Chauveau F, Laudereau K, Libourel P A, Gervasoni D, Thomasson J, Poly B, Pierard C, Beracochea D
IRBA (Armed Biomedical Research Institute) BP73, F-91223 Bretigny-sur-Orge Cedex, France.
Centre de Recherche en Neurosciences de Lyon, INSERM U1028, CNRS UMR 5292, Université Claude Bernard Lyon 1, France.
Neuropharmacology. 2014 Oct;85:349-56. doi: 10.1016/j.neuropharm.2014.04.017. Epub 2014 May 4.
Histamine receptor type 3 (H3) antagonists are promising awakening drugs for treatment of sleep disorders. However, few works have tried to identify their cognitive effects after sleep restriction and their impact on associated neural networks. To that aim, Bl/6J male mice were submitted to acute sleep restriction in a shaker apparatus that prevents sleep by transient (20-40 ms) up and down movements. Number of stimulations (2-4), and delay between 2 stimulations (100-200 ms) were randomized. Each sequence of stimulation was also randomly administered (10-30 s interval) for 20 consecutive hours during light (8 h) and dark (12 h) phases. Immediately after 20 h-sleep restriction, mice were injected with H3 antagonist (ciproxifan 3 mg/kg ip) and submitted 30-min later to a working memory (WM) task using spatial spontaneous alternation behaviour. After behavioural testing, brains were perfused for Fos immunohistochemistry to assess neuronal brain activation in the dorsal dentate gyrus (dDG) and the prefrontal cortex. Results showed that sleep restriction decreased slow wave sleep (from 35.8±1.4% to 9.2±2.7%, p<0.001) and was followed by sleep rebound (58.2±5.9%, p<0.05). Sleep restriction did not modify anxiety-like reactivity and significantly decreased WM at long (30 s) but not short (5 s) inter-trial intervals. Whereas sleep restriction failed to significantly modify immunopositive cells in vehicles, ciproxifan administration prevented WM deficits in sleep restricted mice through significant increases of Fos labelling in prelimbic, infralimbic and cingulate 2 cortex. In conclusion, ciproxifan at 3 mg/kg enhanced WM in sleep restricted mice through specific modulation of prefrontal cortex areas.
组胺3型（H3）受体拮抗剂有望成为治疗睡眠障碍的促醒药物。然而，很少有研究试图确定它们在睡眠限制后的认知效应及其对相关神经网络的影响。为了实现这一目标，将C57BL/6J雄性小鼠置于振动器装置中进行急性睡眠限制，该装置通过短暂（20 - 40毫秒）的上下运动来阻止睡眠。刺激次数（2 - 4次）和两次刺激之间的延迟（100 - 200毫秒）是随机的。在光照（8小时）和黑暗（12小时）阶段，每个刺激序列也以随机方式（间隔10 - 30秒）连续给药20小时。在20小时睡眠限制结束后，立即给小鼠注射H3拮抗剂（西普罗芬3毫克/千克，腹腔注射），30分钟后使用空间自发交替行为让小鼠进行工作记忆（WM）任务。行为测试后，对大脑进行灌注以进行Fos免疫组织化学分析，以评估背侧齿状回（dDG）和前额叶皮质中的神经元脑激活情况。结果显示，睡眠限制减少了慢波睡眠（从35.8±1.4%降至9.2±2.7%，p<0.001），随后出现睡眠反弹（58.2±5.9%，p<0.05）。睡眠限制未改变焦虑样反应性，并且在长（30秒）而非短（5秒）的试验间隔时显著降低了工作记忆。虽然睡眠限制未能显著改变给予载体小鼠的免疫阳性细胞，但给予西普罗芬可通过显著增加前边缘区、下边缘区和扣带回2皮质中的Fos标记来预防睡眠限制小鼠的工作记忆缺陷。总之，3毫克/千克的西普罗芬通过对前额叶皮质区域的特异性调节增强了睡眠限制小鼠的工作记忆。
