）表达中产生长期变化 下丘脑（PVN）以及催产素受体mRNA表达在应力相关投影脑区域 （中央杏仁核； CEA，质末端的床核； BNST）。此外，ot的全身给药 应力（TMT）诱导的与慢性应激病史的小鼠中的酒精复发。建议的 本应用程序中的研究旨在建立和扩展这些引人注目和支持的试点结果。 该提案的总体目的是优化和进一步描述我们的PTSD模型 捕获该疾病的许多关键临床特征，将模型与酒精自我联系起来 给药和复发行为，并检查神经激素催产素在此中的作用 PTSD的鼠标模型 - 合并症。具体而言，在更充分地表征慢性捕食者之后 气味（TMT）模型，我们将检查CES是否同样将小鼠敏感到应激诱导的酒精复发 然后结合使用这些程序来检查CES是否会进一步增强 慢性TMT暴露于随后使小鼠对急性压力挑战的敏感性挑战的能力引起酒精 复发状行为。然后，这种独特的PTSD Aud鼠标模型将用于探测参与 催产素系统，还研究了外源OT治疗能力阻止和/或预防的能力 CES-TMT模型中敏化应力诱导的酒精复发。总体目标是建立和利用 PTSD aud的临床相关小鼠模型，它将促进我们对这些共同的理解 发生疾病并促进开发更有效的PTSD审理合并症。