Long-term neurobehavioral effects of ketamine exposure in adolescent mice

描述（由申请人提供）：这是继首席研究员的I期申请之后，第二份提交的II期前沿基础研究奖（CEBRA），题为小鼠的诱发电位和对氯胺酮的易感性（5-R21-DA-017082-02）。所有审稿人关注的问题都在修订后的申请中得到了充分解决。理由：滥用药物的实验在青少年和年轻人中很常见。虽然中毒的直接后果是已知的，但随意使用的普遍性质导致许多临床医生认为高中和大学期间轻度滥用药物是后来精神症状和综合征的原因。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（如氯胺酮）的持久后果尚不清楚。在本研究的第一阶段，PI显示成年小鼠慢性氯胺酮暴露后事件相关电位（ERPs）持续变化。初步数据和先前的文献也表明氯胺酮引起大脑细胞病理。将要解决的问题：这些发现导致以下两个首要问题：1)青春期间歇性暴露于NMDA受体拮抗剂是否会导致成人持续的生理和认知缺陷？青少年滥用氯胺酮是否会导致成人细胞成分和/或受体信号传导机制的持续改变？方法和方法：因此，拟议的研究将确定小鼠青春期氯胺酮暴露后持续ERP和认知缺陷的持续时间（目的1）。补充研究将通过免疫组化检测细胞特异性标记物，利用成年动物的体视学种群估计，确定氯胺酮选择性改变了哪些细胞类别。此外，我们将分析青春期氯胺酮暴露后直接的细胞病理学测量（目的2）。目的3将利用离体研究来确定发育暴露于氯胺酮后存活细胞群体中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：这三个平行的目的将探讨青春期氯胺酮暴露后存在的生理、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疾病中的潜在作用。虽然氯胺酮（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可能造成的持久、不可逆转的后果。

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.