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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要虽然酒精使用障碍 (AUD) 和创伤后疾病同时发生的患病率很高应激障碍（PTSD），这些疾病的潜在机制尚不完全清楚。此外，很少有治疗对于患有 PTSD-AUD 合并症的患者有效。高度模仿的动物模型这些疾病的关键临床特征对于阐明其背后的机制和因素至关重要这些疾病同时发生并促进新的、更有效的治疗方法的开发。我们有最近进行了一系列试点研究，目标是开发这样一个模型。具体来说，我们有研究表明，长期接触捕食者气味（TMT）会使雄性和雌性小鼠对随后的急性捕食者气味敏感。压力（TMT）诱导的酒精复发样行为的恢复。这种效果是持久的（>60天）并且敏感效应普遍存在于与之前长期接触 TMT 相关的情境线索中。我们还证明了一种新的慢性早期生活压力（CES）模型对焦虑行为和压力反应，以及与压力相关的饮酒量增加。最后，我们的试点工作表明，长期暴露于 TMT 会导致催产素 (OT) 表达发生长期改变。下丘脑 (PVN) 以及应激相关投射脑区催产素受体 mRNA 表达（中央杏仁核；CeA，终纹床核；BNST）。此外，OT 的全身给药受阻在有或没有慢性压力暴露史的小鼠中，压力（TMT）诱导的酒精复发。建议的本申请中的研究旨在建立并扩展这些令人信服和支持性的试点结果。该提案的总体目标是优化并进一步表征我们的 PTSD 模型捕获了该疾病的许多关键临床特征，将该模型的后果与酒精自我相关联给药和复发行为，并检查神经激素催产素在此过程中的作用 PTSD-AUD 合并症的小鼠模型。具体来说，在更全面地描述了慢性捕食者的特征之后气味（TMT）模型，我们将检查 CES 是否同样使小鼠对压力引起的酒精复发敏感然后结合使用这些程序来检验 CES 体验是否进一步增强了长期接触 TMT 会使小鼠对引发酒精的急性应激挑战变得敏感类似复发的行为。这种独特的 PTSD-AUD 小鼠模型将用于探究催产素系统，研究还检验了外源性 OT 治疗阻断和/或预防的能力 CES-TMT模型中敏感的压力诱导的酒精复发。总体目标是建立和利用临床相关的 PTSD-AUD 小鼠模型将增进我们对这些共同的理解发生的疾病并促进针对 PTSD-AUD 合并症开发更有效的治疗方法。