Project 2: Physiological Actions of Novel Antidepressants/Anxiolytics in the Basa

项目2：新型抗抑郁药/抗焦虑药在巴沙人中的生理作用

• 批准号: 8112729
• 负责人: DONALD G RAINNIE
• 金额: $ 20.9万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8112729
• 关键词: Acute; Address; Adverse effects; Affect; Amygdaloid structure; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Anxiety Disorders; Automobile Driving; Behavior; Binding Sites; Brain region; Carrier Proteins; Chronic; Citalopram; Data; Depressed mood; Development; Drug effect disorder; Etiology; Fiber; Goals; In Vitro; Individual; Interneurons; Mediating; Mental Depression; Mental disorders; Modeling; Mood Disorders; Moods; Morbidity - disease rate; Neurons; Output; Pharmaceutical Preparations; Physiological; Play; Preparation; Rattus; Receptor Activation; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Site; Slice; Stress; Synapses; System; Testing; Therapeutic; Therapeutic Effect; Treatment outcome; conditioned fear; density; emotional stimulus; in vivo; mortality; novel; patch clamp; receptor; response; serotonin receptor; serotonin transporter; trait

Activation of the basolateral amygdala (BLA) plays a critical role in the normal adaptive response to negative emotional stimuli. Abnormal activity of BLA output neurons has been implicated in the etiology of several mood disorders. For example, depressed and anxious individuals show exaggerated amygdala activation in response to negative emotional stimuli, which is now recognized as a trait marker for mood disorders. Hyperactivation is also a predictor of positive treatment outcome as it normalizes with the onset of therapeutic action of drug treatment, suggesting that the amygdala is a key component of a mood-regulatory system that is dysregulated in anxiety and depression. Selective serotonin reuptake inhibitors (SSRIs) are a first-line treatment for many mood disorders, and the amygdala has a high density of SSRI binding sites. Significantly, negative emotional stimuli trigger serotonin (5HT) release into the BLA where it acts to decrease the excitability of BLA output neurons. Moreover, 5HT levels in the BLA are finely regulated by the activity of 5HT transporter proteins, suggesting that SSRIs may exert their therapeutic effects by raising BLA 5HT levels and thus normalizing the activity of its output neurons. However, the slow onset of action of SSRIs and their unwanted side effects are driving the search for faster acting, and more targeted treatments for anxiety and depression. Recently, a novel antidepressant agent has been identified, GSK-1, which is a mixed SHTwiB/iD receptor antagonist that has a rapid onset of action. Multiple serotonin receptor subtypes are expressed in the BLA. Hence, drugs acting at one or more 5HT receptors could have a profound impact on the excitability of BLA output neurons, and hence mood disorders. However, little is known about how individual serotonin receptor activation may modulate the activity of BLA output neurons, let alone how mixed 5HT receptor antagonists may affect these neurons. In this study, we will use patch clamp recording in an in vitro slice preparation to compare the response of BLA neurons to administration of a classic SSRI, citalopram, with that of GSK-1 before, during, and after a challenge with exogenous 5HT. The hypothesis to be tested is that: acute administration of GSK-1 will mimic the net effect of chronic administration of SSRIs on the activity of BLA output neurons. Three specific aims will test this hypothesis: Aim 1: Compare and contrast the effects of acute in vitro administration of GSK-1 on serotonin receptor-mediated activity in BLA projection neurons and interneurons. Aim 2: Compare and contrast the effects of in vivo administration of GSK-1 on serotonin receptor-mediated activity in BLA projection neurons and interneurons. Aim 3: Compare and contrast the effects of GSK-1 and citalopram on serotonin receptor-mediated activity in BLA projection neurons and interneurons following sustained fear conditioning.

基底外侧杏仁核（BLA）的激活在正常自适应反应中起关键作用 情绪刺激。 BLA输出神经元的异常活性与多种情绪的病因有关 疾病。例如，沮丧和焦虑的个体显示出夸张的杏仁核激活 负面的情绪刺激，现在被认为是情绪障碍的特征标记。过度激活也是 预测阳性治疗结果的因素，因为它随着药物治疗的治疗作用而归一化， 表明杏仁核是情绪调节系统的关键组成部分，该系统在焦虑和 沮丧。 选择性5-羟色胺再摄取抑制剂（SSRIS）是许多情绪障碍的一线治疗方法，并且 杏仁核具有高密度的SSRI结合位点。值得注意的是，负面情绪刺激触发5-羟色胺 （5HT）释放到BLA中，它的作用可降低BLA输出神经元的兴奋性。此外，5HT级别 在BLA中，由5HT转运蛋白的活性细微地调节，表明SSRIS可能会施加 通过提高BLA 5HT水平，从而使其输出神经元的活性正常化，从而进行治疗作用。然而， SSRI及其不必要的副作用的动作开始缓慢，正在推动寻找更快的行动，并且 焦虑和抑郁的更多针对性治疗方法。最近，已经确定了一种新型的抗抑郁药， GSK-1是一种混合的SHTWIB/ID受体拮抗剂，其作用迅速。多羟色胺 受体亚型在BLA中表达。因此，作用于一个或多个5HT受体的药物可能具有 对BLA输出神经元的兴奋性以及情绪障碍的深远影响。但是，鲜为人知 关于单个5-羟色胺受体激活如何调节BLA输出神经元的活性，更不用说如何 混合的5HT受体拮抗剂可能会影响这些神经元。 在这项研究中，我们将在体外切片准备中使用斑块夹记录来比较BLA的响应 在挑战之前，之中和之后，神经元与经典的SSRI，Citalopram的给药，GSK-1的神经元 与外源5HT。要检验的假设是：GSK-1的急性给药将模仿净效应 SSRI对BLA输出神经元活性的长期给药。三个特定目标将测试 假设：目标1：比较和对比急性在体外给药GSK-1对5-羟色胺的影响 受体介导的活性在BLA投射神经元和中间神经元中。目标2：比较和对比效果 GSK-1在血清素受体介导的BLA投射神经元和 中间神经元。 AIM 3：比较和对比GSK-1和Citalopram对5-羟色胺受体介导的影响 持续的恐惧调节后，BLA投射神经元和中间神经元的活动。