Adolescent Alcohol Abuse, Traumatic Stress, and Vulnerability to Development of PTSD

7.项目概要/摘要 创伤后应激障碍（PTSD）和酒精使用障碍（AUD）是两种最普遍的 精神状况和高度共病。由于缺乏社会和财政援助而造成的社会和财政负担 对这些疾病的有效治疗是巨大的。因此，显然迫切需要获得更大的 了解PTSD和AUD合并症的病理生理学基础。目前的证据表明， PTSD和AUD的神经回路明显重叠，其中包括由神经元对行为的功能失调控制。 前额叶皮层（PFC）。因此，调节行为的前额叶介导的认知过程的改变可能 导致这些疾病的高共病率。发病年龄与年龄之间有很强的相关性。 青少年时期的酒精使用以及在以后的生活中发展为AUD的可能性。此外，青春期是 持续发展的关键时期，越来越多的证据表明， 青春期会对大脑和行为产生长期影响。考虑到高流行率， 青少年酗酒，因此，令人惊讶的是，很少有研究集中在了解其影响 一个人在成年后科普创伤性压力事件的能力。这个最重要的假设是 一项建议是，有青少年酗酒史的成年人，如果经历了创伤性应激事件， 压力恢复力降低，患PTSD和AUD的风险明显更高。该实验 一种方法利用了一个由反复循环的青少年间歇性饮酒组成的酒精狂欢模型。 通过蒸汽吸入和单次延长应力（SPS）程序暴露于乙醇（AIE）， 模拟人类的创伤应激事件在成年早期AIE和SPS暴露后，大鼠将被 测试恐惧行为和乙醇自我管理的变化。以下三个具体目标是 旨在检验总体假设：目标1将检验暴露于AIE-SPS导致 与恐惧相关的行为的不可逆改变。目标2将检验以下假设： AIE-SPS增加暴露于条件性恐惧诱导的酒精消耗和复发样行为 线索目的3将检验AIE-SPS诱导的恐惧行为改变反映了 前边缘和下边缘与恐惧神经回路的核心区域的通信。这些小说的发现 创新的研究将大大促进我们对行为缺陷和神经系统的理解。 AUD和PTSD之间复杂相互作用的潜在机制，以及青少年病史是否 酒精滥用可能是一个预先存在的风险因素，它不仅增加了PTSD的易感性， 与创伤性事件有关，但也与AUD有关。

7. PROJECT SUMMARY/ABSTRACT Post-Traumatic Stress Disorder (PTSD) and Alcohol Use Disorder (AUD) are two of the most prevalent psychiatric conditions and are highly comorbid. The social and financial burden that results from a lack of effective treatments for these disorders is enormous. Therefore, there is a clear and urgent need to gain a greater understanding of the pathophysiological basis of PTSD and AUD comorbidity. Current evidence suggests the neurocircuitry of PTSD and AUD significantly overlap, which includes dysfunctional control of behavior by the prefrontal cortex (PFC). Thus, alterations in prefrontal mediated cognitive processes that regulate behavior may contribute to the high comorbidity of the disorders. There is a strong correlation between the age of onset of alcohol use during adolescence and the likelihood of developing an AUD later in life. In addition, adolescence is a critical period of continued development, and accumulating evidence indicates that the abuse of alcohol during adolescence can have long-term consequences on brain and behavior. Considering the high prevalence of adolescent alcohol abuse, it is therefore surprising that little research has focused on understanding its impact on an individual’s ability to cope with a traumatic stress event in adulthood. The overarching hypothesis of this proposal is that adults with a history of adolescent alcohol abuse who experience a traumatic stress event have reduced stress resiliency and are at a significantly higher risk of developing PTSD and AUD. This experimental approach takes advantage of a binge ethanol model consisting of repeated cycles of Adolescent Intermittent Ethanol (AIE) exposure by vapor inhalation and a Single Prolonged Stress (SPS) procedure that is thought to model a traumatic stress event in humans. Following AIE and SPS exposure in early adulthood, rats will then be tested for alterations in fear behavior and ethanol self-administration. The following three specific aims are designed to test the overarching hypothesis: Aim 1 will test the hypothesis that exposure to AIE-SPS results in pharmacologically reversible alterations in fear-related behaviors. Aim 2 will test the hypothesis that exposure to AIE-SPS increases alcohol consumption and relapse-like behavior induced by exposure to fear conditioned cues. Aim 3 will test the hypothesis that AIE-SPS induced alterations of fear behaviors reflect alterations in prelimbic and infralimbic communication with core regions of the fear neurocircuitry. Findings from these novel and innovative studies will significantly advance our understanding of the behavioral deficits and neural mechanisms underlying the complex interactions between AUD and PTSD, and whether a history of adolescent alcohol abuse may represent a pre-existing risk factor that increases susceptibility of developing not only PTSD associated with a traumatic event but also AUD.