ANXIOLYTIC TREATMENTS--NEUROPHARMACOLOGICAL MECHANISMS

描述(改编自申请人的摘要)：基于工作 由调查人员和其他实验室进行的，有四个 独特的临床有效的抗焦虑治疗，发挥强大的作用 焦虑啮齿动物模型的抗冲突作用：(1)急性 苯二氮卓类或巴比妥类治疗，(2)慢性丁螺环酮治疗， (3)慢性抗抑郁治疗；(4)慢性可乐定治疗。 本研究的目的是检查行为， 这些不同的神经解剖学和神经递质机制 抗焦虑治疗。特定目标1中的研究旨在检查 这些抗焦虑治疗效果的行为机制。第一, 这些抗焦虑治疗的效果将被确定(在一些 实例，重新确定)在高架加迷宫冲突任务中， 被广泛验证为动物的无休克冲突任务 焦虑的模范。其次，冲击波感度测试遵循各种 将进行抗焦虑治疗，以确认抗冲突 条件性戒酒(CSD)治疗效果观察 并不次于抗伤害性作用。特定目标研究2 将决定两个边缘突触后部位的重要性(中央 杏仁核(CNA)和外侧隔核(LS)的表达 各种治疗焦虑症的效果。在这些研究中，影响 这些抗焦虑治疗中的哪一种将在电解治疗后确定 CNA、LS或两者兼有的病变。有针对性的研究 3将决定单胺类神经递质的重要性 去甲肾上腺素(NE)和5-羟色胺(5-HT)对血管紧张素转换酶基因表达的影响 各种治疗方法的反冲突效果。在这些研究中， 抗焦虑治疗的效果将在以下化学物质中确定 (6-OHDA，5，7-DHT)或电解性损毁大鼠脑内NE能神经元 蓝斑(LC)--中缝背侧5-羟色胺能神经元 核(DRN)，或两个部位的神经元。对特定目标4的研究将 确定这些抗焦虑治疗是如何影响排泄率的， 单个LC-NE或DRN-5-HT神经元的形态和药物敏感性。这些 研究将使用标准的电生理记录程序 麻醉大鼠，接受各种抗焦虑治疗。 总之，拟议的研究将开始处理突触前和 一组不同基因表达的突触后机制 抗焦虑治疗。

DESCRIPTION (Adapted from the Applicant's Abstract): Based upon work conducted by the investigator and in other laboratories, there are four distinct clinically effective anxiolytic treatments that exert robust anticonflict effects in rodent models for anxiety: (1) acute benzodiazepine or barbiturate treatment, (2) chronic buspirone treatment, (3) chronic antidepressant treatment and (4) chronic clonidine treatment. The present studies are designed to examine the behavioral, neuroanatomical, and neurotransmitter mechanism for these diverse anxiolytic treatments. Studies in Specific Aim 1 are designed to examine the behavioral mechanisms for these anxiolytic treatment effects. First, the effects of these anxiolytic treatments will be determined (in some instances, re-determined) in the elevated plus maze conflict task, a non-shock conflict task which has been extensively validated as an animal model for anxiety. Second, shock sensitivity testing following the various anxiolytic treatments will be conducted to confirm that the anticonflict effects observed in the conditioned suppression of drinking (CSD) procedure are not secondary to antinociceptive effects. Studies in Specific Aim 2 will determine the importance of two limbic postsynaptic sites (central nucleus of the amygdala (CNA) and lateral septum (LS)) for the expression of the various anxiolytic treatment effects. In these studies, the effects of these anxiolytic treatments will be determined following electrolytic lesions of either the CNA, LS, or both structures. Studies in Specific Aim 3 will determine the importance of the monoamine neurotransmitters norepinephrine (NE) and 5-hydroxytryptamine (5-HT) for the expression of the anticonflict effects of the various treatments. In these studies, the effects of the anxiolytic treatments will be determined following chemical (6-OHDA, 5,7-DHT) or electrolytic lesions of NE-containing neurons in the locus ceruleus (LC), 5-HT-containing neurons within the dorsal raphe nucleus (DRN), or neurons in both sites. Studies in Specific Aim 4 will determine how these anxiolytic treatments affect the discharge rate, pattern, and drug sensitivity of single LC-NE or DRN-5-HT neurons. These studies will use standard electrophysiological recording procedures in anesthetized rats which have received the various anxiolytic treatments. Together, the proposed studies will begin to address both presynaptic and postsynaptic mechanism underlying the expression of a diverse group of anxiolytic treatments.