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

项目摘要 虽然有一个高患病率的共同发生的酒精使用障碍（AUD）和创伤后 虽然创伤后应激障碍（PTSD）是一种常见的精神疾病，但这些疾病的潜在机制尚未完全了解。此外，少数 治疗对于患有PTSD-AUD合并症的患者有效。动物模型， 这些疾病的关键临床特征对于阐明这些疾病的基础机制和因素至关重要。 这些疾病的共同发生，并促进新的和更有效的治疗方法的发展。我们有 最近进行了一系列试点研究，目的是建立这样一个模型。具体来说，我们有 研究表明，慢性捕食者气味（TMT）暴露使雄性和雌性小鼠对后来的急性 压力（TMT）诱导的酒精复发样行为的恢复。这种效果持续时间长（>60天）， 敏化效应一般化到与先前慢性TMT暴露相关的背景线索的暴露。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，以及增加与压力有关的酒精消费。最后， 我们的试验性工作表明，慢性TMT暴露会导致催产素（OT）表达的长期改变， 下丘脑（PVN）和催产素受体mRNA在应激相关投射脑区的表达 （中央杏仁核; CeA，终纹床核; BNST）。此外，全身施用OT阻断了 在有和没有慢性应激暴露史的小鼠中进行应激（TMT）诱导的酒精复发。提出 本申请中的研究旨在建立和扩大这些令人信服和支持性的试点结果。 这项提案的总体目标是优化和进一步表征我们的创伤后应激障碍模型， 捕捉了许多关键的临床特征的障碍，链接的后果模型酒精自我， 管理和复发行为，并检查神经激素催产素在这方面的作用， PTSD-AUD共病小鼠模型。具体来说，在更全面地描述了慢性捕食者之后， 气味（TMT）模型，我们将研究CES是否同样敏感小鼠应激诱导酒精复发 然后结合使用这些程序来检查CES的经验是否进一步增强了 慢性TMT暴露随后使小鼠对急性应激激发酒精敏感的能力 类似复发的行为这种独特的PTSD-AUD小鼠模型随后将用于探测PTSD-AUD的参与。 催产素系统，研究还检查了外源性OT治疗阻断和/或预防催产素系统的能力， 在CES-TMT模型中致敏应激诱导的酒精复发。总体目标是建立和利用 一个临床相关的PTSD-AUD小鼠模型，将促进我们对这些共同作用的理解， 发生的疾病，并促进开发更有效的治疗PTSD-AUD合并症。

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.