NMDA RECEPTOR ANTAGONIST NITROUS OXIDE TARGETS AFFECTIVE BRAIN CIRCUITS

摘要 严重抑郁障碍(MDD)是最常见的精神障碍之一，也是 残疾。据估计，MDD影响了大约1600万美国人。尽管大多数MDD患者对 治疗(心理治疗/药物治疗)，很大一部分(约25%-30%)没有，被称为有 “难治性重度抑郁症”(TRMD)。TRMD给道达尔带来了不成比例的沉重负担 自杀造成的MDD成本、个人财务成本、失业和医疗合并症；因此， 开发针对TRMD的新疗法与国家精神卫生研究所的 (NIMH)通过研究减轻精神疾病负担的使命。大多数现有的抗抑郁药 药物的靶点(通过神经递质受体)在许多年前就确定了。由于高 针对新大脑的新疗法TRMD的流行率和缺乏足够的反应 如果我们要成功地治疗TRMD，区域/神经递质系统是必不可少的。 一种有希望的新型TRMD治疗靶向N-甲基-D-天冬氨酸谷氨酸受体 (NMDAR)。在过去的10年里，许多TRMD患者对NMDAR拮抗剂氯胺酮有反应。 氯胺酮研究正在进行中；然而，它有几个局限性，包括认知问题、高度滥用/ 上瘾的可能性，以及可能的精神诱因。最近，我们小组展示了另一种NMDAR 拮抗剂一氧化二氮(“笑气”)是一种有效的、耐受性良好的快速起效抗抑郁剂。 TRMD。然而，这一潜在的重大发现目前缺乏机械性的理解。 在进行新药物/治疗的大规模临床疗效试验之前，NIMH建议 科学家首先确定该制剂如何产生作用；也就是说，有必要定义一个“生物靶标”。 对治疗的影响。这项目前的提案使用最先进的大脑成像技术，迈出了 了解一氧化二氮如何调节大脑功能。使用功能连接磁力 磁共振成像(FcMRI)，最近的研究表明，人类的某些网络/区域 在MDD中，大脑增加了他们的交流(即“连接”)。研究还表明，抗抑郁剂 治疗会减弱这种增加的连通性。本研究建议使用fcMRI来研究即刻(2 一氧化二氮对特定大脑网络/区域的持续(24小时)影响(默认 模式、情感和认知控制网络以及背侧前额叶神经节、杏仁核和 海马体)被认为是MDD的关键。非抑郁症和TRMD受试者将接受fcMRI扫描 在吸入一氧化二氮或安慰剂之前，以及吸入一小时后的2小时和24小时。我们会 比较这两次暴露如何立即(2小时；目标1)和24小时影响这些网络/区域 吸入亚氮后数小时(目标2)，以及这些变化在队列之间的差异。研究结果将为 未来的研究将探索一氧化二氮如何影响TRMD的大脑。

Abstract Major depressive disorder (MDD) is one of the most common psychiatric disorders and a leading cause of disability. MDD is estimated to affect about 16 million Americans. Although most MDD patients respond to treatments (psychotherapy/medication), a significant subset (~25-30%) does not and is referred to as having “treatment-resistant major depression” (TRMD). TRMD places a disproportionately heavy burden on total MDD costs from suicide, personal financial costs, loss of work, and medical comorbidity; hence, developing new treatments to target TRMD is consistent with the National Institute of Mental Health’s (NIMH) mission of reducing the burden of mental illness through research. Most existing antidepressant medications target (via neurotransmitter receptor) sites in the brain identified many years ago. Due to high prevalence and lack of adequate response in TRMD, new treatments which target novel brain regions/neurotransmitter systems are imperative if we are to successfully treat TRMD. One promising new class of TRMD treatments targets the N-methyl-D-aspartate glutamate receptor (NMDAR). In the past 10 years, many TRMD patients have responded to the NMDAR antagonist ketamine. Ketamine studies are ongoing; however, it has several limitations including cognition problems, high abuse/ addiction potential, and possible psychotic induction. Recently, our group demonstrated that another NMDAR antagonist nitrous oxide (“laughing gas”) is an effective and well-tolerated rapidly acting antidepressant in TRMD. This potentially significant finding is, however, currently lacking mechanistic understanding. Before conducting a large scale clinical efficacy trial of a new agent/treatment, NIMH recommends that scientists first determine how the agent produces an effect; that is, it is necessary to define a “biological target” of the treatment. This current proposal uses state-of-the-art brain imaging to take the first step in understanding how nitrous oxide modulates brain function. Using functional connectivity magnetic resonance imaging (fcMRI), recent studies have demonstrated that certain networks/regions of the human brain increase their communications (i.e., “connectivity”) in MDD. Studies also demonstrate that antidepressant treatments attenuate this increased connectivity. This study proposes to use fcMRI to study immediate (2 hours) and sustained (24 hours) effects of nitrous oxide on specific brain networks/regions (the default mode, affective, and cognitive control networks and dorsal pre-frontal nexus, amygdala, and hippocampus) identified as critical in MDD. Nondepressed and TRMD subjects will undergo fcMRI scans immediately before, and 2 and 24 hours after one hour inhalations of either nitrous oxide or a placebo. We will compare how these two exposures influence these networks/regions immediately (2 hours; Aim 1), and 24 hours after nitrous inhalation (Aim 2), and how these changes differ between cohorts. Study findings will inform future studies exploring how nitrous oxide affects the TRMD brain.