Rodent Model of PTSD-like conditions-Role of Noradrenergic System

描述（由申请人提供）：该基金的总体目标是了解创伤后应激障碍（PTSD）样疾病的神经生物学机制，以及在已建立的啮齿动物模型中治疗这些疾病。具体目标是：1）描述创伤经历对Wistar-Kyoto（WKY）和Wistar（WIS）大鼠的睡眠结构、冻结行为和心率变化的即时和长期影响，并将这些变化与前额叶皮层、杏仁核和海马中的去甲肾上腺素能活性相关联;（二）评价哌唑嗪或普萘洛尔治疗是否能不同程度地改善目标1中测量的行为和神经解剖学结果在脆弱的WKY和抵抗的WIS大鼠中。基本方法是使用恐惧条件反射，通过配对音调（条件刺激[CS]）和足部电击（无条件刺激[US]）来评估条件恐惧。将比较两种品系之间的冷冻、超声波发声、心率和睡眠行为。哌唑嗪（11肾上腺素受体拮抗剂）或普萘洛尔（21肾上腺素受体拮抗剂）治疗将在相对于初始触发和随后加重事件的适当时间进行。睡眠记录后，将动物斩首，取出躯干血液和大脑，用于分析应激激素和去甲肾上腺素能突触前和突触后受体。预期与更抗应激的WIS大鼠相比，应激反应性WKY大鼠中PTSD样症状将更明显。此外，这些应变差异将与前额叶皮层、杏仁核和海马中11和21-肾上腺素受体的表达和功能改变有关，这三个脑区与PTSD的病理生理学密切相关。通过确定这些药物缓解PTSD样症状的去甲肾上腺素能途径，我们的研究将提供难以从临床研究中获得的相关信息，并将提高我们制定有效治疗策略的能力，以改善PTSD患者的生活质量。 公共卫生相关性：我们提出的研究旨在提供有关的信息去甲肾上腺素能机制的基础上创伤后应激障碍（PTSD）样条件下的Wistar-Kyoto大鼠，一个既定的动物模型，研究与压力有关的精神疾病。基本方法是使用恐惧条件反射程序，然后测量冻结，超声波发声，心率和睡眠行为。睡眠记录后，将测量这些动物大脑中的去甲肾上腺素能突触前和突触后受体。哌唑嗪（11肾上腺素受体拮抗剂）或普萘洛尔（21肾上腺素受体拮抗剂）治疗将在相对于初始触发和随后加重事件的适当时间进行。通过确定这些药物缓解PTSD样症状的去甲肾上腺素能途径，我们的研究将提供难以从临床研究中获得的相关信息，并将提高我们制定有效治疗策略的能力，以改善PTSD患者的生活质量。

DESCRIPTION (provided by applicant): The overall goal of this grant is to understand the neurobiological mechanisms that underlie posttraumatic stress disorder (PTSD)-like conditions as well as the treatment of these conditions in an established rodent model. The specific aims are: 1) to delineate the immediate and long term effects of a traumatic experience on sleep architecture, freezing behavior and heart rate changes in Wistar-Kyoto (WKY) and Wistar (WIS) rats and correlate these changes with noradrenergic activity in the prefrontal cortex, amygdala and hippocampus; 2) to evaluate whether treatments with prazosin or propranolol will differentially ameliorate the behavioral and neuroanatomical outcomes measured in Aim 1 in the vulnerable WKY vs. resistant WIS rats. The basic approach will be to use fear conditioning, accomplished by pairing tones (conditioned stimulus [CS]) with foot shocks (unconditioned stimulus [US]), to assess conditioned fear. Freezing, ultrasonic vocalization, heart rate and sleep behavior will be compared between the two strains. Treatment with prazosin (11 adrenoceptor antagonist) or propranolol (21 adrenoceptor antagonist) will take place at appropriate timings relative to the initial triggering and subsequent exacerbating events. Following sleep recording, animals will be decapitated, and trunk blood and brains removed for analysis of stress hormones and noradrenergic pre and post-synaptic receptors. It is expected that PTSD-like symptoms will be more pronounced in the stress-reactive WKY rats compared to the more stress-resistant WIS rats. Furthermore, these strain differences will be related to altered expression and function of 11 and 21-adrenoceptors in the prefrontal cortex, amygdala and hippocampus, the three brain regions strongly implicated in the pathophysiology of PTSD. By defining the noradrenergic pathways by which these drugs alleviate PTSD-like conditions, our studies will provide relevant information which would otherwise be difficult to obtain from clinical studies, and will enhance our ability to develop effective treatment strategies to improve the quality of life for PTSD patients. PUBLIC HEALTH RELEVANCE: Our proposed studies are designed to provide information regarding the noradrenergic mechanisms that underlie posttraumatic stress disorder (PTSD)-like conditions in the Wistar-Kyoto rat, an established animal model for studying stress-related psychiatric disorders. The basic approach will be to use a fear conditioning procedure, followed by measurements of freezing, ultrasonic vocalization, heart rate and sleep behaviors. Following sleep recordings, noradrenergic pre and post-synaptic receptors will be measured in the brains of these animals. Treatment with prazosin (11 adrenoceptor antagonist) or propranolol (21 adrenoceptor antagonist) will take place at appropriate timings relative to the initial triggering and subsequent exacerbating events. By defining the noradrenergic pathways by which these drugs alleviate PTSD-like conditions, our studies will provide relevant information which would otherwise be difficult to obtain from clinical studies, and will enhance our ability to develop effective treatment strategies to improve the quality of life for PTSD patients.