Functional studies of antidepressant exposure during adolescence on the brain

青春期抗抑郁药物暴露对大脑的功能研究

基本信息

批准号：
9366700
负责人：
Sergio Diaz Iniguez
金额：
$ 9.8万
依托单位：
UNIVERSITY OF TEXAS EL PASO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9366700
关键词：
20 year old Address Adolescence Adolescent Adult Aftercare Age Antidepressive Agents Anxiety Disorders Behavior Behavioral Behavioral Model Biochemical Biological Markers Biological Models Brain Brain region CREB1 gene Child Childhood Chronic Cocaine Data Depressed mood Development Diagnosis Disease Disease Management Drug abuse Epidemiology Exposure to Female Fluoxetine Goals Health Hippocampal Formation Hippocampus (Brain)Intervention Investigation Life Link Long-Term Effects MAPK3 gene Major Depressive Disorder Mediating Mediation Memory Memory impairment Molecular Moods Morbidity - disease rate Mus Outcome Performance Pharmaceutical Preparations Phosphorylation Population Prevalence Principal Investigator Protein Kinase Proteins Regulation Reporting Rewards Ribosomal Protein S6 Kinase Risk Second Messenger Systems Selective Serotonin Reuptake Inhibitor Serotonin Signal Pathway Signal Transduction Signaling Molecule Site Stimulus Stress Substance abuse problem System Testing Work addiction behavioral response child depression comorbidity conditioning drug of abuse drug reward drug seeking behavior emotional behavior experience extracellular insight male men&apos s group morris water maze mortality motivated behavior nerve supply neural circuit neuroadaptation neurobiological mechanism neurochemistry novel object recognition postnatal pre-clinical preference research study response second messenger transcription factor treatment choice

项目摘要

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.

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。现在我们不仅知道儿童和青少年存在重度抑郁症（MDD），而且据估计这是儿童和青少年的常见病症。患有 MDD 的人经常会出现行为障碍和焦虑障碍，并且经测试，高达 25% 的人会出现药物滥用障碍，这导致 20 岁以下人群服用抗抑郁药物的比例大幅增加。尽管抗抑郁药物的吸收率很高，但人们对早期发育过程中抗抑郁治疗可能产生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检查长期行为后果。使用 C57BL/6 雄性和雌性小鼠，研究生命早期（出生后 [PD] 35-49）暴露于氟西汀（一种选择性血清素再摄取抑制剂）的情况。这将在以下具体目标的框架内完成： [1] 评估青少年长期抗抑郁治疗对奖励（药物）、情绪相关行为（压力）和成年记忆 (PD80+) 敏感性的长期影响，以及 [2] 评估情绪相关生物标志物的完整性[细胞外信号调节蛋白激酶-1/2 (ERK)]，在青少年长期接触抗抑郁药物后，在海马结构内。预计青春期期间接触抗抑郁药物将引起与反应相关的长期改变。此外，预计特定位点的神经化学适应（海马内的 ERK 波动）是介导这些行为改变的因素，这是青少年抗抑郁药物暴露的结果。这项临床前工作将提供一线青春期期间接触抗抑郁药物潜在风险的证据。