CORTICOTROPIN RELEASING FACTOR AND BENZODIAZEPINES

这个第一个奖项利用有充分记录的技术来研究 促肾上腺皮质激素释放因子(CRF)神经元在 苯二氮卓类药物的治疗作用及其生理意义 与突然停用苯二氮卓类药物相关的影响。在 过去十年，来自许多调查人员的大量证据使用 不同的实验方法与 CRF调节内分泌、行为和自主神经的假说 哺乳动物对压力的反应。基于先前的临床前研究 这表明，暴露在压力下并接受抗焦虑药物治疗 苯二氮卓类药物对CRF神经元产生相反的影响，这一建议 旨在描述不同药物的剂量反应效应，这些药物包括 苯二氮卓类受体活性，包括激动剂，部分 激动剂、拮抗剂和反向激动剂对慢性肾功能衰竭的作用 急性和慢性给药后的神经元。另外，因为 苯二氮类药物的停药与生理症状有关 这项建议让人想起经典的“压力反应”，它将寻求 探讨CRF神经元是否参与急性药物戒断 相位。苯二氮卓类拮抗剂能否间歇给药 氟马西尼在慢性苯二氮卓类减毒药治疗中的应用 戒断对CRF神经元的影响？最后，中央 给药CRF拮抗剂通过以下方式改变药物戒断阶段 改变CRF神经元活动的神经化学或 行为上的吗？目前，对慢性肾功能衰竭神经元活性的最佳估计是 CRF浓度、CRF mRNA表达和CRF的同时测量 先前涉及脑内不同区域的受体结合 调节CRF的作用。下丘脑CRF的附加测量 活性将通过测量血浆ACTH和皮质酮来获得 浓度。这些研究将提供更多关于 CRF在中枢神经系统中的作用(S)，特别是CRF在 潜在地调节了部分治疗性(抗焦虑)和 苯二氮卓类药物的有害(戒毒)作用。这类研究 对开发新的治疗方法具有重要意义 焦虑症及其治疗新药的开发 药物戒断症状。

This FIRST award utilizes well-documented techniques to investigate the role of corticotropin-releasing factor (CRF) neurons in both the therapeutic actions of benzodiazepines as well as the physiological effects associated with abrupt discontinuation of benzodiazepines. In the last decade considerable evidence from a number of investigators using different experimental approaches has accrued consistent with the hypothesis that CRF mediates the endocrine, behavioral and autonomic responses of mammals to stress. Based upon previous preclinical studies which revealed that exposure to stress and treatment with anxiolytic benzodiazepines produce opposite effects on CRF neurons, this proposal seeks to characterize the dose-response effects of various drugs which are active at the benzodiazepine receptor including agonists, partial agonists, antagonists and inverse agonists for their actions on CRF neurons after both acute and chronic administration. In addition, because benzodiazepine withdrawal is associated with physiological symptoms reminiscent of a classic "stress response", this proposal will seek to investigate whether CRF neurons are involved in the acute drug withdrawal phase. Can intermittent administration of the benzodiazepine antagonist flumazenil during chronic benzodiazepine treatment attenuate drug withdrawal via effects on CRF neurons? Finally, does central administration of a CRF antagonist modify the drug withdrawal phase by altering CRF neuronal activity as measured neurochemically or behaviorally? Currently, the best estimates of CRF neuronal activity are concurrent measurement of CRF concentrations, CRF mRNA expression, and CRF receptor binding in discrete brain regions previously implicated in mediating the actions of CRF. Additional measures of hypothalamic CRF activity will be obtained by measuring plasma ACTH and corticosterone concentrations. These studies will provide further information on the role(s) of CRF in the CNS, and in particular the role of CRF in potentially mediating a portion of the therapeutic (anxiolytic) and deleterious (drug withdrawal) actions of benzodiazepines. Such studies have important implications for the development of novel treatments for anxiety disorders as well as the development of novel agents to ameliorate drug withdrawal symptoms.