STRESS AND ANIMAL MODEL FOR CHEMICAL INTOLERANCE

化学不耐受的压力和动物模型

• 批准号: 2691434
• 负责人: Barbara A Sorg
• 金额: $ 16.49万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2691434
• 关键词: adrenalectomy; behavioral /social science research tag; behavioral habituation /sensitization; chemical hypersensitivity; chemical stimulation; chemosensitizing agent; cocaine; conditioning; disease /disorder model; fear; formaldehyde; hypothalamic pituitary adrenal axis; laboratory rat; model design /development; olfactory stimulus; physiologic stressor; posttraumatic stress disorder; psychological stressor

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.

描述：（改编自调查员的摘要）化学 人类中的不宽容（CI）被定义为无法忍受 环境化学物质由于与症状相关的症状经验而引起的 化学物质。 尽管CI在个人声称先验的个人中普遍存在 化学暴露会产生其不宽容，即基本的病因 仍然未知。 报告CI的个人中有很大比例的人 精神病学症状学，一些研究人员建议CI是 创伤后应激障碍（PTSD）的非典型形式。 拟议的工作 强调PTSD和CI之间的相似之处 CI的潜在动物模型。 四种现象的动物模型似乎最 适合检查PTSD，因此CI：1） 中枢神经系统（CNS），2）有条件的恐惧，3） 有条件的恐惧反应和4）避免有条件的刺激。 在 对CI作为PTSD样现象的支持，该实验室的最新研究 已经发现，每天重复吸入低水平的大鼠 甲醛（形式）表现出长期的交叉敏感性 可卡因引起的运动。 此外，表现出每日治疗的大鼠 增加对随后形式的回避，以及熄灭的能力降低 有条件的恐惧反应对气味和脚部冲击。 从形式开始 不会穿透高空之外，形式可能是 产生敏化的压力源。 对于拟议的研究，四个 将采用暴露剂量的形式。 第一个特定目标将测试 重复暴露的假设在 随后形式表达后的压力/焦虑反应在同一或 发生原始暴露的不同环境。 血清 皮质酮的水平和行为反映焦虑/压力将是 在重新暴露形式期间和之后监视。 第二个特定目标 将研究以下假设，即重复形式引起对 以后形成表现和交叉敏化通过 下丘脑 - 垂体 - 肾上腺（HPA）轴。 对可卡因的交叉敏感性 将受到行为监测，伏隔核多巴胺水平将 通过体内微透析测量。 形式的敏化本身将是 通过评估伏隔核多巴胺水平的评估 通过监视对以后形式演示的避免响应的行为。 该目标还将在一半的大鼠中进行肾上腺切除术以确定 是否需要完整的HPA轴才能进行形式诱导的效果。 第三 具体目标将检验重复形式暴露会产生的假设 熄灭条件恐惧反应的能力降低。 这 还将探索效果的特异性（上下文与气味或音调）。 行为和神经化学敏化，条件恐惧的研究 表单暴露啮齿动物的灭绝将提供基于机械的 动物模型系统，用于研究CI的开发和维护 人类。