Animal Models of Childhood and Adolescent Depression

描述(申请人提供)：严重抑郁障碍(临床抑郁症)是一种严重的和潜在的丧失能力的精神疾病，在儿童和青少年中很常见，估计在这一人群中终生患病率为15%-20%。与成人相比，儿童和青少年临床抑郁症的一个重要区别是对抗抑郁药物的反应。三环类抗抑郁药尚未被证明对治疗儿童和青少年的临床抑郁有效。尽管抗抑郁药物具有多种神经化学作用，但抗抑郁药物缓解抑郁的治疗机制尚不清楚。在非抑郁症患者中，抗抑郁药物不能使人愉悦或兴奋。因此，有关抗抑郁药物的多种神经化学作用中哪些与其缓解抑郁的疗效有关的研究需要使用临床抑郁的行为动物模型进行研究。为了更好地了解儿童和青少年以及成人对临床抑郁症药物治疗的反应差异的神经生物学，需要儿童和青少年抑郁症的动物模型。目前，还没有建立起临床抑郁症幼年动物模型。虽然在成年动物身上开发的模型可以作为一个起点，但由于幼年动物和成年动物之间的许多差异，它们必须在幼年动物中进行适应和验证。这项建议的总体目标是评估两种成熟的成人临床抑郁症大鼠动物模型作为儿童和青少年临床抑郁症模型的有效性和有用性。具体地说，我们建议评估强迫游泳测试和习得性无助作为幼年大鼠临床抑郁的动物模型的有用性。这一建议解决的关键问题是：1)幼年大鼠在强迫游泳中是否对减少静止的抗抑郁药物有反应？2)幼年大鼠在急性和持续性范式中都经历了不可避免的应激后是否会出现习得性无助，如羽毛球测试所证明的那样？3)幼年大鼠在急性和持续性习得性无助范式中是否对抗抑郁药物有反应，并在羽毛盒测试中减少逃避潜伏期？最终，这些模型可能有助于更好地理解临床抑郁症的潜在神经生物学，并作为儿童和青少年抗抑郁疗效的预测指标。

DESCRIPTION (provided by applicant): Major Depressive Disorder (clinical depression) is a severe and potentially incapacitating mental illness that is common in children and adolescents, with an estimated lifetime prevalence of 15 -20 % in this population. An important difference between clinical depression in children and adolescents, as compared to adults, is its response to antidepressant drugs. Tricyclic antidepressants have not been shown to be effective in treatment of child and adolescent clinical depression. Although antidepressant drugs have numerous neurochemical actions, the therapeutic mechanisms of action of antidepressant drugs in relieving depression remain unknown. In non-depressed persons antidepressant drugs are not euphoriant or stimulant. Therefore, investigations related to which of the many neurochemical effects of antidepressant drugs are functionally related to their therapeutic efficacy in relieving depression requires research using a behavioral animal model of clinical depression. To better understand the neurobiology underlying the differences between children and adolescents, and adults in the response to pharmacological treatment of clinical depression, animal models of childhood and adolescent depression are needed. Currently, there are no established juvenile animal models of clinical depression. Although the models developed in adult animals can serve as a starting point, they must be adapted and validated in juvenile animals due the many differences between juvenile and adult animals. The overall goal of this proposal is to assess the validity and usefulness of two well-established rat animal models of adult clinical depression as models of childhood and adolescent clinical depression. Specifically, we propose to assess the usefulness of the forced-swim test and of learned helplessness as animal models for clinical depression in juvenile rats. The key questions which are addressed by this proposal are: 1) Do juvenile rats respond to antidepressant drugs with decreased immobility in the forced swim? 2) Do juvenile rats develop learned helplessness after inescapable stress in both the acute and persistent paradigms, as demonstrated by shuttlebox testing? 3) Do juvenile rats respond to antidepressant drugs in the both acute and persistent learned helplessness paradigms with decreased escape latencies in shuttlebox testing? Ultimately, the models may facilitate a better understanding of the underlying neurobiology of clinical depression, and serve as predictive measures of antidepressant efficacy in children and adolescents.