Examining Mu Opioid Mechanisms of Ketamine's Rapid Effects in OCD

项目总结 强迫症(OCD)通常从儿童时期开始，导致终生疾病，以及 每年给经济造成21亿美元(直接成本)和62亿美元(间接成本，如生产力损失)的损失。 强迫症通常对5-羟色胺再摄取抑制剂(SRI)反应不足。此外，典型的SRI反应 只是部分的，被推迟了2-3个月。考虑到强迫症强加给数百万美国成年人的功能障碍， 探索SRI无应答者是否通过添加具有不同作用机制的药物来获得帮助 急需之物。新的数据支持氯胺酮在强迫症中快速和持续的抗强迫作用。我们 试图了解氯胺酮快速产生强迫症作用的机制，从而加快 开发更有效的强迫症药物。 出于几个原因，这项建议侧重于氯胺酮对Mu-阿片系统和强迫症的作用 神经回路。首先，我们之前的工作发现，u阿片受体拮抗剂纳曲酮可以阻断氯胺酮的作用。 急性、戏剧性的抗抑郁作用。其次，纳曲酮也会加重强迫症的症状，而吗啡(a 阿片受体激动剂)可减轻强迫症症状。第三，在严重的抑郁症中，试图发展跟随- 通过NMDA拮抗剂发挥作用的药物尚未成功。一种可能的解释是NMDA 拮抗作用可能不能完全解释氯胺酮快速持久的抗抑郁作用。为了评估神经 受Mu-阿片受体拮抗调节的靶点，我们关注额纹状体认知控制回路。 神经成像研究表明，它们直接受到类阿片系统的影响。事实上，Mu-阿片受体 分布于与强迫症相关的额纹状体环路。根据这一理论基础， 拟议的机械性试验将是第一次探索氯胺酮的阿片特性在调制中的作用 额-纹状体环路与强迫症的抗强迫效应。 我们将通过使用纳曲酮进行预治疗来测试阿片受体拮抗剂是否阻断 氯胺酮对控制和奖赏电路以及电路连接的影响。阿片系统的低成本标记物 需要能够预测反强迫症反应的参与。因此，我们将探索两个有希望的、低成本的-- 人类阿片系统参与的成本标记物。建议的项目结合了试验性的 药物和神经成像方法，为治疗学的变革开辟新的途径 精神治疗。

PROJECT SUMMARY Obsessive-compulsive disorder (OCD) typically starts in childhood, leads to lifelong morbidity, and costs the economy $2.1 billion (direct costs) and $6.2 billion (indirect costs such as lost productivity) annually. OCD often responds inadequately to serotonin reuptake inhibitors (SRIs). Moreover, the typical SRI response is only partial and is delayed by 2-3 months. Given the dysfunction OCD imposes on millions of U.S. adults, exploring whether SRI non-responders are helped by adding drugs with different mechanisms of action is urgently needed. Emerging data support ketamine’s rapid and sustained anti-obsessional effects in OCD. We seek to understand the mechanisms underlying ketamine’s rapid OCD effect and thereby to speed development of more effective agents for OCD. For several reasons, this proposal focuses on ketamine’s action on the mu-opioid system and OCD neural circuits. First, our prior work found that the mu-opioid receptor antagonist naltrexone blocks ketamine’s acute, dramatic antidepressant effects. Second, naltrexone also worsens OCD symptoms, while morphine (a mu-opioid receptor agonist) diminishes OCD symptoms. Third, in major depression, attempts to develop follow- on agents that work via NMDA antagonism have not been successful. One possible explanation is that NMDA antagonism may not fully explain ketamine’s rapid and enduring antidepressant effects. To assess the neural targets modulated by mu-opioid receptor antagonism, we focus on fronto-striatal cognitive control circuits which neuroimaging studies show are directly influenced by the mu-opioid system. Indeed, mu-opioid receptors are distributed throughout the fronto-striatal circuits associated with OCD. Drawing on this rationale, the proposed mechanistic trial would be the first to probe the role of ketamine’s opioid properties in modulating fronto-striatal circuitry and bringing about anti-obsessional effects in OCD. We will test, by administering pre-treatment with naltrexone, whether opioid receptor antagonism blocks ketamine’s effects on control and reward circuits and circuit connectivity. Low-cost markers of opioid system engagement that predict anti-obsessional response are needed. We will therefore explore two promising, low- cost markers of opioid system engagement in humans. The proposed projects combine experimental medication and neuroimaging approaches in order to open a new avenue for therapeutics to transform psychiatric treatments.