Sex Differences in Ketamine Antidepressant Effects

描述（由申请人提供）：目前治疗重度抑郁症的药物有许多局限性。一旦确定了正确的治疗药物，它仍然需要几个星期才能生效并改善情绪。在处理有自杀想法的患者时，这种时间滞后一直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）具有快速的抗抑郁作用，可在数小时内观察到，并且持续时间长，即使在对各种其他抗抑郁药反应不佳的患者中也是如此。在临床前研究中，内侧前额叶皮质（mPFC）中的哺乳动物雷帕霉素靶蛋白（mTOR）和海马中的真核细胞延伸因子（eEF 2）已被认为是氯胺酮快速抗抑郁作用的关键介质。然而，到目前为止，所有研究氯胺酮的快速抗抑郁作用的研究都集中在男性受试者身上。这是非常令人惊讶的，因为严重抑郁症影响的女性是男性的两倍。因此，确定在男性受试者中有益的相同剂量的氯胺酮是否在女性受试者中也有效尤为重要。阿索重要的是确定氯胺酮在雌性大鼠中的抗抑郁作用是否涉及在雄性大鼠中描述的相同分子途径（mPFC中的mTOR和/或海马中的eEF 2）并确定性腺激素，特别是17 β-雌二醇（E2）及其受体（ER β和/或ER β）在这些效应中发挥作用（鉴于大量文献显示雌激素与NMDAR下游信号之间的相互作用）。我们的初步数据表明，与雄性大鼠相比，雌性大鼠对氯胺酮抗抑郁作用更敏感;低剂量氯胺酮（2.5 mg/kg）在雄性中不具有抗抑郁作用，但在雌性大鼠中具有明确的长期抗抑郁作用。令人兴奋的是，当雌性大鼠卵巢切除后，这种低剂量氯胺酮的抗抑郁作用完全消失。当补充E2苯甲酸盐（E2 B）而不是孕酮（P4）时，这种作用完全逆转，表明E2在增强氯胺酮在雌性大鼠中的抗抑郁作用方面的作用。因此，在本申请中，我们将测试性腺E2在氯胺酮抗抑郁作用的性别差异中起主要作用的一般假设。

DESCRIPTION (provided by applicant): Current medications for major depression suffer from numerous limitations. Once the right drug for treatment has been determined, it will still take several weeks for it to take effect and improve mood. This time lag has been 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, even in patients who do not respond well to various other anti-depressants. In preclinical studies, the mammalian target of rapamycin (mTOR) in the medial prefrontal cortex (mPFC) and the eukaryotic elongation factor (eEF2) in the hippocampus have been proposed as critical mediators of ketamine rapid antidepressant actions. However, so far, all studies examining the rapid antidepressant effects of ketamine have focused on male subjects. This is very surprising in light of the fact that major depression affects twice as many women as men. Thus, it is especially important to determine whether the same doses of ketamine that are beneficial in male subjects will be efficient in female subjects as well. It is aso important to determine whether the antidepressant effects of ketamine in female rats will implicate the same molecular pathways described in male rats (mTOR in the mPFC and/or eEF2 in the hippocampus) and determine if gonadal hormones, and in particular 17 � -estradiol (E2) and its receptors (ER� and/or ER�), play a role in these effects (in view of the large literature showing interactions between estrogen and the downstream signaling of the NMDAR). Our preliminary data showed that female rats are more sensitive to ketamine antidepressant effects when compared to male rats; a low dose of ketamine (2.5 mg/kg), that is not antidepressant in males, had clear and long-term antidepressant effects in female rats. Excitedly, the antidepressant effects of this low dose of ketamine were completely abolished when female rats were ovariectomized. This effect was completely reversed when E2 benzoate (E2B) -but not progesterone (P4) - was supplemented, suggesting a role for E2 at enhancing the antidepressant effects of ketamine in female rats. Accordingly, in this application we will tes the general hypothesis that gonadal E2 plays a major role in sex differences in the antidepressant effects of ketamine.