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

• 批准号: 9222768
• 负责人: Sergio Diaz Iniguez
• 金额: $ 15.1万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9222768
• 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; C57BL/6 Mouse; CREB1 gene; Child; Childhood; Chronic; Cocaine; Comorbidity; Data; Depressed mood; Development; Diagnosis; Disease; Disease Management; Drug abuse; Epidemiology; Exposure to; Female; Fluoxetine; Goals; 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; Pharmacology; Phosphorylation; Population; Prevalence; Principal Investigator; Protein Kinase; Proteins; Regulation; Reporting; Rewards; Ribosomal Protein S6 Kinase; Ribosomes; Risk; Second Messenger Systems; Selective Serotonin Reuptake Inhibitor; Serotonin; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Stimulus; Stress; Substance abuse problem; System; Testing; Women' s Group; Work; addiction; antidepressant effect; behavior influence; behavioral response; child depression; conditioning; drug of abuse; drug reward; drug seeking behavior; emotional behavior; experience; experimental study; extracellular; insight; male; men' s group; morris water maze; mortality; motivated behavior; nerve supply; neural circuit; neuroadaptation; neurobiological mechanism; neurochemistry; novel; object recognition; postnatal; pre-clinical; preference; public health relevance; response; transcription factor; treatment choice

 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），而且它是一种常见疾病。据估计，患有 MDD 的儿童和青少年经常会出现行为障碍和焦虑障碍，其中高达 25% 的人会出现药物滥用障碍。因此，这导致 20 岁以下人群的抗抑郁药物使用率不成比例地增加。尽管抗抑郁药物的使用率很高，但人们对早期发育过程中抗抑郁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 雄性和雌性小鼠检查生命早期（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）的长期行为后果。这将在以下具体目标的框架内完成：[1] 评估长期青少年抗抑郁治疗对奖励（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] 评估海马内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 青少年长期服用抗抑郁药物后形成。预计青春期期间接触抗抑郁药物将引起与压力反应、药物奖励行为和记忆相关的长期改变。此外，预计位点特异性神经化学适应（海马内的 ERK 波动）是介导这些行为改变的一个因素，作为青少年抗抑郁药物暴露的函数。总的来说，这项临床前工作的结果将提供一线 青春期期间接触抗抑郁药物潜在风险的证据。

项目成果

Adolescent fluoxetine history impairs spatial memory in adult male, but not female, C57BL/6 mice

• DOI: 10.1016/j.jad.2019.02.051
• 发表时间: 2019-04-15
• 期刊: JOURNAL OF AFFECTIVE DISORDERS
• 影响因子: 6.6
• 作者: Flores-Ramirez, Francisco J.;Parise, Lyonna F.;Iniguez, Sergio D.
• 通讯作者: Iniguez, Sergio D.

Adolescent Fluoxetine Exposure Induces Persistent Gene Expression Changes in the Hippocampus of Adult Male C57BL/6 Mice.

• DOI: 10.1007/s12035-020-02221-9
• 发表时间: 2021-04
• 期刊: Molecular neurobiology
• 影响因子: 5.1
• 作者: Iñiguez SD;Flores-Ramirez FJ;Themann A;Lira O
• 通讯作者: Lira O

Dorsal Hippocampus ERK2 Signaling Mediates Anxiolytic-Related Behavior in Male Rats

• DOI: 10.1177/2470547019897030
• 发表时间: 2019-01
• 期刊: Chronic Stress
• 作者: Jorge A Sierra-Fonseca;Lyonna F. Parise;F. Flores-Ramirez;E. Robles;Israel Garcia-Carachure;S. Iñiguez

Autophagy Induction and Accumulation of Phosphorylated Tau in the Hippocampus and Prefrontal Cortex of Adult C57BL/6 Mice Subjected to Adolescent Fluoxetine Treatment.

• DOI: 10.3233/jad-210475
• 发表时间: 2021
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Sierra-Fonseca JA;Rodriguez M;Themann A;Lira O;Flores-Ramirez FJ;Vargas-Medrano J;Gadad BS;Iñiguez SD
• 通讯作者: Iñiguez SD