Functional studies of antidepressant exposure during adolescence on the brain

 描述（由申请人提供）：直到几年前，儿童抑郁症几乎是不可想象的。现在我们不仅知道重度抑郁症（MDD）存在于儿童和青少年中，而且它是一种常见的疾病。据估计，患有MDD的儿童和青少年经常发展为行为和焦虑障碍，高达25%的人发展为物质滥用障碍。因此，这导致20岁以下人群使用抗抑郁药的比例不成比例地增加。尽管抗抑郁药的使用率提高，但人们对早期发育过程中抗抑郁药治疗引起的潜在长期行为和神经适应知之甚少。为了解决这个问题，本提案中描述的实验将使用C57 BL/6雄性和雌性小鼠，检查早期（出生后[PD] 35-49天）暴露于氟西汀（一种选择性5-羟色胺再摄取抑制剂）的长期行为后果。这将在以下具体目标的框架内实现：[1]评估长期青少年抗抑郁药治疗对奖励（药物）敏感性、情绪相关行为（压力）和成年期记忆（PD 80+）的长期影响，[2]评估情绪相关生物标志物[细胞外信号调节蛋白激酶-1/2（ERK）]的完整性，在海马结构内，慢性青少年抗抑郁药暴露后。预计青春期抗抑郁药暴露将诱导与压力反应、药物奖励行为和记忆相关的长期改变。此外，它是预期的网站特定的神经化学适应（海马内的ERK波动）是一个因素介导这些行为的改变作为青少年抗抑郁药暴露的函数。总的来说，这项临床前工作的结果将提供一线 关于青春期抗抑郁药暴露潜在风险的证据。

 DESCRIPTION (provided by applicant): Pediatric depression was almost unthinkable until several years ago. Now we not only know that major depressive disorder (MDD) exists in children and adolescents, but that it is a common condition. It is estimated that children and adolescents who suffer from MDD often develop conduct and anxiety disorders, and that up to 25% develop substance abuse disorder. Consequently, this has resulted in a disproportionate increase in the prevalence of antidepressants prescribed to populations below 20 years of age. Despite the heightened rates in antidepressant use, little is known about the potential long-term behavioral and neural adaptations resulting from antidepressant treatment during early development. To address this problem, the experiments described in this proposal will examine the long-term behavioral consequences of early life (postnatal day [PD] 35-49) exposure to fluoxetine, a selective serotonin reuptake inhibitor, using C57BL/6 male and female mice. This will be accomplished within the framework of the following specific aims: [1] assess long-term consequences of chronic adolescent antidepressant treatment on the sensitivity to reward (drug), mood related behaviors (stress), and memory in adulthood (PD80+), and [2] evaluate the integrity of mood-related biological markers [extracellular signal regulated protein kinase-1/2 (ERK)], within the hippocampal formation, following chronic adolescent antidepressant exposure. It is expected that antidepressant exposure during adolescence will induce long-lived alterations associated with responses to stress, drug-rewarded behaviors, and memory. Furthermore, it is expected that site-specific neurochemical adaptations (ERK fluctuations within the hippocampus) to be a factor mediating these behavioral alterations as a function of juvenile antidepressant exposure. Collectively, the results of this preclinical work will provide first-line evidence on the potential risks of antidepressant exposure during adolescence.