Long-term neurobehavioral effects of ketamine exposure in adolescent mice

描述(由申请人提供)：这是第二期尖端基础研究奖(CEBRA)的第二次提交，该奖项遵循首席研究员的第一阶段申请，题为《老鼠的诱发电位和对氯胺酮的脆弱性》(5-R21-DA-017082-02)。在这份修订的申请中，审查员的所有关切都得到了充分的解决。理由：滥用药物的实验在青少年和年轻人中很常见。尽管醉酒的直接后果是已知的，但随处可见的随意使用的性质导致许多临床医生认为，在高中和大学期间轻微的药物滥用会导致后来的精神症状和综合征。尽管有这样的假设，但全国各地出现在校园和俱乐部的毒品，如氯胺酮，其持久后果尚不清楚。在这项研究的第一阶段，PI显示了慢性氯胺酮暴露后成年小鼠事件相关电位(ERPs)的持续变化。初步数据和以前的文献也表明，氯胺酮会导致脑细胞病变。将解决的问题：这些发现导致以下两个主要问题：1)青春期间歇性暴露于NMDA受体拮抗剂是否会导致成年人持续的生理和认知障碍？2)青少年滥用氯胺酮是否会导致成年人细胞成分和/或受体信号机制的持续变化？方法和方法：因此，建议的研究将确定在小鼠青春期暴露氯胺酮后持续的事件相关电位和认知障碍的持续时间(目标1)。补充研究将确定氯胺酮选择性地改变了哪些细胞类别，在细胞特异性标记的免疫组织化学之后，使用成年动物的体视学种群估计。此外，我们将分析在青春期直接接触氯胺酮后立即发生的细胞病理学指标(目标2)。然后，AIM 3将利用体外研究来确定发育过程中暴露于氯胺酮后存活细胞群体中NMDA受体介导的信号转导机制的功能变化模式。意义：这三个平行的目标将解决在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，拟议工作的完成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宝贵的证据。此外，这些研究将探讨早期药物滥用在后来的认知和精神障碍中的潜在作用。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，我们之前证明了氯胺酮会导致成年小鼠大脑活动和脑损伤迹象的短期变化。拟议的研究将确定氯胺酮对青春期小鼠大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的、不可逆转的后果的可能性。

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.