Sex Differences in Effects of Ketamine on Behavior, Spine Density, and Synaptic Proteins in Socially Isolated Rats.
Sex Differences in Effects of Ketamine on Behavior, Spine Density, and Synaptic Proteins in Socially Isolated Rats.
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DOI：
10.1016/j.biopsych.2015.12.025
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发表时间：
2016-09-15
影响因子：
10.6
通讯作者：
Kabbaj M
中科院分区：
文献类型：
--
作者：
Sarkar A;Kabbaj M
抑郁症发生的性别差异和抗抑郁治疗的有效性的机制基础尚不清楚。在这里，我们研究了隔离应激和快速作用的抗抑郁药氯胺酮对雄性和雌性大鼠快感缺失和抑郁样行为、脊柱密度和突触蛋白的影响。采用慢性社会隔离应激(IS)模型，观察氯胺酮(0、2.5、5 mg/kg)对动情间期雄性和雌性大鼠行为学及突触蛋白突触蛋白Synapsin1、PSD95和GluR1水平的影响。在发情周期的间情期或发情前期分别服用氯胺酮的男性和女性的mPFC脊椎密度也进行了检测。8周后，男性表现出快感缺乏和抑郁样行为，伴随着脊柱密度和mPFC中突触蛋白1、PSD95和GluR1水平的下降；这些变化可被一次注射氯胺酮(5 mg/kg)逆转。11周后，女性表现出类似抑郁的行为，但没有快感缺乏的迹象。虽然两种剂量的氯胺酮都能挽救雌性大鼠的抑郁样行为，但在雌性和发情间期雌性大鼠中观察到的突触蛋白和脊椎密度的下降不能被氯胺酮逆转。雌性动情前期的脊椎密度高于动情间期。我们的发现暗示突触蛋白Synapsin1、PSD95和GluR1以及mPFC脊柱密度在氯胺酮的抗抑郁作用中起作用，在IS男性中，而在IS女性中不是，这表明氯胺酮在两性中的疗效的潜在机制不同。
The mechanistic underpinnings of sex differences in occurrence of depression and efficacy of antidepressant treatments are poorly understood. Here we examined the effects of isolation stress and the fast acting antidepressant ketamine, on anhedonia and depression-like behavior, spine density and synaptic proteins in male and female rats. We used chronic social isolation stress (IS) paradigm to test the effects of ketamine (0, 2.5 and 5mg/kg) on behavior and levels of synaptic proteins Synapsin1, PSD95 and GluR1 in male and female rats in diestrus. mPFC spine density was also examined in males and in females that received ketamine either during diestrus or proestrus phase of their estrous cycle. Males showed anhedonia and depression-like behavior after 8 weeks of IS, concomitant with decreases in spine density and levels of Synapsin1, PSD95 and GluR1 in the mPFC; changes that were reversed by a single injection of ketamine (5 mg/kg). Females, after 11 weeks of IS, showed depression-like behavior but no signs of anhedonia. Although both doses of ketamine rescued depression-like behavior in female rats, the decline observed in synaptic proteins and spine density in IS and in diestrus females, could not be reversed by ketamine. Spine density was higher in females during proestrus than in diestrus. Our findings implicate a role for synaptic proteins Synapsin1, PSD95 and GluR1, and mPFC spine density in the antidepressant effects of ketamine in IS males but not in IS females, suggesting dissimilar underlying mechanisms for efficacy of ketamine in the two sexes.