Therapeutic Efficacy of Ketamine Metabolites for Depression Treatment

摘要 世界上约16%的人口患有严重抑郁障碍(MDD)。尽管有几个类可用 以及各种类型的抗抑郁药物，患者通常需要几周甚至几个月的时间才能对这些药物产生反应 大多数人的症状从未得到持续缓解。这是一个了不起的发展 MDD的药物治疗是发现非竞争性N-甲基-D-天冬氨酸受体 (NMDAR)拮抗剂氯胺酮是治疗难治性患者的一种有效、快速起效的抗抑郁药。 在我们之前的资助周期中，我们开始探索氯胺酮的代谢物在治疗 以及氯胺酮的不良反应。我们确定了(2R，6R)-的行为、突触和神经化学效应- 羟基去甲氯胺酮(HNK)代谢物。与氯胺酮相比，(2R，6R)-HNK对NMDAR的亲和力较低， 这与临床前研究中测量的其减少的不良反应是一致的。我们还发现， (2R，6R)-HNK通过一种浓度- 依赖NMDAR活性的谷氨酸释放几率增加。我们的长期目标是 阐明(2R，6R)-HNK的生物活性，以及氯胺酮的另外11种HNK代谢物，以及 利用我们的发现开发新的、有效的化合物来治疗抑郁症。中心假说 HNKs对突触前可塑性施加一种急性的、突触选择性的形式，从而导致持续的 加强与情绪相关的神经回路。在特定的目标#1中，我们将使用切片电生理来解决 (2R，6R)-HNK的突触作用，并明确(2R，6R)-HNK的突触作用机制(S) 突触释放谷氨酸的概率。我们假设(2R，6R)-HNK通过突触前阵营- 脑源性神经营养因子依赖促进谷氨酸释放的机制。在特定的目标2中，我们将使用体内纤维 比色法测定(2R，6R)-HNK对海马神经元活性的影响 回路，特别是海马区CA1区的Schaffer侧支突触。这些实验 将决定(2R，6R)-HNK在完整回路中的突触活动。最后，在特定目标#3中，我们将在体外定义 在体内，通过氯胺酮代谢产生的所有12个HNK的相对突触和行为能力。 这些实验将在突触功能水平上定义结构-活性关系，这将使我们能够 提纯HNKs的结构，以优化其抗抑郁和药代动力学活性。总的来说， 到目前为止，我们的工作强烈地暗示了药物对突触前可塑性的直接影响，当 这种作用的机制被阐明，将为新型抗抑郁药物的发现开辟新的途径 基于这一机制。我们建议的实验的完成将对 了解速效抗抑郁药的药理作用，开发新的创新药物 治疗，以及未来抑郁症的治疗。

SUMMARY Major depressive disorder (MDD) afflicts ~16% of the world population. Despite the availability of several classes and types of antidepressant medications, patients typically take many weeks, if not months, to respond to these drugs, and the majority never attain sustained remission of their symptoms. A remarkable development for the pharmacological treatment of MDD is the finding that the non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, ketamine, is an effective, rapidly acting antidepressant in treatment-refractory patients. During our previous funding cycle, we began exploring the role of ketamine’s metabolites in both the therapeutic and adverse effects of ketamine. We identified behavioral, synaptic, and neurochemical effects of the (2R,6R)- hydroxynorketamine (HNK) metabolite. In contrast to ketamine, (2R,6R)-HNK has low affinity for the NMDAR, which is consistent with its reduced adverse effects as measured in preclinical studies. We have also found that (2R,6R)-HNK enhances excitatory synaptic transmission in the hippocampus through a concentration- dependent, NMDAR activity-independent increase in glutamate release probability. Our long-term goal is to elucidate the biological activities of (2R,6R)-HNK, as well as ketamine’s eleven additional HNK metabolites, and utilize our findings to develop novel, effective compounds for the treatment of depression. The central hypothesis is that HNKs exert an acute, synapse-selective form of presynaptic plasticity that leads to a sustained strengthening of mood-relevant circuits. In Specific Aim #1 we will use slice electrophysiology to resolve the synaptic actions of (2R,6R)-HNK, and identify the mechanism(s) by which (2R,6R)-HNK acutely enhances the probability of synaptic glutamate release. We hypothesize that (2R,6R)-HNK acts through a presynaptic cAMP- BDNF-dependent mechanism to promote glutamate release. In Specific Aim #2 we will use in vivo fiber photometry assessments of neuronal activity to determine the synaptic effects of (2R,6R)-HNK on hippocampal circuitry, specifically the Schaffer collateral synapses in the CA1 region of the hippocampus. These experiments will determine (2R,6R)-HNK’s synaptic action in an intact circuit. Finally, in Specific Aim #3 we will define, in vitro and in vivo, the relative synaptic and behavioral potencies for all 12 HNKs produced via ketamine metabolism. These experiments will define structure-activity relationships at the level of synaptic function, which will allow us to refine the structure of the HNKs, in order to optimize their antidepressant and pharmacokinetic activity. Overall, our work thus far strongly implicates an immediate drug effect on presynaptic plasticity, which when the mechanism underlying this action is clarified, will open up new avenues for novel antidepressant drug discovery based upon this mechanism. The completion of our proposed experiments will have implications for the understanding of rapid-acting antidepressant drug pharmacology, development of novel and innovative therapies, and the future treatment of depression.