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）的激活在对负面情绪的正常适应性反应中起着至关重要的作用 情绪刺激。 BLA 输出神经元的异常活动与多种情绪的病因有关 失调。例如，抑郁和焦虑的人会表现出过度的杏仁核激活反应 负面情绪刺激，现在被认为是情绪障碍的特征标记。过度活跃也是一种 积极治疗结果的预测因素，因为它随着药物治疗的治疗作用的开始而正常化， 表明杏仁核是情绪调节系统的关键组成部分，该系统在焦虑和焦虑时失调。 沮丧。 选择性血清素再摄取抑制剂（SSRI）是许多情绪障碍的一线治疗方法， 杏仁核具有高密度的 SSRI 结合位点。值得注意的是，负面情绪刺激会触发血清素 (5HT) 释放到 BLA 中，从而降低 BLA 输出神经元的兴奋性。此外，5HT水平 BLA 中的 5HT 转运蛋白的活性对其进行精细调节，表明 SSRIs 可能发挥其作用 通过提高 BLA 5HT 水平从而使其输出神经元的活动正常化来发挥治疗作用。然而， SSRI 起效缓慢及其不良副作用正在推动寻找起效更快的药物，并且 对焦虑和抑郁进行更有针对性的治疗。最近，一种新型抗抑郁药被发现， GSK-1 是一种混合的 SHTwiB/iD 受体拮抗剂，起效迅速。多种血清素 受体亚型在 BLA 中表达。因此，作用于一种或多种 5HT 受体的药物可能具有 对 BLA 输出神经元的兴奋性产生深远影响，从而导致情绪障碍。然而，鲜为人知 关于个体血清素受体激活如何调节 BLA 输出神经元的活动，更不用说如何 混合 5HT 受体拮抗剂可能会影响这些神经元。 在本研究中，我们将在体外切片制备中使用膜片钳记录来比较 BLA 的反应 在攻击之前、期间和之后对神经元施用经典 SSRI、西酞普兰和 GSK-1 与外源性5HT。要测试的假设是：GSK-1 的急性给药将模拟净效应 长期服用 SSRIs 对 BLA 输出神经元活性的影响。三个具体目标将对此进行测试 假设：目标 1：比较和对比 GSK-1 急性体外给药对血清素的影响 BLA 投射神经元和中间神经元中受体介导的活性。目标 2：比较和对比效果 体内施用 GSK-1 对 BLA 投射神经元中血清素受体介导的活性的影响 中间神经元。目标 3：比较 GSK-1 和西酞普兰对血清素受体介导的影响 持续恐惧调节后 BLA 投射神经元和中间神经元的活动。