Paradoxical Antidepressant Action in Locus Coeruleus during Development

描述(由申请人提供)：最近的担忧是，在某些情况下，使用抗抑郁药物(AD)治疗会增加自杀率，这给临床医生治疗抑郁症患者带来了一个难题。争论的焦点集中在药物治疗的三个方面：(1)青少年(儿童和青少年)使用AD药物，(2)选择性5-羟色胺再摄取抑制剂(SSRI)的使用，特别是帕罗西汀，以及(3)AD治疗早期过程中的效果。辩论双方都可以提出实质性的证据，我们的目标不是试图解决这一问题。相反，我们的目标是提出一个机械动物模型，以解释在特定条件下，ADS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，从而降低LC的活性。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“治疗性”下降)，这可能会促进抑郁症状和不良事件，包括自杀。如果给青少年服用SSRI确实会对LC产生这种不良影响，那么对策(即联合用药)应该防止这种情况发生。这项拟议的研究将通过比较短期和长期给予AD药物对幼鼠LC神经元活性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，我们将比较不同剂量的SSRI(帕罗西汀)、一种双重5-羟色胺-去甲肾上腺素再摄取抑制剂(文拉法辛)和一种“标准”三环(地塞帕明)通过渗透压小泵持续给药在幼年(45天大)和成年(5个月大)大鼠身上的效果。其次，将通过测量每天口服一次AD的动物的LC活动来检验低和/或波动的血液ADS水平可能促进LC多动的可能性，以模仿患者服药的方式。第三，通过将SSRI与可能阻断LC多动的药物(可乐定、阿普唑仑)联合应用，将探索SSRI导致自杀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。游泳测试活动已被广泛用于(A)检测AD药物的效果和(B)表明存在抑郁状况，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，在疑似加重抑郁相关症状的药物治疗的早期阶段，测试幼鼠抑郁加重的迹象。

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.