Martin Anna E, Schober Douglas A, Nikolayev Alexander, Tolstikov Vladimir V, Anderson Wesley H, Higgs Richard E, Kuo Ming-Shang, Laksmanan Anastasia, Catlow John T, Li Xia, Felder Christian C, Witkin Jeffrey M
Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, United States.
Neuroscience Discovery Research, Lilly Research Labs, Lilly Corporate Center, Indianapolis, IN 46285-0510, United States.
CNS Neurol Disord Drug Targets. 2017;16(4):492-500. doi: 10.2174/1871527316666170309142646.
Conventional antidepressants lack efficacy for many patients (treatmentresistant depression or TRD) and generally take weeks to produce full therapeutic response in others. Emerging data has identified certain drugs such as ketamine as rapidly-acting antidepressants for major depressive disorder and TRD. Scopolamine, a drug used to treat motion sickness and nausea, has also been demonstrated to function as a rapidly-acting antidepressant. The mechanisms associated with efficacy in TRD patients and rapid onset of action have been suggested to involve a-Amino-3-hydroxy- 5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mammalian target of rapamycin (mTOR) signaling. Since the work on these mechanisms with scopolamine has been limited, the present set of experiments was designed to further explore these mechanisms of action.
Male, NIH Swiss mice demonstrated a robust and immediate antidepressant signature with ketamine or scopolamine when studied under the forced-swim test.
The AMPA receptor antagonist NBQX prevented this antidepressant-like effect of scopolamine and ketamine. An orally-bioavilable mTOR inhibitor (AZD8055) also attenuated the antidepressant- like effects of scopolamine and ketamine. Scopolamine was also shown to augment the antidepressant- like effect of the selective serotonin reuptake inhibitor citalopram. When given in combination, scopolamine and ketamine acted synergistically to produce antidepressant-like effects. Although drug interaction data suggested that additional mechanisms might be at play, metabolomic analysis of frontal cortex and plasma from muscarinic M1+/+ and M1 -/- mice given scopolamine or vehicle did not reveal any hints as to the nature of these additional mechanisms of action.
Overall, the data substantiate and extend the idea that AMPA and mTOR signaling pathways are necessary for the antidepressant-like effects of scopolamine and ketamine, mechanisms that appear to be of general significance for TRD therapeutic agents.
传统抗抑郁药对许多患者（难治性抑郁症或TRD）缺乏疗效，并且在其他患者中通常需要数周才能产生完全的治疗反应。新出现的数据已确定某些药物，如氯胺酮，是用于治疗重度抑郁症和TRD的速效抗抑郁药。东莨菪碱是一种用于治疗晕动病和恶心的药物，也已被证明可作为速效抗抑郁药发挥作用。已表明与TRD患者疗效和快速起效相关的机制涉及α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体和雷帕霉素的哺乳动物靶标（mTOR）信号传导。由于关于东莨菪碱这些机制的研究工作有限，因此设计了本系列实验以进一步探索这些作用机制。
在强迫游泳试验中研究时，雄性NIH瑞士小鼠对氯胺酮或东莨菪碱表现出强烈且即时的抗抑郁特征。
AMPA受体拮抗剂NBQX可预防东莨菪碱和氯胺酮的这种类抗抑郁作用。一种口服生物可利用的mTOR抑制剂（AZD8055）也减弱了东莨菪碱和氯胺酮的类抗抑郁作用。东莨菪碱还显示出增强选择性5-羟色胺再摄取抑制剂西酞普兰的类抗抑郁作用。当联合使用时，东莨菪碱和氯胺酮协同作用产生类抗抑郁作用。尽管药物相互作用数据表明可能还有其他机制在起作用，但对给予东莨菪碱或赋形剂的毒蕈碱M1 +/+和M1 -/-小鼠的额叶皮质和血浆进行代谢组学分析，并未揭示这些额外作用机制的性质的任何线索。
总体而言，数据证实并扩展了以下观点，即AMPA和mTOR信号通路对于东莨菪碱和氯胺酮的类抗抑郁作用是必需的，这些机制似乎对TRD治疗药物具有普遍意义。
