STRESS AND ANIMAL MODEL FOR CHEMICAL INTOLERANCE

描述：(改编自《调查者摘要》)化学品 人类的不耐受(CI)被定义为不能容忍 环境化学品由于经历了与之相关的症状 化学制品。尽管CI在声称之前 接触化学物质导致了他们的不耐受，这是根本的病因 仍然不为人知。报告CI的个人中有很高比例的人 精神症状学，一些研究人员认为CI是 一种非典型的创伤后应激障碍(PTSD)。拟议中的工作 强调创伤后应激障碍和CI在发展为 脑梗塞的潜在动物模型。四种现象出现最多的动物模型 适用于检查创伤后应激障碍，因此，CI：1) 中枢神经系统(CNS)，2)条件性恐惧，3)消亡 条件性恐惧反应和避免条件性刺激。在……里面 脑梗塞作为一种创伤后应激障碍样现象的支持，本实验室最近的研究 已经发现，每天重复吸入低水平的 甲醛(Form)对以下物质有长期交叉敏化作用 可卡因诱导的运动。此外，每日形态处理的大鼠也表现出 增加对后续形态的回避，并降低扑灭的能力 对气味的一种条件性恐惧反应，伴随着脚部电击。自表以来 不会渗透到上呼吸道之外，很可能是形态作为 产生敏感反应的压力源。在拟议的研究中，有四项 将使用曝光剂量的表格。第一个明确的目标是测试 假设反复接触表格会增加 在随后的表格演示后的压力/焦虑反应 发生原始曝光的不同环境。血清 反映焦虑/压力的皮质酮水平和行为将是 在再次暴露于Form期间和之后进行监测。第二个具体目标 我将检验这样的假设，即重复形式导致对 后来的形式呈现和交叉敏化可卡因通过 下丘脑-垂体-肾上腺(HPA)轴。对可卡因的交叉敏感 将受到行为监测，伏隔核多巴胺水平将 用体内微透析法测定。形式对自身的敏感化将是 通过评估伏隔核多巴胺水平来测量，还 通过监控对较晚形式陈述的回避反应来实现行为。 这一目标还将在一半的大鼠身上进行肾上腺切除术，以确定 形状诱导效应是否需要完整的HPA轴。第三 特定的目标将检验这样的假设，即重复的形式暴露会产生 消除条件性恐惧反应的能力减弱。这个 还将探讨效果的特殊性(上下文与气味或音调)。 行为和神经化学敏化、条件性恐惧的研究 而暴露在形态中的啮齿动物的灭绝将提供一个基于机械的 研究脑梗塞发生和维持的动物模型系统 人类。

DESCRIPTION: (Adapted from the Investigator's Abstract) Chemical Intolerance (CI) in humans is defined as the inability to tolerate environmental chemicals due to experience of symptoms associated with those chemicals. Although CI is prevalent in individuals claiming that prior chemical exposures produced their intolerance, the underlying etiology remains unknown. A high percentage of individuals reporting CI present with psychiatric symptomatology, and some investigators have suggested that CI is an atypical form of posttraumatic stress disorder (PTSD). The proposed work emphasizes the parallels between PTSD and CI in the development of a potential animal model for CI. Animal models of four phenomena appear most suitable for examining PTSD and, therefore, CI: 1) sensitization of the central nervous system (CNS), 2) conditioned fear, 3) extinction of a conditioned fear response and 4) avoidance of a conditioned stimulus. In support of CI as a PTSD-like phenomenon, recent studies in this laboratory have found that rats given repeated daily inhalation of low levels of formaldehyde (Form) demonstrated long-term cross-sensitization to cocaine-induced locomotion. In addition, daily Form treated rats exhibited increased avoidance to subsequent Form, and a reduced ability to extinguish a conditioned fear response to an odor paired with foot shock. Since Form does not penetrate beyond the upper airway, it is likely that Form serves as a stressor to produce sensitization. For the proposed studies, four exposure doses of Form will be employed. The first specific aim will test the hypothesis that repeated Form exposure produces increases in stress/anxiety responses after subsequent Form presentation in the same or different environment from which original exposures occurred. Serum corticosterone levels and behaviors reflective of anxiety/stress will be monitored during and after re-exposure to Form. The second specific aim will examine the hypothesis that repeated Form induces sensitization to later Form presentation and cross-sensitization to cocaine via the hypothalamic-pituitary-adrenal (HPA) axis. Cross-sensitivity to cocaine will be monitored behaviorally, and nucleus accumbens dopamine levels will be measured by in vivo microdialysis. Form sensitization to itself will be measured by assessment of nucleus accumbens dopamine levels and also behaviorally by monitoring avoidance responses to later Form presentation. This aim will also perform adrenalectomy in one-half of rats to determine whether an intact HPA axis is required for Form-induced effects. The third specific aim will test the hypothesis that repeated Form exposure produces a decreased ability to extinguish a conditioned fear response. The specificity of the effect (context vs odor or tone) will also be explored. The study of behavioral and neurochemical sensitization, conditioned fear and extinction in Form-exposed rodents will provide a mechanistically-based animal model system for studying the development and maintenance of CI in humans.