Rapid actions of ketamine in the prefrontal cortex

氯胺酮在前额皮质中的快速作用

• 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
• 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' 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

 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（由申请人提供）：NMDA受体（NMDAR）拮抗剂氯胺酮目前正用于治疗重度难治性抑郁症的实验性用途。新的临床数据表明，氯胺酮鼻内给药可在数分钟内（5~40分钟）缓解，认知副作用比全身注射氯胺酮少。拟议的研究将使用非人类灵长类动物范例来研究鼻内与注射氯胺酮给药在与抑郁和认知直接相关的前额叶皮层（PFC）回路中的影响的细胞和回路机制。我们已经观察到持续的神经元活动在内侧PFC相关的厌恶事件的决策任务，这可能有助于消极的情感状态，并异常升高抑郁症。我们将测试的假设，氯胺酮迅速侵蚀的持久性表示的损失和惩罚产生的内侧前额叶神经元，类似于氯胺酮的能力，侵蚀持久性表示的视觉空间的背外侧前额叶皮层（dlPFC）神经元。我们假设，代表损失的神经回路的中断可能是鼻内氯胺酮在患者中的超快速作用（几分钟内）的基础，而高阶PFC区域的棘生可能有助于更持续的抗癫痫作用（数小时至数天）。由于鼻内吸入通过筛状板中的孔将药物直接递送至大脑，我们进一步假设鼻内氯胺酮的直接轨迹中的内侧PFC区域可能比更远的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。目的1将比较亚麻醉剂量氯胺酮鼻内与肌内给药对决策与空间工作记忆任务表现的影响。我们预测，氯胺酮将减弱先前的惩罚对决策的影响，允许更有弹性的行为反应，鼻内给药将优先影响这种行为，而IM注射将对这两项任务的表现产生更多的全球影响。目的2将比较鼻内与肌肉注射氯胺酮对持续性神经元放电的影响， 与dlPFC相比，与抑郁相关的内侧PFC区域（BA24，BA25和dmPFC）。我们预测，氯胺酮将迅速侵蚀内侧PFC区域的持续性损失。我们进一步假设，鼻内给药将对内侧PFC神经元产生更多的靶向作用，而IM氯胺酮将改变内侧和外侧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由内侧PFC中的局部作用介导，使用氯胺酮和其他更具选择性的NMDAR NR2A与NR2B拮抗剂直接离子电渗应用于内侧PFC神经元，类似于先前在dlPFC中的实验。这些实验的结果将提供重要的见解氯胺酮的快速抗癫痫作用的细胞和电路机制。