Enduring effects of juvenile ketamine exposure

青少年接触氯胺酮的持久影响

基本信息

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
项目类别：
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

项目摘要

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、Sergio Diaz 抽象的儿童重度抑郁症 (MDD) 是儿童和青少年的常见病症。 MDD 患者通常会出现行为障碍和焦虑障碍，高达 25% 的人会出现药物滥用障碍。经测试，这导致抗抑郁药物的流行率不成比例地增加尽管抗抑郁药处方中存在呼吸频率，但针对 20 岁以下人群青少年不太可能对传统治疗（即选择性血清素再摄取抑制剂）产生反应最近，氯胺酮 (KET) 作为一种麻醉剂，在治疗 MDD 方面表现出了良好的前景。一种新型药物可用于缓解抑郁症症状，这对精神病学领域来说是令人兴奋的 – 开发过程中 KET 暴露的功效/安全性尚未得到彻底检查。令人惊讶的是，已知 KET 具有药物滥用的可能性。因此，为了解决这个问题，该提案中描述的实验将检查早期生活的持久神经行为后果（出生后 [PD] 35-44）暴露于 KET，使用 C57BL/6 小鼠这将在体内完成。以下具体目标的框架： [1] 评估青少年慢性 KET 的长期后果（有/没有社会压力暴露）对奖励（药物）、情绪和记忆表现的敏感性成年期 (PD80+) 和 [2] 评估情绪相关生物标志物的完整性 [哺乳动物目标雷帕霉素（mTOR）相关信号]，在海马结构内预计幼年 KET。暴露会介导与药物滥用潜力增强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伤此外，预计站点-。特定的神经化学适应（海马内的 mTOR 波动）将是介导药物滥用和与记忆相关的行为适应是青少年 KET 暴露的函数。总的来说，这项临床前工作的结果将为以下方面的潜在持久风险提供一线证据：青少年 KET 暴露。 PHS 398/2590（修订版 06/09）页面延续格式页面