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.

杏仁基底外侧核(BLA)的激活在正常的负性适应性反应中起着关键作用 情感刺激。BLA输出神经元的异常活动与几种情绪的病因有关 精神错乱。例如，抑郁和焦虑的人表现出杏仁核激活的夸大反应 负性情绪刺激，现在被认为是情绪障碍的特征标志。过度激活也是一种 随着药物治疗治疗作用的开始，阳性治疗结果的预测指标恢复正常， 这表明杏仁核是情绪调节系统的关键组成部分，而情绪调节系统在焦虑和 抑郁症。 选择性5-羟色胺再摄取抑制剂(SSRI)是许多情绪障碍的一线治疗药物，而 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5-羟色胺 (5-羟色胺)释放到BLA，在那里它降低BLA输出神经元的兴奋性。此外，5-羟色胺水平 在血乳酸中受5-羟色胺转运蛋白活性的精细调节，这表明SSRI可能发挥其 通过提高血乳酸-5-羟色胺水平，从而使其输出神经元的活动正常化，从而发挥治疗作用。然而， SSRI的缓慢起效及其不受欢迎的副作用正在推动人们寻求更快的行动，以及 对焦虑和抑郁进行更有针对性的治疗。最近，一种新型的抗抑郁剂被发现， GSK-1，这是一种混合的SHTwiB/ID受体拮抗剂，具有快速起效。多重5-羟色胺 受体亚型在血乳酸中表达。因此，作用于一个或多个5-羟色胺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，人们对此知之甚少 关于个体5-羟色胺受体激活如何调节BLA输出神经元的活动，更不用说如何 混合使用的5-羟色胺受体拮抗剂可能会影响这些神经元。 在这项研究中，我们将在体外切片制备中使用膜片钳记录来比较血乳酸的反应 神经元对经典SSRI西酞普兰和GSK-1在激发前、期间和之后的给药 外源性5-羟色胺。需要检验的假设是：急性服用GSK-1将模拟净效应 慢性给予SSRIs对BLA输出神经元活动的影响。三个具体目标将检验这一点 假设：目标1：比较和对比急性体外给予GSK-1对5-羟色胺的影响 BLA投射神经元和中间神经元中受体介导的活动。目标2：比较和对比效果 GSK-1体内给药对BLA投射神经元5-羟色胺受体介导活性的影响 中间神经元。目的3：比较葛兰素史克-1和西酞普兰对5-羟色胺受体介导的作用 持续恐惧条件反射后BLA投射神经元和中间神经元的活动。