Functional studies of antidepressant exposure during adolescence on the brain

 描述(申请人提供)：直到几年前，儿童抑郁症几乎是不可想象的。现在我们不仅知道严重抑郁障碍(MDD)存在于儿童和青少年中，而且这是一种常见的疾病。据估计，患有MDD的儿童和青少年经常发展为品行障碍和焦虑症，高达25%的儿童和青少年发展为药物滥用障碍。因此，这导致20岁以下人群服用抗抑郁药的流行率不成比例地增加。尽管抗抑郁药物的使用率增加，但人们对早期发育阶段抗抑郁药物治疗可能导致的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C57BL/6雄性和雌性小鼠来研究早期(出生后35-49天)暴露于氟西汀的长期行为后果，氟西汀是一种选择性的5-羟色胺再摄取抑制剂。这将在以下特定目标的框架内完成：[1]评估慢性青少年抗抑郁药物治疗对奖励(药物)、情绪相关行为(压力)和成年记忆(PD80+)的敏感性的长期后果，以及[2]评估慢性青少年抗抑郁药物暴露后，海马体结构中情绪相关生物标记物[细胞外信号调节蛋白激酶-1/2(ERK)]的完整性。预计青春期接触抗抑郁药物将导致与压力反应、药物奖励行为和记忆相关的长期变化。此外，预计特定部位的神经化学适应(海马区内ERK的波动)将是作为青少年抗抑郁药物暴露的功能而调节这些行为变化的因素。总的来说，这项临床前工作的结果将提供第一线 青春期接触抗抑郁药物的潜在风险的证据。

 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.