Department of Medical Pharmacology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
Department of Medical Pharmacology, School of Medicine, Marmara University, Istanbul, Turkey.
Naunyn Schmiedebergs Arch Pharmacol. 2021 Apr;394(4):619-629. doi: 10.1007/s00210-020-02001-1. Epub 2020 Oct 26.
Protein kinase C inhibitor tamoxifen reduces symptoms of acute mania in bipolar patients and mania-like behaviors in animals. Memory impairment and altered levels of glutamate and glutamate/glutamine ratio have been reported in mania. Tamoxifen suppresses glutamate release which plays an important role in memory. The present study evaluated whether tamoxifen's activity participates in its antimanic efficacy in repeated sleep deprivation mania model. Mice were divided into control and 24-h sleep-deprived groups and were treated with vehicle or 1 mg/kg tamoxifen twice daily for 8 days. Sleep deprivation was repeated three times at intervals of 2 days. Square crossing and rearing were recorded as measures of locomotor activity. Memory and risk taking behavior were evaluated using novel object recognition and staircase tests, respectively. Glutamate and glutamine levels were measured in the frontal cortex and hippocampus. Behavioral tests were conducted 24 h after the second or immediately after the third sleep deprivations. Sleep deprivation increased locomotor activity and risk taking. Glutamate and glutamine levels and glutamate/glutamine ratio in the frontal cortex and hippocampus were unaffected. Locomotor hyperactivity was prevented by tamoxifen treatment. No change in the recognition index suggested lack of memory impairment in the model. These findings confirm the relevance of repeated sleep deprivation as a mania model and tamoxifen as an antimanic agent. However, future research is needed to further address lack of memory impairment in the model and lack of glutamatergic influence on the model and antimanic effect of tamoxifen.
蛋白激酶 C 抑制剂他莫昔芬可减轻双相情感障碍患者的急性躁狂症状和动物的躁狂样行为。躁狂症患者存在记忆障碍以及谷氨酸和谷氨酸/谷氨酰胺比值改变。他莫昔芬可抑制谷氨酸释放，谷氨酸释放对记忆具有重要作用。本研究评估了他莫昔芬的活性是否参与了其在反复睡眠剥夺躁狂模型中的抗躁狂作用。将小鼠分为对照组和 24 小时睡眠剥夺组，并每天两次用载体或 1mg/kg 他莫昔芬治疗 8 天。睡眠剥夺每 2 天重复 3 次。记录穿越和竖起次数作为运动活动的测量。使用新物体识别和阶梯测试分别评估记忆和冒险行为。在额叶皮质和海马体中测量谷氨酸和谷氨酰胺水平。在第二次或第三次睡眠剥夺后 24 小时进行行为测试。睡眠剥夺增加了运动活动和冒险行为。额叶皮质和海马体中的谷氨酸和谷氨酰胺水平以及谷氨酸/谷氨酰胺比值没有变化。他莫昔芬治疗可预防运动过度活跃。模型中无识别指数变化表明无记忆障碍。这些发现证实了反复睡眠剥夺作为躁狂模型和他莫昔芬作为抗躁狂药物的相关性。然而，需要进一步研究来解决模型中缺乏记忆障碍以及模型中谷氨酸能影响和他莫昔芬的抗躁狂作用问题。
