Paradoxical Antidepressant Action in Locus Coeruleus during Development

描述（由申请人提供）：最近对抗抑郁药（AD）治疗在某些情况下会增加自杀率的关注，给临床医生治疗抑郁症患者带来了一个难题。争议主要集中在药物治疗的三个方面：(i)青少年（儿童和青少年）使用阿尔茨海默病药物；(2)选择性血清素再摄取抑制剂（SSRIs）的使用，尤其是帕罗西汀；(3)阿尔茨海默病治疗早期的作用。辩论双方都可以拿出确凿的证据，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制动物模型来解释在某些条件下，ad可能会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群中。有效的阿尔茨海默病治疗——即长期服用阿尔茨海默病药物和电休克——对降低LC活性产生相反的影响。在这里，我们建议使用SSRIs治疗，特别是在青少年和治疗早期，实际上可以产生LC活性的增加（而不是正常的“治疗”减少），这可能会促进抑郁症状和包括自杀在内的不良事件。如果给青少年服用SSRIs确实会对LC产生不良影响，那么应对措施（即联合用药）应该防止这种情况发生。我们提出的研究将通过比较短期和长期服用AD药物对年轻大鼠LC神经元活动的影响来测试我们的动物模型，与成熟的成年大鼠相比。首先，在幼龄大鼠（45天大鼠）和成年大鼠（5个月大鼠）中，通过渗透微型泵连续给予一定剂量的SSRI（帕罗西汀）、双5 -羟色胺-去甲肾上腺素再摄取抑制剂（文拉法辛）和“标准”三环（地西帕明）的效果将进行比较。其次，通过测量每天口服一次AD的动物的LC活性，以模拟患者服用药物作为药丸的方式，来检测低水平和/或波动的AD血液水平可能促进LC过度活跃的可能性。第三，通过将SSRI与可能阻断LC多动的药物（可乐定、阿普唑仑）联合使用，探索SSRI诱导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。Swim-test活性已被广泛用于(a)检测AD药物的效果和(b)表明抑郁状态的存在，因此测量大鼠的Swim-test活性将被用于确认抗抑郁作用，最重要的是，在怀疑加重抑郁相关症状的药物治疗的早期阶段，测试年轻大鼠抑郁症增加的迹象。

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.