Long-term neurobehavioral effects of ketamine exposure in adolescent mice

青少年小鼠暴露于氯胺酮的长期神经行为影响

• 批准号: 8017430
• 负责人: STEVEN J SIEGEL
• 金额: $ 37.81万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8017430
• 关键词: Accounting; Address; Adolescence; Adolescent; Adult; American; Animal Model; Animals; Award; Basic Science; Behavior; Biochemical; Brain; Brain Injuries; Cell Death; Cells; Chronic; Clinical Data; Cognition Disorders; Cognitive deficits; Coupled; Data; Development; Dose; Drug abuse; Event-Related Potentials; Evoked Potentials; Exposure to; FVB Mouse; Future; Hippocampus (Brain); Human; Immunohistochemistry; Inbred C3H Mice; Inbred Strain; Incidence; Individual; Injection of therapeutic agent; Intoxication; Investigation; Ketamine; Knowledge; Lead; Learning; Life; Literature; Measures; Mental disorders; Methods; Metric; Modeling; Mus; N-Methyl-D-Aspartate Receptors; NMDA receptor antagonist; Nature; Nerve Degeneration; Neuronal Plasticity; Pattern; Pharmaceutical Preparations; Phase; Physiological; Population; Principal Investigator; Process; Receptor Mediated Signal Transduction; Receptor Signaling; Regimen; Relative (related person); Research Personnel; Risk; Role; Saline; Silver; Stress; Structure; Symptoms; Syndrome; Time; Work; arm; base; brain behavior; cellular pathology; college; discount; drug of abuse; emerging adult; high school; ketamine abuse; mature animal; neurobehavioral; neurotoxic; neurotoxicity; phase 2 study; programs; research study; young adult

DESCRIPTION (provided by applicant): This is the second submission of a Phase II Cutting Edge Basic Research Award (CEBRA) that follows the Principal Investigator's Phase I application entitled, Evoked potentials and vulnerability to ketamine in mice (5-R21-DA-017082-02). All of the reviewers' concerns have been fully addressed in this revised application. Rationale: Experimentation with drugs of abuse is common among adolescents and young adults. Although the immediate consequences of intoxication are known, the ubiquitous nature of casual use leads many clinicians to discount mild drug abuse during high school and college as causal of later psychiatric symptoms and syndromes. Despite such assumptions, the lasting consequences of drugs that are emerging on campuses and in clubs across the nation, such as ketamine, are not known. During the Phase I portion of this study, the PI demonstrated persistent changes in Event Related Potentials (ERPs) following chronic ketamine exposure in adult mice. Preliminary data and previous literature also demonstrate that ketamine causes cellular pathology in brain. Questions that will be addressed: These findings lead to the following two overarching questions: 1) Does intermittent exposure to NMDA receptor antagonists during adolescence cause persistent physiological and cognitive deficits in adults? 2) Can adolescent ketamine abuse cause persistent alterations in cellular constituents and/or receptor signaling mechanisms in adults? Approach and Methods: Therefore, proposed studies will determine the duration of persistent ERP and cognitive deficits following ketamine exposure during adolescence in mice (Aim 1). Complementary studies will determine which cell classes are selectively altered by ketamine using stereological population estimates in adult animals following immunohistochemistry for cell-specific markers. Additionally, we will analyze measures of immediate cellular pathology directly following ketamine exposure during adolescence (Aim 2). Aim 3 will then utilize ex-vivo studies to determine the pattern of functional alterations of intracellular mechanisms of NMDA receptor mediated signal transduction among surviving cell populations following developmental exposure to ketamine. Significance: These three parallel Aims will address the degree of physiological, anatomical and biochemical functional neuroplasticity that exits following adolescent ketamine exposure. Therefore, completion of the proposed body of work will provide valuable evidence regarding the long-term, possibly irreversible, consequences of intermittent drug abuse during adolescence and early adulthood. Furthermore, these studies will address the potential roles of early drug abuse in later cognitive and psychiatric disorders throughout life.Although ketamine (Special K) abuse is common among adolescents, the consequences of this behavior are not known. To address this issue, we previously demonstrated that ketamine causes short-term changes in brain activity and signs of brain damage in adult mice. Proposed studies will determine the duration of abnormal brain function and the extent of brain damage following ketamine in adolescent mice to assess the potential for lasting, irreversible consequences of drug abuse during adolescence.

描述（由申请人提供）：这是继首席研究员题为小鼠氯胺酮诱发电位和脆弱性 (5-R21-DA-017082-02) 的第一阶段申请之后第二次提交第二阶段尖端基础研究奖 (CEBRA)。审阅者的所有担忧均已在修订后的申请中得到充分解决。理由：尝试滥用药物在青少年和年轻人中很常见。尽管中毒的直接后果是已知的，但随意使用的普遍性导致许多临床医生将高中和大学期间的轻度药物滥用视为后来精神症状和综合症的原因。尽管有这样的假设，但全国各地校园和俱乐部中出现的毒品（例如氯胺酮）的持久后果尚不清楚。在本研究的第一阶段部分，PI 证明了成年小鼠长期接触氯胺酮后事件相关电位 (ERP) 发生持续变化。初步数据和先前的文献还表明，氯胺酮会导致大脑细胞病理学。将要解决的问题：这些发现引出了以下两个首要问题：1）青春期期间间歇性接触 NMDA 受体拮抗剂是否会导致成人持续的生理和认知缺陷？ 2) 青少年滥用氯胺酮是否会导致成人细胞成分和/或受体信号机制的持续改变？途径和方法：因此，拟议的研究将确定小鼠青春期接触氯胺酮后持续性 ERP 和认知缺陷的持续时间（目标 1）。补充研究将在对细胞特异性标记进行免疫组织化学分析后，使用成年动物的体视群体估计来确定氯胺酮选择性改变哪些细胞类别。此外，我们将分析青春期接触氯胺酮后直接细胞病理学的测量（目标 2）。然后，目标 3 将利用离体研究来确定在发育暴露于氯胺酮后存活细胞群中 NMDA 受体介导的信号转导的细胞内机制的功能改变模式。意义：这三个平行的目标将解决青少年接触氯胺酮后存在的生理、解剖和生化功能神经可塑性的程度。因此，完成拟议的工作将为青春期和成年早期间歇性药物滥用的长期、可能不可逆转的后果提供有价值的证据。此外，这些研究将探讨早期药物滥用对以后一生认知和精神疾病的潜在作用。尽管氯胺酮（特殊 K）滥用在青少年中很常见，但这种行为的后果尚不清楚。为了解决这个问题，我们之前证明氯胺酮会导致成年小鼠大脑活动的短期变化和脑损伤的迹象。拟议的研究将确定青春期小鼠服用氯胺酮后脑功能异常的持续时间和脑损伤的程度，以评估青春期药物滥用造成持久、不可逆转后果的可能性。