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存在许多局限性。一旦确定了正确的治疗药物，它仍然需要几周的时间才能起效并改善情绪。在处理有自杀念头的患者时，这一时间滞后一直是医疗界的严重关切。然而，最近的临床研究表明，一次小剂量注射N-甲基D-天冬氨酸受体(NMDAR)拮抗剂氯胺酮，具有快速的抗抑郁作用，在几个小时内就能观察到，并且持续很长时间，即使在对各种其他抗抑郁药物反应不佳的患者中也是如此。在临床前研究中，哺乳动物内侧前额叶皮质(MPFC)的雷帕霉素靶点(MTOR)和海马区的真核延长因子(EEF2)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，所有研究氯胺酮快速抗抑郁作用的研究都集中在男性受试者身上。鉴于严重抑郁症影响的女性人数是男性的两倍，这一点非常令人惊讶。因此，确定同样剂量的氯胺酮对男性受试者有益，是否对女性受试者也有效，这一点尤为重要。同样重要的是，确定氯胺酮对雌性大鼠的抗抑郁作用是否会涉及与雄性大鼠相同的分子通路(mTOR在mPFC和/或eF2在海马区)，并确定性腺激素，特别是17�-雌二醇(E2)及其受体(ER�和/或ER�)是否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)。我们的初步数据显示，与雄性大鼠相比，雌性大鼠对氯胺酮的抗抑郁作用更敏感；低剂量的氯胺酮(2.5 mg/kg)对雄性大鼠没有抗抑郁作用，但对雌性大鼠有明显的长期抗抑郁作用。令人兴奋的是，当雌性大鼠去卵巢时，这种低剂量的氯胺酮的抗抑郁作用完全消失。当补充E2苯甲酸酯(E2b)而不是孕酮(P4)时，这种作用被完全逆转，这表明E2在增强氯胺酮对雌性大鼠的抗抑郁作用方面起到了作用。因此，在这个应用中，我们将测试一般假设，性腺E2在氯胺酮的抗抑郁作用中扮演着性别差异的主要角色。

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.