Prefrontal Cortex Stress Peptides in Traumatic Stress-Induced Escalation of Alcohol Drinking

 描述（由申请人提供）：酒精使用障碍（AUD）影响约12%的世界人口，仅在美国每年就造成250多万人死亡，每年给美国造成2200亿美元的损失。创伤性应激障碍（例如，创伤后应激障碍;创伤后应激障碍（PTSD）是目前影响770万美国人的衰弱性疾病，在约30%的美国退伍军人中观察到，每年花费美国数十亿美元。AUD和PTSD都增加了人类的死亡率，缩短了人类的寿命，增加了慢性疾病的发病率。AUD是受PTSD影响的人类中最常见的心理健康障碍，22-43%的PTSD患者符合AUD标准（而一般人群为8%）。合并症的高发病率表明PTSD和AUD之间存在重叠的神经生物学机制，但PTSD和AUD之间合并症的高发病率的生物学基础尚不清楚。该建议的一个重要方面是先验识别压力反应性（脆弱性与弹性）的个体差异，其仅在暴露于压力的人的亚群中模拟创伤性压力障碍的发展。在这里，我们建议使用啮齿动物模型来检查共病PTSD和AUD的神经生物学基础。我们实验室的初步和已发表的数据表明，创伤应激通过影响促肾上腺皮质激素释放因子（CRF;一种促应激肽）信号传导，使大鼠饮酒升级并产生痛觉过敏，还改变了腹内侧前额叶皮质（vmPFC）中细胞外信号相关激酶磷酸化（pERK），vmPFC是一个重要的大脑区域，通过自上而下控制皮质下结构来协调对环境的反应。拟议的工作旨在扩大这些研究结果，探索的作用，CRF-ERK的相互作用，在介导创伤性应激引起的升级饮酒和痛觉过敏的vmPFC。该提议的首要假设是，vmPFC CRF-CRF 1 R信号通过ERK途径介导了表现出高应激反应性的大鼠中饮酒和痛觉过敏的升级。这一建议将提供一个有前途的医学博士/博士通过使用综合方法来测试以下预测的研究，对学生进行重要的研究培训：1）创伤应激上调vmPFC中的CRF-CRF 1-ERK信号通路，2）该通路介导高应激反应动物饮酒的升级。这些实验将培养未来的精神疾病动物模型的医生-科学家，这些研究的结果将为共病PTSD和AUD的有效治疗策略的发展提供信息，从而改善受影响个体的生活质量和健康，降低与这些疾病相关的发病率，并可能为美国节省数百万美元的医疗保健费用 成本

 DESCRIPTION (provided by applicant): Alcohol use disorder (AUD) affects ~12% of the world population, contributing to more than 2.5 million deaths each year in the United States alone and costing the United States $220 billion annually. Traumatic stress disorders (e.g., post-traumatic stress disorder; PTSD) are debilitating disorders currently affecting 7.7 million Americans, are observed in ~30% of U.S. combat veterans, and cost the U.S. billions of dollars annually. AUD and PTSD both increase mortality rates and shorten life spans in humans, increasing the incidence of chronic disease states. AUD is the most commonly occurring mental health disorder in humans affected by PTSD, with 22-43% of individuals with PTSD meeting criteria for AUD (compared to 8% of the general population). The high rate of co-morbidity suggests an overlapping neurobiological mechanism between PTSD and AUD, but the biological basis for the high rate of co-morbidity between PTSD and AUD is not known. An important aspect of this proposal is the a priori identification of individual differences in stres reactivity (vulnerability vs. resilience), which models the development of traumatic stress disorders in only a subpopulation of stress- exposed humans. Here, we propose to use a rodent model to examine the neurobiological basis for co-morbid PTSD and AUD. Preliminary and published data from our lab suggest that traumatic stress escalates alcohol drinking and produces hyperalgesia in rats via effects on corticotropin-releasing factor (CRF; a pro-stress peptide) signaling, and also alters extracellular signal-related kinase phosphorylation (pERK) in the ventromedial prefrontal cortex (vmPFC), a brain region important for coordinating responses to the environment via top-down control of sub-cortical structures. The proposed work seeks to extend these findings by exploring the role of CRF-ERK interactions in the vmPFC in mediating traumatic stress-induced escalation of alcohol drinking and hyperalgesia. The overarching hypothesis of this proposal is that vmPFC CRF-CRF1R signaling via ERK pathways mediates escalated alcohol drinking and hyperalgesia in rats that exhibit high stress reactivity. This proposal will provide a promising M.D./Ph.D. student with vital research training through studies that use an integrative approach to test the predictions that: 1) traumatic stress upregulates CRF- CRF1-ERK signaling pathways in the vmPFC, and 2) this pathway mediates escalation of alcohol drinking in high-stress reactive animals. These experiments will train a future physician-scientist in animal models of psychiatric disorders, and the results of these studies will inform the development of effective treatment strategies for co-morbid PTSD and AUD, leading to improvements in quality of life and health of affected individuals, decreasing morbidity associated with these disorders, and potentially saving the U.S. millions of dollars in health care costs.