Enduring effects of juvenile ketamine exposure

首席调查员伊尼格斯，塞尔吉奥·迪亚兹 摘要 儿童重度抑郁障碍(MDD)是一种常见的疾病。受苦的儿童和青少年 MDD患者通常会出现行为和焦虑障碍，高达25%的人会出现药物滥用障碍。 因此，这导致了抗抑郁药物流行率的不成比例的增加。 开给20岁以下人群的处方。尽管抗抑郁药处方中的比率较高， 青少年不太可能对传统的治疗方法(即选择性5-羟色胺再摄取抑制剂)产生反应 MDD的管理。最近，氯胺酮(KET)，一种麻醉剂，已经显示出作为MDD治疗的希望。 虽然精神病学领域令人兴奋-一种新的药物可以用来缓解MDD症状 -在发育过程中暴露于KET的有效性/安全性尚未得到彻底检查。这是 令人惊讶的是，鉴于KET众所周知具有药物滥用的潜力。因此，为了解决这个问题， 这项提案中描述的实验将检验早期生活的持久的神经行为后果。 (出生后第1天[PD]35-44)使用C57BL/6小鼠暴露于KET。这将在 以下具体目标的框架：[1]评估慢性青少年KET的长期后果 (有/无社会压力暴露)对奖励(药物)、情绪和记忆的敏感性-表现 成年期(PD80+)，和[2]评估情绪相关生物标记物的完整性[哺乳动物的目标 雷帕霉素(MTOR)相关信号]，在海马区。预计少年儿童KET 暴露将调解与药物滥用潜力增加相关的长期行为改变(即， 可卡因)、压力反应改变以及与记忆相关的损伤(S)。此外，预计该地点- 特定的神经化学适应(海马区的mTOR波动)将是调节 药物滥用和记忆相关的行为适应作为青少年KET暴露的函数。 总而言之，这项临床前工作的结果将为潜在的持久风险提供第一线证据。 青少年KET暴露。 PHS 398/2590(06/09版)页面续格式页面

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