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）是儿童和青少年中常见的一种严重的和潜在的丧失能力的精神疾病，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其对抗抑郁药物的反应。三环抗抑郁药在治疗儿童和青少年临床抑郁症方面尚未显示出有效。虽然抗抑郁药物具有多种神经化学作用，但抗抑郁药物在缓解抑郁症方面的治疗机制尚不清楚。对于非抑郁症患者，抗抑郁药物不具有欣快或兴奋作用。因此，研究抗抑郁药物的许多神经化学作用中，哪一种与它们缓解抑郁症的治疗效果在功能上相关，需要使用临床抑郁症的行为动物模型进行研究。为了更好地理解儿童、青少年和成人对临床抑郁症药物治疗反应差异的神经生物学基础，需要建立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。虽然在成年动物身上建立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存在许多差异，它们必须在幼年动物身上进行调整和验证。本提案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。具体来说，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症动物模型的有效性。该提案解决的关键问题是：1)幼年大鼠对抗抑郁药物的反应是否与强迫游泳中静止不动的减少有关？2)幼年大鼠在不可避免的应激后是否会出现习得性无助（急性范式和持续性范式）？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的反应是否会降低逃避潜伏期？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药物疗效的预测措施。

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.