Enduring effects of juvenile ketamine exposure

青少年接触氯胺酮的持久影响

• 批准号: 10059143
• 负责人: Sergio Diaz Iniguez
• 金额: $ 11.33万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-26 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059143
• 关键词: 20 year old; Address; Adolescence; Adolescent; Adult; Affect; Age; Anesthetics; Antidepressive Agents; Anxiety Disorders; Behavior; Behavioral; Biochemical; Biological Markers; Biological Models; Brain; Brain region; C57BL/6 Mouse; Child; Childhood; Chronic; Cocaine; Data; Depressive disorder; Development; Disease; Disease Management; Drug Prescriptions; Drug abuse; Epidemiology; Exposure to; FRAP1 gene; Fluoxetine; Goals; Hippocampal Formation; Hippocampus (Brain); Impairment; Individual; Intervention; Investigation; Ketamine; Label; Life; Long-Term Effects; Major Depressive Disorder; Mediating; Mediation; Memory; Memory impairment; Mental Depression; Molecular; Molecular Target; Moods; Morbidity - disease rate; N-Methyl-D-Aspartate Receptors; Outcome Study; Peptide Initiation Factors; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phosphorylation; Population; Prevalence; Principal Investigator; Proteins; Psychiatry; Recording of previous events; Regulation; Reporting; Rewards; Ribosomal Protein S6 Kinase; Ribosomes; Risk; Rodent Model; Safety; Selective Serotonin Reuptake Inhibitor; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Social Interaction; Stimulus; Stress; Substance abuse problem; Sucrose; Symptoms; Tail Suspension; Testing; Work; alternative treatment; behavior influence; behavioral response; comorbidity; conditioning; depression model; drug of abuse; evidence base; experience; experimental study; innovation; insight; ketamine abuse; male; morris water maze; mortality; neurobehavioral; neurobiological mechanism; neurochemistry; novel; object recognition; off-label use; postnatal; pre-clinical; preclinical study; preference; response; side effect; social; social stress

Principal Investigator Iñiguez, Sergio Diaz ABSTRACT Pediatric major depressive disorder (MDD) is a common condition. Children and adolescents who suffer from MDD often develop conduct and anxiety disorders, and up to 25% develop substance abuse disorder. Consequently, this has resulted in a disproportionate increase in the prevalence of antidepressant medications prescribed to populations below 20 years of age. Despite the heightened rates in antidepressant prescriptions, juveniles are less likely to respond to traditional treatments (i.e., selective serotonin reuptake inhibitors) for the management of MDD. Recently, ketamine (KET), an anesthetic, has shown promise as a treatment for MDD. While exciting for the field of psychiatry – that a novel pharmaceutical can be used to alleviate MDD symptoms – the efficacy/safety of KET exposure during development has not been thoroughly examined. This is surprising, given that KET is known to have drug-abuse potential. Thus, to address this problem, the experiments described in this proposal will examine the enduring neurobehavioral consequences of early life (postnatal-day [PD] 35-44) exposure to KET, using C57BL/6 mice. This will be accomplished within the framework of the following specific aims: [1] assess the long-term consequences of chronic adolescent KET (with/without social stress exposure) on sensitivity to reward (drug), mood, and memory-performance in adulthood (PD80+), and [2] to evaluate the integrity of mood-related biological markers [mammalian target of rapamycin (mTOR)-related signaling], within the hippocampal formation. It is expected that juvenile KET exposure will mediate long-lived behavioral alterations associated with enhanced drug abuse potential (i.e., cocaine), altered responses to stress, and memory-related impairment(s). Furthermore, it is expected that site- specific neurochemical adaptations (mTOR fluctuations within the hippocampus) will be a factor mediating the drug-abuse and memory-associated behavioral adaptations as a function of adolescent KET exposure. Collectively, the results of this preclinical work will provide first-line evidence on the potential enduring risks of juvenile KET exposure. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page

首席研究员Iñiguez，塞尔吉奥·迪亚兹（Sergio Diaz） 抽象的 小儿重大抑郁症（MDD）是常见的疾病。受苦的儿童和青少年 来自MDD经常发展行为和焦虑症，多达25％的人患有药物滥用障碍。 因此，这导致抗抑郁药的患病率不成比例 规定20岁以下的人口。尽管抗抑郁处处方率提高，但 少年对传统治疗的反应（即选择性5-羟色胺再摄取抑制剂） MDD的管理。最近，氯胺酮（KET）是一种麻醉剂，已显示出有望作为MDD的治疗方法。 虽然精神病学领域令人兴奋，但可以使用新颖的药物来缓解MDD症状 - 尚未彻底检查开发过程中KET暴露的效率/安全性。这是 令人惊讶的是，众所周知KET具有滥用药物的潜力。为了解决这个问题， 本提案中描述的实验将检查早期的持久神经行为后果 （产后[PD] 35-44）使用C57BL/6小鼠接触KET。这将在 以下特定目的的框架：[1]评估慢性青少年KET的长期后果 （有/没有社交压力暴露）对奖励的敏感性（药物），情绪和记忆绩效 成年（PD80+）和[2]评估与情绪相关的生物学标记的完整性[ 雷帕霉素（MTOR）相关的信号传导]，在海马形成中。预计少年肯特 暴露将介导与增强药物滥用潜力相关的长期行为改变（即 可卡因），对压力的反应改变以及与记忆相关的损害。此外，可以预期 特定的神经化学适应（海马内的mTOR波动）将是介导的因素 药物滥用和与记忆相关的行为适应与青少年KET暴露的关系。 总的来说，这项临床前工作的结果将提供有关潜在持久风险的一线证据 少年肯特的暴露。 PHS 398/2590（修订版06/09）页面延续格式页面