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

基底外侧杏仁核（BLA）的激活在对负性刺激的正常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。 紊乱例如，抑郁和焦虑的人表现出过度的杏仁核激活， 负面情绪刺激，现在被认为是情绪障碍的特征标志。超激活也是一种 积极治疗结果的预测因子，因为它随着药物治疗的治疗作用的开始而正常化， 这表明杏仁核是情绪调节系统的一个关键组成部分，在焦虑时会失调， 萧条 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药物， 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，在那里它起到降低BLA输出神经元的兴奋性的作用。此外，5 HT水平 在BLA中，5-HT转运蛋白的活性精细调节，表明SSRIs可能发挥其 通过提高BLA 5 HT水平，从而使其输出神经元的活性正常化，从而达到治疗效果。然而，在这方面， SSRIs的缓慢起效和它们不必要的副作用正在推动对更快起效的研究， 更有针对性地治疗焦虑和抑郁症。最近，一种新的抗抑郁剂已经被鉴定， GSK-1是一种混合型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5 HT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， 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 混合的5 HT受体拮抗剂可能影响这些神经元。 在本研究中，我们将使用膜片钳记录在体外切片制备，比较BLA的反应 神经元对经典SSRI、西酞普兰和GSK-1在激发前、激发中和激发后给药的反应 外源性5 HT待检验的假设是：GSK-1的急性给药将模拟净效应 SSRIs对BLA输出神经元活性的影响。三个具体目标将检验这一点 假设：目的1：比较和对比GSK-1体外急性给药对5-羟色胺的影响 受体介导的活动在BLA投射神经元和中间神经元。目标2：比较和对比效果 GSK-1体内给药对BLA投射神经元中5-羟色胺受体介导的活性的影响， 中间神经元。目的3：比较GSK-1和西酞普兰对5-羟色胺受体介导的 活动的BLA投射神经元和中间神经元后持续的恐惧条件。

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.