Antidepressant-like effects of guanfacine and sex-specific differences in effects on c-fos immunoreactivity and paired-pulse ratio in male and female mice.
Antidepressant-like effects of guanfacine and sex-specific differences in effects on c-fos immunoreactivity and paired-pulse ratio in male and female mice.
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DOI：
10.1007/s00213-015-4001-3
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发表时间：
2015-10
影响因子：
3.4
通讯作者：
Picciotto MR
中科院分区：
文献类型：
--
作者：
Mineur YS;Bentham MP;Zhou WL;Plantenga ME;McKee SA;Picciotto MR
α 2a-去甲肾上腺素能激动剂胍法辛减少女性吸烟者的应激诱导吸烟，但对男性吸烟者无影响。目前尚不清楚这些作用是否是由于对情绪调节的影响和/或尼古丁-胆碱能相互作用的结果。确定胍法辛在小鼠基线抗焦虑和抗抑郁疗效试验中以及在乙酰胆碱酯酶抑制剂毒扁豆碱诱导的高胆碱能抑郁模型中的作用是否存在性别差异。在雌性和雄性C57 BL/6 J小鼠的光/暗箱、悬尾和强迫游泳试验中测量胍法辛的作用。与此同时，在前额叶皮层，一个关键的大脑区域参与应激反应的电生理特性进行了评估。在已知调节情绪的其他脑区测量c-fos免疫反应性。尽管强迫游泳试验中的行为存在基线性别差异（雌性小鼠更不动），但胍法辛在两种性别小鼠中具有相似的剂量依赖性抗抑郁剂样作用（最佳剂量：0.15 mg/kg）。在用毒扁豆碱预处理后也观察到胍法辛的抗抑郁样作用。在基线时观察到PFC的成对脉搏比存在性别差异（男性：1.4;女性：2.1），通过胍法辛使其标准化。其他参与抑郁样行为的胆碱能控制的脑区，包括基底外侧杏仁核和外侧隔，c-fos的表达表现出性别特异性变化。胍法辛具有强大的抗抑郁样作用，可以逆转由ACh信号传导增加诱导的抑郁样状态。这些数据表明，尽管对胍法辛的行为反应相似，但雌性和雄性小鼠的大脑区域不同。
The α2a-noradrenergic agonist guanfacine decreases stress-induced smoking in female, but not male, human smokers. It is not known whether these effects are due to effects on mood regulation and/or result from nicotinic-cholinergic interactions. To determine whether there are sex-differences in the effect of guanfacine in tests of anxiolytic- and antidepressant-efficacy in mice at baseline and in a hypercholinergic model of depression induced by the acetylcholinesterase inhibitor physostigmine. The effects of guanfacine were measured in the light/dark box, tail suspension and the forced swim test in female and male C57BL/6J mice. In parallel, electrophysiological properties were evaluated in prefrontal cortex, a critical brain region involved in stress responses. c-fos immunoreactivity was measured in other brain regions known to regulate mood. Despite a baseline sex difference in behavior in the forced swim test (female mice were more immobile), guanfacine had similar, dose-dependent, antidepressant-like effects in mice of both sexes (optimal dose: 0.15 mg/kg). An antidepressant-like effect of guanfacine was also observed following pre-treatment with physostigmine. A sex difference in the paired-pulse ratio in PFC (male: 1.4; female, 2.1) was observed at baseline that was normalized by guanfacine. Other brain regions areas involved in cholinergic control of depression-like behaviors, including basolateral amygdala and lateral septum, showed sex-specific changes in c-fos expression. Guanfacine has a robust antidepressant-like effect and can reverse a depression-like state induced by increased ACh signaling. These data suggest that different brain areas are recruited in female and male mice, despite similar behavioral responses to guanfacine.