NEUROCHEMICAL MECHANISMS OF RESISTANCE TO STRESS

这项研究的目的是确定中枢神经化学变化。 以确定这些变化是否有助于 适应和抗逆性的发展。在以前的工作中 我们在这个项目中发现，大鼠的慢性应激会导致 大脑去甲肾上腺素(NE)受体的敏感性。既然有 有证据表明，对去甲肾上腺素不敏感是导致 抵抗压力，也是抗抑郁药的一个重要因素 治疗方面，目前的研究方向将是进一步研究 这种现象。拟议研究的第一个目标是获得基本的 关于压力诱导的亚敏感机制的信息，这将 促进随后对其功能的调查。这将是 完成(A)确定所需的最小应力量 诱导亚敏感，(B)通过研究生理和 导致这一变化的内分泌事件，以及(C)通过定义 这一现象的分子基础。从这些研究中获得的数据将 用来开发在实验中操纵次敏感度的方法 以测试其在适应中的作用。该项目的第二个目标是 确定压力诱导的亚敏感性是否是一种适应性反应 艾滋病在发展中对应激的抵抗力。我们会就此进行研究(A) 通过确定在糖尿病的发展过程中是否发生对去甲肾上腺素的亚敏感 抵抗各种形式的压力，以及(B)通过确定动物是否 在应激前通过预先处理使其对NE变得亚敏感 抗抑郁药物、应激激素或肾上腺素能阻滞剂显示 增强了对后续压力的抵抗力。 除了提供有关压力适应的基本信息外，目前 研究还将提供关于适应的相关假设的数据 应激和抗抑郁治疗都是类似的现象，两者都是中介的 由相同的中枢神经化学变化引起。后一种假设 将促进对开发新的治疗方法的研究 涉及应激激素和对轻微应激源的适应的抑郁症 作为锻炼。

The objective of this research is to identify central neurochemical changes that occur during stress and to determine if these changes aid in the development of adaptation and resistance to stress. In previous work on this project we have found that chronic stress in rats leads to a reduction in the sensitivity of brain norepinephrine (NE) receptors. Since there is evidence that subsensitivity to NE is one of the factors leading to resistance to stress and is also an important factor in antidepressant therapy, the present research will be directed toward a further study of this phenomenon. The first aim of the proposed research is to obtain basic information on the mechanism of stress-induced subsensitivity which will facilitate subsequent investigation of its function. This will be accomplished (a) by determining the minimum amount of stress necessary to induce subsensitivity, (b) by studying the physiological and endocrinological events that lead to this change, and (c) by defining the molecular basis of this phenomenon. Data obtained from these studies will be used to develop methods to experimentally manipulate subsensitivity in order to test its role in adaptation. The second aim of the project is to determine if stress-induced subsensitivity is an adaptive response which aids in the development of resistance to stress. This will be studied (a) by determining if subsensitivity to NE occurs during the development of resistance to various forms of stress, and (b) by determining if animals who are made subsensitive to NE prior to stress by pretreatment with antidepressant drugs, stress hormones or adrenergic blocking agents show an increased resistance to subsequent stress. In addition to providing basic information on stress adaptation the present research will also provide data on the related hypothesis that adaptation to stress and antidepressant therapy are analagous phenomena both mediated by the same set of central neurochemical changes. The latter hypothesis will stimulate research on the development of new therapeutic approaches to depression involving stress hormones and adaptation to mild stressors such as exercise.