Department of Psychiatry and Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, Missouri; Center for Brain Research in Mood Disorders, Washington University School of Medicine, St. Louis, Missouri.
Department of Medicine and Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri.
Biol Psychiatry. 2022 Dec 15;92(12):964-972. doi: 10.1016/j.biopsych.2022.06.016. Epub 2022 Jun 22.
Nitrous oxide (NO) is a noncompetitive inhibitor of NMDA receptors that appears to have ketamine-like rapid antidepressant effects in patients with treatment-resistant major depression. In preclinical studies, ketamine enhances glutamate-mediated synaptic transmission in the hippocampus and prefrontal cortex. In this study, we examined the effects of NO on glutamate transmission in the hippocampus and compared its effects to those of ketamine.
Glutamate-mediated synaptic transmission was studied in the CA1 region of hippocampal slices from adult albino rats using standard extracellular recording methods. Effects of NO and ketamine at subanesthetic concentrations were evaluated by acute administration.
Akin to 1 μM ketamine, 30% NO administered for 15-20 minutes resulted in persistent enhancement of synaptic responses mediated by both AMPA receptors and NMDA receptors. Synaptic enhancement by both NO and ketamine was blocked by co-administration of a competitive NMDA receptor antagonist at saturating concentration, but only ketamine was blocked by an AMPA receptor antagonist. Synaptic enhancement by both agents involved TrkB (tropomyosin receptor kinase B), mTOR (mechanistic target of rapamycin), and NOS (nitric oxide synthase) with some differences between NO and ketamine. NO potentiation occluded enhancement by ketamine, and in vivo NO exposure occluded further potentiation by both NO and ketamine.
These results indicate that NO has ketamine-like effects on hippocampal synaptic function at a subanesthetic, but therapeutically relevant concentration. These 2 rapid antidepressants have similar, but not identical mechanisms that result in persisting synaptic enhancement, possibly contributing to psychotropic actions.
一氧化二氮（NO）是非竞争性 NMDA 受体抑制剂，似乎对治疗抵抗性重度抑郁症患者具有类似氯胺酮的快速抗抑郁作用。在临床前研究中，氯胺酮增强了海马体和前额叶皮层中的谷氨酸能突触传递。在这项研究中，我们研究了 NO 对海马体中谷氨酸传递的影响，并将其与氯胺酮的作用进行了比较。
使用标准的细胞外记录方法研究成年白化大鼠海马切片中 CA1 区的谷氨酸能突触传递。通过急性给药评估亚麻醉浓度下的 NO 和氯胺酮的作用。
类似于 1 μM 氯胺酮，30%的 NO 给药 15-20 分钟可导致 AMPA 受体和 NMDA 受体介导的突触反应持续增强。NO 和氯胺酮均通过共给予饱和浓度的竞争性 NMDA 受体拮抗剂阻断了突触增强，但仅氯胺酮被 AMPA 受体拮抗剂阻断。两种药物的突触增强都涉及 TrkB（原肌球蛋白受体激酶 B）、mTOR（雷帕霉素的靶蛋白）和 NOS（一氧化氮合酶），NO 和氯胺酮之间存在一些差异。NO 增强会阻断氯胺酮的增强，体内 NO 暴露会阻断 NO 和氯胺酮的进一步增强。
这些结果表明，NO 在亚麻醉但治疗相关浓度下具有类似氯胺酮的海马体突触功能作用。这两种快速抗抑郁药具有相似但不完全相同的机制，导致持续的突触增强，可能有助于精神药物的作用。
