NEUROCHEMICAL MECHANISMS OF RESISTANCE TO STRESS

本研究的目的是确定中枢神经化学变化 并确定这些变化是否有助于 发展适应和抵抗压力。 在以前的工作中， 在这个项目中，我们发现老鼠的慢性压力会导致 大脑去甲肾上腺素（NE）受体的敏感性。 由于 有证据表明，对NE的不敏感性是导致 抗压力，也是抗抑郁药的重要因素 治疗，本研究将针对进一步研究， 这种现象。 本研究的第一个目的是获得基本的 关于应力引起的次敏感性机制的信息， 便于后续对其功能的调查。 这将是 （a）通过确定所需的最小应力来实现， 诱导次敏感性，（B）通过研究生理和 导致这种变化的内分泌事件，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 用于开发实验性操纵次敏感性的方法， 以测试其在适应中的作用。 该项目的第二个目标是 确定压力引起的不敏感是否是一种适应性反应， 有助于发展抗压力能力。 将对此进行研究（a） 通过确定在发展过程中是否发生对NE的不敏感性， 对各种形式的应激的抗性，和（B）通过确定动物是否 在应激前，通过预处理 抗抑郁药物、应激激素或肾上腺素能阻滞剂显示， 增强对后续压力的抵抗力。 除了提供关于压力适应的基本信息之外， 研究还将提供相关假设的数据， 压力和抗抑郁治疗是类似的现象， 同样的中枢神经化学变化。 后一种假设 将刺激研究开发新的治疗方法， 抑郁症涉及应激激素和适应轻度应激源， 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.