Long-term adverse effect of postnatal fluoxetine in mice

氟西汀对小鼠产后的长期不良反应

• 批准号: 7140395
• 负责人: Miklos Toth
• 金额: $ 16.41万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7140395
• 关键词: anxiety; behavior disorders; behavioral /social science research tag; blood tests; brain disorders; brain electrical activity; brain morphology; capillary electrophoresis; developmental neurobiology; drug adverse effect; ethology; fluoxetine; high performance liquid chromatography; laboratory mouse; liquid chromatography mass spectrometry; longitudinal animal study; mass spectrometry; mental disorder chemotherapy; neural information processing; neurogenesis; newborn animals; psychological stressor; serotonin inhibitor; terminal nick end labeling

DESCRIPTION (provided by applicant): Selective serotonin reuptake inhibitors (SSRIs) are important drugs in the treatment of child and adolescent psychiatric disorders. SSRIs achieve their therapeutic effect by increasing the extracellular level of 5-HT. Animal experiments indicate that supra-physiological 5-HT levels during brain development can lead to irreversible cytoarchitectural and behavioral abnormalities. Our data also indicate that postnatal administration of fluoxetine in mice results in permanent brain abnormalities including neuronal hyperexcitability in a sensory pathway and audiogenic seizures. There have been no longitudinal studies to assess the long-term effects of SSRI-administration in adults who received treatment during childhood. Such studies require many years and even decades. Developmental processes are much faster in rodents allowing the evaluation of postnatal SSRI-treatment on adult behavior in a relatively short time scale. The goals of this proposal are to better characterize the long-term adverse effects associated with the postnatal administration of SSRI in clinically relevant doses and to specify some of the mechanisms that underlie these effects.

描述（由申请人提供）：选择性血清素再摄取抑制剂（SSRI）是治疗儿童和青少年精神疾病的重要药物。 SSRIs 通过增加细胞外 5-HT 水平来达到治疗效果。 动物实验表明，大脑发育过程中超生理的 5-HT 水平可能导致不可逆的细胞结构和行为异常。我们的数据还表明，小鼠出生后服用氟西汀会导致永久性大脑异常，包括感觉通路中的神经元过度兴奋和听源性癫痫发作。目前还没有纵向研究来评估 SSRI 给药对儿童时期接受治疗的成年人的长期影响。 这样的研究需要很多年甚至几十年的时间。啮齿动物的发育过程要快得多，因此可以在相对较短的时间内评估出生后 SSRI 治疗对成年行为的影响。该提案的目标是更好地描述与临床相关剂量的产后 SSRI 相关的长期不良反应的特征，并明确这些影响背后的一些机制。

项目成果

Epigenetic Neuropharmacology: Drugs Affecting the Epigenome in the Brain.

• DOI: 10.1146/annurev-pharmtox-030220-022920
• 发表时间: 2021-01-06
• 期刊: Annual review of pharmacology and toxicology
• 影响因子: 12.5