胍法辛的抗抑郁样作用以及对雄性和雌性小鼠c-fos免疫反应性和配对脉冲比率影响的性别差异
Antidepressant-like effects of guanfacine and sex-specific differences in effects on c-fos immunoreactivity and paired-pulse ratio in male and female mice.
作者信息
Mineur Yann S, Bentham Matthew P, Zhou Wen-Liang, Plantenga Margreet E, McKee Sherry A, Picciotto Marina R
机构信息
Department of Psychiatry, Yale University School of Medicine, 34 Park Street-3rd floor research, New Haven, CT, 06508, USA.
出版信息
Psychopharmacology (Berl). 2015 Oct;232(19):3539-49. doi: 10.1007/s00213-015-4001-3. Epub 2015 Jul 7.
RATIONALE
The a2A-noradrenergic agonist guanfacine can 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.
OBJECTIVES
The objective of the study was 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.
METHODS
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 the prefrontal cortex, a critical brain region involved in stress responses. c-fos immunoreactivity was measured in other brain regions known to regulate mood.
RESULTS
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 the prefrontal cortex (PFC) (male, 1.4; female, 2.1) was observed at baseline that was normalized by guanfacine. Other brain areas involved in cholinergic control of depression-like behaviors, including the basolateral amygdala and lateral septum, showed sex-specific changes in c-fos expression.
CONCLUSIONS
Guanfacine has a robust antidepressant-like effect and can reverse a depression-like state induced by increased acetylcholine (ACh) signaling. These data suggest that different brain areas are recruited in female and male mice, despite similar behavioral responses to guanfacine.
理论依据
α2A-去甲肾上腺素能激动剂胍法辛可减少女性吸烟者因压力诱发的吸烟行为，但对男性吸烟者无效。目前尚不清楚这些作用是由于对情绪调节的影响，还是源于烟碱-胆碱能相互作用。
目的
本研究的目的是确定胍法辛在基础状态以及在由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，对小鼠抗焦虑和抗抑郁功效测试的影响是否存在性别差异。
方法
在雌性和雄性C57BL/6J小鼠的明暗箱、悬尾试验和强迫游泳试验中测量胍法辛的作用。同时，在前额叶皮质（一个参与应激反应的关键脑区）评估电生理特性。在已知调节情绪的其他脑区测量c-fos免疫反应性。
结果
尽管在强迫游泳试验中行为存在基线性别差异（雌性小鼠更不动），但胍法辛对两性小鼠具有相似的、剂量依赖性的抗抑郁样作用（最佳剂量，0.15mg/kg）。在毒扁豆碱预处理后也观察到胍法辛的抗抑郁样作用。在基线时观察到前额叶皮质（PFC）配对脉冲比率存在性别差异（雄性，1.4；雌性，2.1），而胍法辛可使其正常化。参与胆碱能控制抑郁样行为的其他脑区，包括基底外侧杏仁核和外侧隔，在c-fos表达上显示出性别特异性变化。
结论
胍法辛具有强大的抗抑郁样作用，可逆转由乙酰胆碱（ACh）信号增加诱导的抑郁样状态。这些数据表明，尽管对胍法辛有相似的行为反应，但雌性和雄性小鼠招募了不同的脑区。
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