Sex Differences in Ketamine Antidepressant Effects

氯胺酮抗抑郁作用的性别差异

基本信息

批准号：
9247036
负责人：
MOHAMED KABBAJ
金额：
$ 38万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-21 至 2019-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9247036
关键词：
Acute Address Adult Affect Antidepressive Agents Behavior Behavioral Benzoates Biochemical Brain Chronic stress Clinical Research Data Diestrus Dose Elongation Factor Estradiol Estrogens Excitatory Postsynaptic Potentials FRAP1 gene Feeling suicidal Female Gonadal Hormones Hippocampus (Brain)Hour Injectable Injection of therapeutic agent Ketamine Knockout Mice Light Literature Major Depressive Disorder Measures Medial Mediating Mediator of activation protein Mental Depression Modeling Molecular Moods Morphology Mus N-Methyl-D-Aspartate Receptors Ovarian Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phase Physiological Play Prefrontal Cortex Proestrus Rattus Resistance Role Sex Characteristics Signal Pathway Signal Transduction Site Social isolation Synapses Testing Time Woman Women&apos s Group antidepressant effect behavior test cell cortex depressive symptoms healthcare community improved male men preclinical study public health relevance receptor response suicidal patient

项目摘要

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.

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，一旦确定了合适的治疗药物，仍需要几周的时间才能发挥作用并改善情绪，这种时间滞后是一个严重的问题。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。在临床前研究中，内侧前额皮质 (mPFC) 中的哺乳动物雷帕霉素靶点 (mTOR) 和真核延伸因子 (eEF2) 在数小时内即可观察到，并且效果持久，即使是对其他各种抗抑郁药物反应不佳的患者。）已被提议作为氯胺酮快速抗抑郁作用的关键介质，但迄今为止，所有研究氯胺酮快速抗抑郁作用的研究都集中在这一点上。这是非常令人惊讶的，因为重度抑郁症影响的女性人数是男性的两倍。因此，确定对男性受试者有益的相同剂量的氯胺酮是否对女性受试者也有效这一事实尤为重要。确定氯胺酮对雌性大鼠的抗抑郁作用是否与雄性大鼠中描述的分子途径相同（mPFC 中的 mTOR 和/或海马中的 eEF2）并确定性腺激素是否也具有同样重要的作用。特别是 17β-雌二醇 (E2) 及其受体（ERβ 和/或 ERβ）在这些效应中发挥作用（鉴于大量文献显示雌激素与 NMDAR 下游信号传导之间的相互作用）。初步数据表明，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，但具有明显且长期的作用。令人兴奋的是，当雌性大鼠切除卵巢后，补充苯甲酸 E2 (E2B)，但补充黄体酮 (P4) 后，这种低剂量氯胺酮的抗抑郁作用完全消失。 E2 在雌性大鼠中增强氯胺酮抗抑郁作用的作用因此，在本申请中，我们将测试性腺 E2 发挥作用的一般假设。氯胺酮抗抑郁作用中性别差异的主要作用。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chemogenetic selective manipulation of nucleus accumbens medium spiny neurons bidirectionally controls alcohol intake in male and female rats.

伏隔核中棘神经元的化学遗传学选择性操作双向控制雄性和雌性大鼠的酒精摄入量。

DOI：
发表时间：
2020
期刊：
影响因子：
4.6
作者：
Strong, C E;Hagarty, D P;Brea Guerrero, A;Schoepfer, K J;Cajuste, S M;Kabbaj, M
通讯作者：
Kabbaj, M

Sex differences and effects of the estrous stage on hippocampal-prefrontal theta communications.

性别差异和发情阶段对海马-前额叶θ通讯的影响。

DOI：
发表时间：
2020-11
期刊：
影响因子：
2.5
作者：
Schoepfer, Kristin J;Xu, Yiqi;Wilber, Aaron A;Wu, Wei;Kabbaj, Mohamed
通讯作者：
Kabbaj, Mohamed

On the safety of repeated ketamine infusions for the treatment of depression: Effects of sex and developmental periods.

关于重复氯胺酮输注治疗抑郁症的安全性：性别和发育期的影响。

DOI：
发表时间：
2018-11
期刊：
影响因子：
0
作者：
Strong, C E;Kabbaj, Mohamed
通讯作者：
Kabbaj, Mohamed

Sex-Dependent Ketamine Addiction-Like Behavior Profile Following Exposure to Chronic Mild Stress.

暴露于慢性轻度压力后的性别依赖性氯胺酮成瘾样行为特征。

DOI：
发表时间：
2019-01
期刊：
影响因子：
0
作者：
Wright, Katherine N;Hagarty, Devin P;Strong, Caroline E;Schoepfer, Kristin J;Kabbaj, Mohamed
通讯作者：
Kabbaj, Mohamed

Sex- and dose-dependent abuse liability of repeated subanesthetic ketamine in rats.

大鼠重复亚麻醉氯胺酮的性别和剂量依赖性滥用倾向。

DOI：
发表时间：
2019-05-01
期刊：
影响因子：
2.9
作者：
Schoepfer, Kristin J;Strong, Caroline E;Saland, Samantha K;Wright, Katherine N;Kabbaj, Mohamed
通讯作者：
Kabbaj, Mohamed