CORTICOTROPIN RELEASING FACTOR AND BENZODIAZEPINES

这个第一个奖项利用有据可查的技术来调查 促肾上腺皮质激素释放因子（CRF）神经元在这两个方面的作用 苯二氮卓类药物的治疗作用以及 与突然停用苯二氮卓类药物相关的影响。在 在过去的十年里，许多调查人员使用了大量证据， 不同的实验方法已经积累一致， 假设CRF介导内分泌、行为和自主神经 哺乳动物对压力的反应基于先前的临床前研究 结果显示，暴露于压力和抗焦虑药治疗 苯二氮卓类药物对CRF神经元产生相反的作用， 旨在描述各种药物的剂量反应效应， 对苯二氮卓受体有活性的，包括激动剂、部分激动剂 激动剂、拮抗剂和反向激动剂对CRF的作用 急性和慢性给药后的神经元。另外由于 苯二氮卓类药物戒断与生理症状有关 这一建议让人想起经典的“压力反应”， 研究CRF神经元是否参与急性药物戒断 相位间歇性服用苯二氮卓类拮抗剂 慢性苯二氮卓类药物治疗中的氟马西尼 通过对CRF神经元的影响而戒断？最后，中央 CRF拮抗剂的给药通过以下方式改变停药期： 改变CRF神经元活性，如神经化学测量的，或 行为上？目前，CRF神经元活动的最佳估计是 同时测量CRF浓度、CRF mRNA表达和CRF 受体结合在离散的大脑区域， 调解CRF的行动。下丘脑CRF的其他测量 通过测量血浆ACTH和皮质酮来获得活性 浓度的这些研究将提供关于 CRF在CNS中的作用，特别是CRF在 潜在地介导一部分治疗剂（抗焦虑剂）， 苯二氮卓类药物的有害（药物戒断）作用。此类研究 对开发新的治疗方法具有重要意义， 焦虑症以及开发新的药物，以改善 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.