Rapid actions of ketamine in the prefrontal cortex

氯胺酮在前额皮质中的快速作用

基本信息

批准号：
9901576
负责人：
AMY F.T. ARNSTEN
金额：
$ 65.29万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-13 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9901576
关键词：
Accident and Emergency department Address Affect Affective Analgesics Anesthetics Anguish Animals Anterior Antidepressive Agents Area Attenuated Aversive Stimulus Behavioral Brain Brodmann&apos s area Clinical Clinical Data Clinical Research Cognition Cognitive Complement Computers Data Decision Making Deep Brain Stimulation Distant Dorsal Dose Drug Delivery Systems Event Future Hour Human Impaired cognition Inhalation Injections Intramuscular Intramuscular Injections Intranasal Administration Iontophoresis Ketamine Lateral Medial Mediating Mental Depression Methods Mood Disorders N-Methyl-D-Aspartate Receptors NMDA receptor antagonist NR2A NMDA receptor Neurons Olfactory Pathways Pain Patients Pattern Performance Pharmaceutical Preparations Physiological Play Prefrontal Cortex Psychological reinforcement Punishment Research Rewards Rodent Short-Term Memory Testing Vertebral column Visual Visuospatial antidepressant effect base behavior influence behavior measurement behavioral response cingulate cortex experimental study insight negative affect neural circuit neurophysiology nonhuman primate public health relevance reduce symptoms relating to nervous system resilience side effect treatment-resistant depression

项目摘要

DESCRIPTION (provided by applicant): The NMDA receptor (NMDAR) antagonist, ketamine, is currently in experimental use for the treatment of severe, intractable depression. Emerging clinical data indicate that intranasal ketamine administration can produce relief within minutes (5~40min), with fewer cognitive side effects than systemic ketamine injections. The proposed research will use a non-human primate paradigm to study the cellular and circuit mechanisms underlying the effects of intranasal vs. injected ketamine administration in prefrontal cortical (PFC) circuits immediately relevant to depression and cognition. We have observed persistent neuronal activity in medial PFC related to aversive events in a decision-making task, which may contribute to negative affective states and be abnormally heightened in depression. We will test the hypothesis that ketamine rapidly erodes the persistent representations of loss and punishment generated by medial prefrontal neurons, similar to ketamine's ability to erode persistent representations of visual space by dorsolateral prefrontal cortical (dlPFC) neurons. We hypothesize that the disruption of neural circuits representing loss may underlie the ultra-rapid effects of intranasal ketamine in patients (within minutes), while spinogenesis in higher order PFC regions may contribute to the more sustained anti-depressant actions (hours to days). As intranasal inhalation delivers drug directly to the brain through the holes in the cribiform plate, we further hypothesize that the medial PFC regions in the direct trajectory of intranasal ketamine may be more affected than the dlPFC neurons that are more distant. Such data would help to explain why intranasal administration has a more rapid onset with fewer cognitive side effects than ketamine injections. Aim 1 will compare the effects of intranasal vs. intramuscular administration of sub-anesthetic doses of ketamine on performance of the decision-making vs. spatial working memory tasks. We predict that ketamine will attenuate the effects of previous punishment on decision-making, allowing a more resilient behavioral response, and that intranasal administration will preferentially influence this behavior, while IM injections will have more global effects on performance in both tasks. Aim 2 will compare the effects of intranasal vs. intramuscular administration of ketamine on persistent neuronal firing in medial PFC regions relevant to depression (BA24, BA25 and dmPFC) compared to the dlPFC. We predict that ketamine will rapidly erode persistent representations of loss in medial PFC areas. We further hypothesize that intranasal administration will have more targeted effect on medial PFC neurons, while IM ketamine will alter neuronal firing in both medial and lateral PFC areas. Finally, Aim 3 will test whether the effects of ketamine are mediated by local actions in the medial PFC using iontophoretic application of ketamine and other more selective NMDAR NR2A vs. NR2B antagonists directly onto medial PFC neurons, similar to previous experiments in the dlPFC. The results from these experiments will provide important insights into the cellular and circuit mechanisms underlying the rapid anti-depressant effects of ketamine.

描述（申请人提供）：NMDA 受体（NMDAR）拮抗剂氯胺酮目前正在实验性地用于治疗严重、顽固性抑郁症，新出现的临床数据表明鼻内给药氯胺酮可以在几分钟（5~40 分钟）内产生缓解。与全身注射氯胺酮相比，认知副作用更少。拟议的研究将使用非人类灵长类动物范式来研究鼻内注射与注射的影响背后的细胞和回路机制。前额皮质（PFC）回路中的氯胺酮与抑郁和认知直接相关，我们观察到内侧 PFC 中与决策任务中的厌恶事件相关的持续神经元活动，这可能导致消极情感状态并导致抑郁症中的异常哮喘。我们将检验这样的假设：氯胺酮迅速侵蚀内侧前额叶神经元产生的损失和惩罚的持久表征，类似于氯胺酮侵蚀背外侧视觉空间的持久表征的能力我们发现，代表损失的神经回路的破坏可能是鼻内氯胺酮对患者产生超快速作用的原因（几分钟内），而高阶 PFC 区域的棘发生可能有助于更持久的抗抑郁作用。由于鼻内吸入药物通过筛板上的孔直接输送到大脑，我们进一步追踪鼻内直接轨迹中的内侧PFC区域。氯胺酮可能比更远的 dlPFC 神经元受到更大的影响，这些数据将有助于解释为什么鼻内给药比氯胺酮注射起效更快，认知副作用更少。目标 1 将比较鼻内注射与肌肉注射的效果。亚麻醉剂量的氯胺酮对决策与空间工作记忆任务表现的影响我们预测，氯胺酮会减弱先前惩罚对决策的影响，从而产生更有弹性的行为反应。鼻内给药将优先影响这种行为，而肌注注射将对这两项任务的表现产生更大的整体影响。目标 2 将比较鼻内与肌内注射氯胺酮对持续神经元放电的影响。与 dlPFC 相比，我们预测氯胺酮将迅速消除与抑郁相关的内侧 PFC 区域（BA24、BA25 和 dmPFC），我们进一步发现鼻内给药将对内侧 PFC 神经元产生更有针对性的影响。而肌肉注射氯胺酮会改变内侧和外侧 PFC 区域的神经元放电。最后，目标 3 将测试氯胺酮的作用是否是由局部介导的。使用氯胺酮和其他更具选择性的 NMDAR NR2A 与 NR2B 拮抗剂的离子电渗疗法直接作用于内侧 PFC 神经元，类似于先前在 dlPFC 中的实验，这些实验的结果将为了解潜在的细胞和回路机制提供重要的见解。氯胺酮的快速抗抑郁作用。