Behavioral and biochemical sensitivity to low doses of ketamine: Influence of estrous cycle in C57BL/6 mice.
Behavioral and biochemical sensitivity to low doses of ketamine: Influence of estrous cycle in C57BL/6 mice.
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DOI：
10.1016/j.neuropharm.2017.11.022
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发表时间：
2018-03-01
影响因子：
4.7
通讯作者：
Kabbaj M
中科院分区：
文献类型：
--
作者：
Dossat AM;Wright KN;Strong CE;Kabbaj M
低剂量氯胺酮是一种速效抗抑郁药，雌性啮齿动物比雄性更敏感。然而，介导氯胺酮敏感性性别差异的机制仍然难以捉摸。我们试图确定雄性和雌性小鼠对低剂量氯胺酮的行为敏感性是否不同，并揭示卵巢激素如何影响雌性小鼠的氯胺酮敏感性。我们还旨在揭示情绪相关脑区中介导氯胺酮抗抑郁作用性别差异的一些分子机制。雄性和雌性小鼠（自由骑行、动情间期1 [D1]、动情前期[Pro]或雌激素受体（ER）α、ERβ或孕酮受体（PR）激动剂处理的D1）接受氯胺酮（0、1.5或3 mg/kg腹腔注射），并在30 min后进行强迫游泳试验（FST）。在给药后1 h，通过蛋白质印迹法定量测定氯胺酮对雄性、D1和Pro雌性的前额叶皮质（PFC）和海马（HPC）中突触可塑性标志物的影响。雄性、自由骑自行车的雌性、D1和Pro雌性对3 mg/kg氯胺酮表现出抗抑郁样反应。亲雌性动物是氯胺酮在1.5 mg/g剂量下表现出抗抑郁作用的唯一组。接受ERα和ERβ激动剂给药的D1雌性动物对1.5 mg/kg氯胺酮表现出抗抑郁样反应。氯胺酮（3 mg/kg）增加了雄性、D1和Pro雌性PFC和HPC中的突触可塑性相关蛋白。然而，Pro雌性动物对1.5和3 mg/kg氯胺酮的反应显示p-Akt和p-CaMKIIα增加。我们的研究结果表明，女性在Pro期间对氯胺酮的敏感性增强可能是通过雌二醇作用于ERα和ERβ介导的，从而导致PFC和HPC内突触可塑性相关激酶的更大激活。
Low-dose ketamine is a rapid-acting antidepressant, to which female rodents are more sensitive as compared to males. However, the mechanism mediating this sex difference in ketamine sensitivity remains elusive. We sought to determine whether male and female mice differ in their behavioral sensitivity to low doses of ketamine, and uncover how ovarian hormones influence females’ ketamine sensitivity. We also aimed to uncover some of the molecular mechanism(s) in mood-related brain regions that mediate sex differences in ketamine antidepressant effects. Male and female mice (freely-cycling, diestrus 1 [D1], proestrus [Pro], or D1 treated with an estrogen receptor (ER) α, ERβ, or progesterone receptor (PR) agonist) received ketamine (0, 1.5, or 3 mg/kg intraperitoneally) and were tested in the forced swim test (FST) 30 min later. Ketamine’s influence over synaptic plasticity markers in the prefrontal cortex (PFC) and hippocampus (HPC) of males, D1, and Pro females was quantified by Western blot 1 h post-treatment. Males, freely-cycling females, D1 and Pro females exhibited antidepressant-like responses to 3 mg/kg ketamine. Pro females were the only group where ketamine exhibited an antidepressant effect at 1.5 mg/g. D1 females treated with an agonist for ERα and ERβ exhibited an antidepressant-like response to 1.5 mg/kg ketamine. Ketamine (3 mg/kg) increased synaptic plasticity-related proteins in the PFC and HPC of males, D1, and Pro females. Yet, Pro females exhibited an increase in p-Akt and p-CaMKIIα in response to 1.5 and 3 mg/kg ketamine. Our results indicate that females’ enhanced sensitivity to ketamine during Pro is likely mediated through estradiol acting on ERα and ERβ, leading to greater activation of synaptic plasticity-related kinases within the PFC and HPC.
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影响因子：
3.6
作者：
Frye, Cheryl A.
通讯作者：
Frye, Cheryl A.
氯胺酮和快速作用的抗抑郁药：介绍新的神经生物学的窗口，用于情绪障碍疗法。
影响因子：
10.5
作者：
Abdallah CG;Sanacora G;Duman RS;Krystal JH
通讯作者：
Krystal JH
影响因子：
64.8
作者：
Autry, Anita E.;Adachi, Megunai;Nosyreva, Elena;Na, Elisa S.;Los, Maarten F.;Cheng, Peng-fei;Kavalali, Ege T.;Monteggia, Lisa M.
通讯作者：
Monteggia, Lisa M.
影响因子：
3.5
作者：
Frye, CA;Walf, AA
通讯作者：
Walf, AA
影响因子：
10.6
作者：
Berman, RM;Cappiello, A;Krystal, JH
通讯作者：
Krystal, JH