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

7.项目摘要/摘要 创伤后应激障碍(PTSD)和酒精使用障碍(AUD)是最常见的两种 精神疾病和高度并存。由于缺乏资金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，有一种明确而紧迫的需要，需要获得更大的 了解创伤后应激障碍和AUD共病的病理生理学基础。目前的证据表明 创伤后应激障碍和AUD的神经回路明显重叠，包括由 前额叶皮质(PFC)因此，前额叶调节行为的认知过程的改变可能 导致这些疾病的高共病。有很强的相关性在发病年龄之间 青春期饮酒和晚年患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，在 青春期可能会对大脑和行为产生长期影响。考虑到艾滋病的高流行率 青少年酗酒，因此令人惊讶的是，很少有研究专注于了解其影响 关于一个人在成年后应对创伤应激事件的能力。其中最重要的假设是 建议有青少年酗酒史的成年人经历创伤性应激事件 压力恢复力降低，患创伤后应激障碍和澳门氏症的风险明显更高。这项实验 方法利用了由青少年间歇性反复循环组成的酗酒模型 通过蒸汽吸入接触乙醇(AIE)和单一的延长应激(SPS)程序，被认为是 在人类身上模拟创伤性应激事件。在成年早期暴露于AIE和SPS之后，大鼠将被 测试恐惧行为和酒精自我管理的变化。以下三个具体目标是 旨在测试总体假设：目标1将测试暴露于AIE-SPS会导致 与恐惧相关的行为的药物可逆性改变。目标2将检验暴露在空气中的假设 AIE-SPS增加酒精摄入量和因暴露在条件性恐惧中而导致的复发行为 暗示。目的3将检验AIE-SPS诱导的恐惧行为改变反映在 与恐惧神经回路的核心区域进行初步的和边缘下的交流。这些小说中的发现 创新的研究将极大地促进我们对行为缺陷和神经功能障碍的理解 AUD和创伤后应激障碍之间复杂相互作用的机制以及青春期病史 酗酒可能是一个预先存在的危险因素，不仅会增加患上创伤后应激障碍的易感性 与创伤性事件有关，但也与澳门氏症有关。

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.