Animal Models of Childhood and Adolescent Depression

描述（由申请人提供）：重度抑郁症（临床抑郁症）是一种严重且可能导致失能的精神疾病，常见于儿童和青少年，估计该人群的终生患病率为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其对抗抑郁药物的反应。三环类抗抑郁药尚未被证明是有效的治疗儿童和青少年的临床抑郁症。虽然抗抑郁药物具有多种神经化学作用，但其治疗抑郁症的作用机制尚不清楚。在非抑郁症患者中，抗抑郁药物不是欣快剂或兴奋剂。因此，研究抗抑郁药物的许多神经化学作用中的哪一种与其缓解抑郁症的疗效在功能上相关，需要使用临床抑郁症的行为动物模型进行研究。为了更好地了解儿童和青少年之间的差异，以及成人对临床抑郁症药物治疗的反应，需要儿童和青少年抑郁症的动物模型。目前，还没有建立临床抑郁症的幼年动物模型。虽然在成年动物中开发的模型可以作为起点，但由于幼年动物和成年动物之间存在许多差异，因此必须在幼年动物中进行调整和验证。本提案的总体目标是评估两种成熟的成年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实用性。具体而言，我们建议评估的实用性，强迫游泳测试和习得性无助的动物模型，为临床抑郁症的幼年大鼠。这一建议所解决的关键问题是：1）幼年大鼠对抗抑郁药物的反应是否会导致强迫游泳中的不动性降低？2)穿梭箱实验表明，幼年大鼠在急性和持续性应激后是否会产生习得性无助？3)幼年大鼠在急性和持续性习得性无助模式下对抗抑郁药物有反应吗？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药疗效的预测指标。

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.