Paradoxical Antidepressant Action in Locus Coeruleus during Development

蓝斑在发育过程中的矛盾抗抑郁作用

• 批准号: 7318974
• 负责人: JAY MICHAEL WEISS
• 金额: $ 29.26万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7318974
• 关键词: Adolescent; Adult; Adverse event; Alprazolam; Animal Model; Animals; Antidepressive Agents; Behavior; Behavioral; Blood; Blood drug level result; Brain; Cells; Child; Chronic; Clinical; Clonidine; Condition; Desipramine; Development; Dose; Electroconvulsive Shock; Goals; Human; Hyperactive behavior; Intake; Measurement; Measures; Mental Depression; Methods; Neurons; Norepinephrine; Paroxetine; Patients; Pharmaceutical Preparations; Pharmacotherapy; Range; Rattus; Recording of previous events; Research; Research Personnel; Selective Serotonin Reuptake Inhibitor; Serotonin; Side; Staging; Standards of Weights and Measures; Suicide; Swimming; Symptoms; Testing; Therapeutic; Time; day; depressive symptoms; inhibitor/antagonist; locus ceruleus structure; noradrenergic; osmotic minipump; pill; pre-clinical; prevent; programs; reuptake; venlafaxine

DESCRIPTION (provided by applicant): Recent concern that treatment with antidepressant (AD) drugs can, under certain circumstances, increase suicidality has created a difficult problem for clinicians treating depressive patients. The controversy has focused on three aspects of pharmacotherapy: (i) administration of AD drugs to juveniles (children and adolescents), (2) use of selective serotonin reuptake inhibitors (SSRIs), especially paroxetine, and (3) effects during the early course of AD treatment. Substantial evidence can be presented for both sides of the debate, and our goal is not to attempt to resolve this issue. Rather, our goal is to propose a mechan- istic animal model to explain how, under certain conditions, ADs may exacerbate rather than ameliorate the depressive state. Both clinical and preclinical evidence suggests that the principle noradrenergic cell group in the brain, the locus coeruleus (LC), is over-active in depressives and, in particular, in people who die from suicide. Effective AD treatments - that is, chronic administration of AD drugs and electroconvulsive shock - exert the opposite influence to decrease LC activity. Here we propose that treatment with SSRIs, especially in juveniles and early in treatment, can actually produce an increase in LC activity (rather than the normal "therapeutic" decrease) which may promote depressive symptoms and adverse events including suicidality. If indeed this unwanted effect on LC does occur with SSRIs given to juveniles, then countermeasures (i.e., co- medication) should prevent this from occurring. The proposed research will test our animal model by comparing the effects of short-term and long-term administration of AD drugs on the activity of LC neurons in young rats as compared to mature, adult rats. First, effects of a range of doses of an SSRI (paroxetine), a dual serotonin-norepinephrine reuptake inhibitor (venlafaxine), and a "standard" tricyclic (desipramine), administered continuously via osmotic minipump, will be compared in juvenile (45 days old) and mature adult (5 months old) rats. Second, the possibility that low and/or fluctuating blood levels of ADs may promote LC hyperactivity will be examined by measuring LC activity in animals that have been given an AD orally once-per-day, in a manner mimicking a patient taking medication as a pill. Third, a potential therapeutic countermeasure for SSRI-induced increase in suicidality will be explored by co-administering an SSRI with drugs (clonidine, alprazolam) having the potential to block LC hyperactivity. In parallel with measurement of LC activity, we will also measure effects on swim-test activity of rats. Swim-test activity has been widely used to (a) detect effects of AD drugs and (b) indicate the presence of a depressive condition, so measurement of swim-test activity of the rats will be used to confirm antidepressant action and, most importantly, to test for indication of increased depression in young rats during the early stages of treatment with drugs suspected to exacerbate depression-related symptoms.

描述（由申请人提供）：最近人们担心抗抑郁（AD）药物治疗在某些情况下会增加自杀倾向，这给治疗抑郁症患者的临床医生带来了难题。争议集中在药物治疗的三个方面：(i) 对青少年（儿童和青少年）使用 AD 药物，(2) 使用选择性血清素再摄取抑制剂 (SSRI)，尤其是帕罗西汀，以及 (3) 早期病程的影响AD 治疗。可以为辩论双方提供大量证据，我们的目标不是试图解决这个问题。相反，我们的目标是提出一种机械动物模型来解释在某些条件下AD如何可能加剧而不是改善抑郁状态。临床和临床前证据都表明，大脑中主要的去甲肾上腺素能细胞群蓝斑（LC）在抑郁症患者中过度活跃，特别是在自杀死亡的人中。有效的 AD 治疗（即长期服用 AD 药物和电休克）会产生相反的影响，降低 LC 活性。在这里，我们建议用 SSRIs 治疗，尤其是青少年和治疗早期，实际上可以增加 LC 活性（而不是正常的“治疗性”减少），这可能会促进抑郁症状和包括自杀在内的不良事件。如果青少年服用 S​​SRI 确实会出现这种对 LC 的不良影响，那么应采取对策（即联合用药）来防止这种情况发生。拟议的研究将通过比较短期和长期服用 AD 药物对幼年大鼠和成熟大鼠 LC 神经元活性的影响来测试我们的动物模型。首先，将通过渗透微型泵连续给药一系列剂量的 SSRI（帕罗西汀）、双血清素-去甲肾上腺素再摄取抑制剂（文拉法辛）和“标准”三环药物（地昔帕明）在青少年（45 天）中的效果进行比较。老）和成熟的成年（5个月大）大鼠。其次，通过测量每天一次口服 AD 的动物的 LC 活性，以模仿患者服用药物作为治疗方法，来检查低和/或波动的 AD 血液水平可能促进 LC 过度活跃的可能性。丸。第三，通过将 SSRI 与具有阻断 LC 过度活跃潜力的药物（可乐定、阿普唑仑）共同给药，将探索针对 SSRI 引起的自杀率增加的潜在治疗对策。在测量 LC 活性的同时，我们还将测量对大鼠游泳测试活动的影响。游泳测试活动已广泛用于 (a) 检测 AD 药物的效果和 (b) 表明抑郁状况的存在，因此对大鼠游泳测试活动的测量将用于确认抗抑郁作用，最重要的是，以测试幼鼠在使用疑似加剧抑郁相关症状的药物治疗的早期阶段抑郁症增加的迹象。