Department of Biomedical Sciences, Program in Neurosciences, College of Medicine, Florida State University, 1115 W Call Street, Tallahassee, FL 32306, United States.
Neuropharmacology. 2013 Jul;70:27-34. doi: 10.1016/j.neuropharm.2012.12.009. Epub 2013 Jan 19.
Current medications for major depression suffer from numerous limitations. Once the right drug for treatment has been determined, it still takes several weeks for it to take effect and improve mood. This time lag is a serious concern for the healthcare community when dealing with patients with suicidal thoughts. However, recent clinical studies have shown that a single low-dose injection of ketamine, an N-methyl D-aspartate receptor (NMDAR) antagonist, has rapid antidepressant effects that are observed within hours and are long lasting. Although major depression affects twice as many women as men, all studies examining the rapid antidepressant effects of ketamine have focused on male subjects. Thus, we have investigated the behavioral and molecular effects of ketamine in both male and female rats and demonstrated greater sensitivity in female rats at a low dose of ketamine, a dose does not have antidepressant-like effects in male rats. The antidepressant-like effects of this low dose of ketamine were completely abolished when female rats were ovariectomized (OVX), and restored when physiological levels of estrogen and progesterone were supplemented, suggesting a critical role for gonadal hormones in enhancing the antidepressant-like effects of ketamine in female rats. In preclinical studies, the mammalian target of rapamycin (mTOR) in the medial prefrontal cortex and the eukaryotic elongation factor (eEF2) in the hippocampus have been proposed as critical mediators of ketamine's rapid antidepressant actions. In our hands, the increased sensitivity of female rats to a low dose of ketamine was not mediated through phosphorylation of mTOR or eEF2.
目前用于重度抑郁症的药物存在诸多局限性。一旦确定了治疗的正确药物，它仍然需要数周的时间才能生效并改善情绪。当涉及到有自杀念头的患者时，这种滞后时间是医疗保健界的一个严重问题。然而，最近的临床研究表明，单次低剂量注射氯胺酮（一种 N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂）具有快速抗抑郁作用，可在数小时内观察到，并具有持久的效果。尽管重度抑郁症影响的女性是男性的两倍，但所有研究都集中在男性研究对象上，研究氯胺酮的快速抗抑郁作用。因此，我们研究了氯胺酮对雄性和雌性大鼠的行为和分子影响，并证明了低剂量氯胺酮对雌性大鼠的敏感性更高，而这种剂量对雄性大鼠没有抗抑郁样作用。当雌性大鼠接受卵巢切除术（OVX）时，这种低剂量氯胺酮的抗抑郁样作用完全被消除，当补充生理水平的雌激素和孕激素时，这种作用得到恢复，这表明性腺激素在增强雌性大鼠对氯胺酮的抗抑郁样作用方面起着关键作用。在临床前研究中，哺乳动物雷帕霉素靶蛋白（mTOR）在前额叶皮质的中脑和真核伸长因子（eEF2）在海马中被提出作为氯胺酮快速抗抑郁作用的关键介质。在我们的研究中，低剂量氯胺酮对雌性大鼠的敏感性增加并不是通过 mTOR 或 eEF2 的磷酸化介导的。
