Hydroxynorketamine for the Treatment of PTSD and Anhedonia

压力后有害的精神病后果困扰着许多最近部署的战斗退伍军人。 最近的证据表明，低剂量的麻醉剂氯胺酮迅速改善抑郁症， 创伤后应激障碍（PTSD）、快感缺乏（体验快乐的能力降低）和自杀倾向 在单次给药后数小时内。这些影响延伸到耐药人群， 暗示氯胺酮是治疗精神疾病的一种新颖独特的药理学选择， 不成比例地影响我们的战斗退伍军人。尽管有这些有希望的结果，氯胺酮的使用作为治疗 在医院或诊所环境之外，由于其即使在低浓度下也能产生分离效应， 剂量和滥用责任。 氯胺酮的麻醉作用可能通过抑制NMDA谷氨酸受体介导 （NMDAR），因此，所有药物的精神影响（包括负面和治疗）， 假设具有类似的潜在作用机制。氯胺酮会迅速代谢成多种 代谢物，包括作为NMDAR的弱得多的有效抑制剂的羟基去甲氯胺酮（HNK）。我们 最近证实（Nature，2016），（2 R，6 R）-HNK代谢物在体内发挥与氯胺酮相同的作用， 临床前试验预测快速和持续的抗抑郁疗效。重要的是，我们发现， 非常高剂量的（2 R，6 R）-HNK缺乏麻醉和解离作用，以及临床前滥用倾向。 试验.我们的目标是开发一种改进的干预措施，用于治疗退伍军人的压力相关疾病， 因为我们知道氯胺酮的相关药理作用 我们的初步数据表明，（2 R，6 R）-HNK代谢产物，是在人体内产生的， 氯胺酮管理，可能是一个理想的治疗创伤后应激障碍和快感缺乏折磨退伍军人暴露于 应力在具体目标#1中，我们将定义氯胺酮与（2 R，6 R）-HNK在小鼠试验中的作用， PTSD领域包括条件性恐惧反应和恐惧消退，通过声学测量的过度觉醒 惊吓反应和脑电图睡眠异常，无论是在控制条件下， 应力我们将测试症状前和症状后给药的效果，预测（2 R，6 R）-HNK将是有效的。 对不同结构域/内表型发挥氯胺酮治疗作用的必要性和充分性 与创伤后应激障碍有关在具体目标#2中，我们将确定氯胺酮及其（2 R，6 R）-HNK的作用 代谢物对快感缺乏的完成性、预期性和动机性亚型的影响， 快感缺失是PTSD患者的一种症状，抑郁症，精神分裂症， 帕金森氏症和老年痴呆症。 我们预期（2 R，6 R）-HNK将在几个重要的实验测量中被证明是有效的，并且 该项目的成功完成将为（2 R，6 R）-HNK提供所需的临床前证据， 作为创伤后应激障碍和快感缺乏症的临床治疗的评估。这项工作可能会有一个 鉴于（2 R，6 R）-HNK目前正在开发治疗抑郁症的药物，因此我们认为 完成拟议的实验将提供一个坚实的基础，从一流的 治疗可以提供给我们的退伍军人谁是不成比例的创伤后应激障碍的影响， 快感缺乏

Deleterious psychiatric outcomes following stress afflict many recently deployed combat Veterans. Recent evidence has shown that low doses of the anesthetic ketamine rapidly ameliorate depression, posttraumatic stress disorder (PTSD), anhedonia (a reduced capacity to experience pleasure), and suicidality within hours following a single administration. These effects extend to treatment-resistant populations, implicating ketamine as a novel and unique pharmacological option for treating psychiatric illnesses that disproportionately impact our combat Veterans. Despite these promising results, ketamine's use as a treatment outside of a hospital or clinic setting is limited due to its capacity to produce dissociative effects even at low doses and abuse liability. Ketamine's anesthetic effects are likely mediated by inhibition of the NMDA glutamate receptor (NMDAR) and as a consequence all of the drug's psychiatric effects (both negative and therapeutic), were assumed to have a similar underlying mechanism of action. Ketamine is rapidly metabolized into a number of metabolites, including hydroxynorketamines (HNKs) that are much less potent inhibitors of the NMDAR. We recently demonstrated (Nature, 2016) that the (2R,6R)-HNK metabolite exerts actions identical to ketamine in preclinical tests predictive of rapid and sustained antidepressant efficacy. Of significance, we found that even very high doses of (2R,6R)-HNK lack anesthetic and dissociative effects, as well as abuse liability in preclinical tests. Our goal is to develop an improved intervention for the treatment of stress-related disorders in Veterans, given what we know of ketamine's relevant pharmacological actions. Our preliminary data indicates that the (2R,6R)-HNK metabolite that is produced in humans after ketamine administration, may be an ideal treatment for PTSD and anhedonia afflicting Veterans exposed to stress. In Specific Aim #1, we will define the actions of ketamine compared to (2R,6R)-HNK in mouse tests of PTSD domains including conditioned fear responses and fear extinction, hyperarousal measured by acoustic startle responses, and electroencephalogram sleep abnormalities, both under control conditions and following stress. We will test effects of both pre- and post- symptom administration, predicting that (2R,6R)-HNK will be necessary and sufficient to exert the therapeutic effects of ketamine on different domains/endophenotypes associated with PTSD. In Specific Aim #2, we will determine actions of ketamine and its (2R,6R)-HNK metabolite on consummatory, anticipatory, and motivational subtypes of anhedonia, which has relevance to anhedonia observed as a symptom in patients with PTSD; as well as those with depression, schizophrenia, Parkinson's, and Alzheimer's disease. We anticipate that (2R,6R)-HNK will prove efficacious in several important experimental measures, and that successful completion of the project will provide the preclinical evidence that is needed for (2R,6R)-HNK to move forward in assessment as a clinical treatment for PTSD and anhedonia. This work could have an immediate impact, given that (2R,6R)-HNK is currently in drug development for depression. Thus, we believe that completion of the proposed experiments will provide a strong foundation from which a first-in-class treatment could be made available for our Veterans who are disproportionately affected by PTSD and anhedonia.