Abstract：
BACKGROUND: Motivation and inhibitory control are dominantly regulated by the dopaminergic (DA) and noradrenergic (NA) systems, respectively. Hypothalamic hypocretin (orexin) neurons provide afferent inputs to DA and NA nuclei and hypocretin-1 receptors (HcrtR1) are implicated in reward and addiction. However, the role of the HcrtR1 in inhibitory control is not well understood.
OBJECTIVE: To determine the effects of HcrtR1 antagonism and motivational state in inhibitory control using the go/no-go task in mice.
METHODS: n = 23 male C57Bl/6JArc mice were trained in a go/no-go task. Decision tree dendrogram analysis of training data identified more and less impulsive clusters of animals. A HcrtR1 antagonist (BI001, 12.5 mg/kg, per os) or vehicle were then administered 30 min before go/no-go testing, once daily for 5 days, under high (food-restricted) and low (free-feeding) motivational states in a latin-square crossover design. Compound exposure levels were assessed in a satellite group of animals.
RESULTS: HcrtR1 antagonism increased go accuracy and decreased no-go accuracy in free-feeding animals overall, whereas it decreased go accuracy and increased no-go accuracy only in more impulsive, food restricted mice. HcrtR1 antagonism also showed differential effects in premature responding, which was increased in response to the antagonist in free-feeding, less impulsive animals, and decreased in food restricted, more impulsive animals. HcrtR1 receptor occupancy by BI001 was estimated at ~ 66% during the task.
CONCLUSIONS: These data indicate that hypocretin signalling plays roles in goal-directed behaviour and inhibitory control in a motivational state-dependant manner. While likely not useful in all settings, HcrtR1 antagonism may be beneficial in improving inhibitory control in impulsive subpopulations.
OBJECTIVE: To determine the effects of HcrtR1 antagonism and motivational state in inhibitory control using the go/no-go task in mice.
METHODS: n = 23 male C57Bl/6JArc mice were trained in a go/no-go task. Decision tree dendrogram analysis of training data identified more and less impulsive clusters of animals. A HcrtR1 antagonist (BI001, 12.5 mg/kg, per os) or vehicle were then administered 30 min before go/no-go testing, once daily for 5 days, under high (food-restricted) and low (free-feeding) motivational states in a latin-square crossover design. Compound exposure levels were assessed in a satellite group of animals.
RESULTS: HcrtR1 antagonism increased go accuracy and decreased no-go accuracy in free-feeding animals overall, whereas it decreased go accuracy and increased no-go accuracy only in more impulsive, food restricted mice. HcrtR1 antagonism also showed differential effects in premature responding, which was increased in response to the antagonist in free-feeding, less impulsive animals, and decreased in food restricted, more impulsive animals. HcrtR1 receptor occupancy by BI001 was estimated at ~ 66% during the task.
CONCLUSIONS: These data indicate that hypocretin signalling plays roles in goal-directed behaviour and inhibitory control in a motivational state-dependant manner. While likely not useful in all settings, HcrtR1 antagonism may be beneficial in improving inhibitory control in impulsive subpopulations.
摘要：
背景：激活和抑制控制主要由多巴胺能（DA）和去甲肾上腺素能（NA）系统调节，分别。下丘脑降血糖素（orexin）神经元向DA和NA核提供传入输入，而降血糖素-1受体（HcrtR1）与奖励和成瘾有关。然而,HcrtR1在抑制控制中的作用尚不清楚。
目的：在小鼠中使用go/no-go任务来确定HcrtR1拮抗作用和动机状态在抑制对照中的作用。
方法:n=23只雄性C57Bl/6JArc小鼠在进行/不进行任务中进行训练。对训练数据的决策树树状图分析识别出越来越少的脉冲动物簇。HcrtR1拮抗剂（BI001，12.5mg/kg，然后在进行/不进行测试之前30分钟给予每个操作系统)或载体，每天一次，持续5天，在拉丁方交叉设计中处于高（食物限制）和低（自由喂养）动机状态。在动物的卫星组中评估化合物暴露水平。
结果：HcrtR1拮抗作用提高了自由饲养动物的围棋准确性，降低了围棋准确性，而它仅在更冲动的情况下降低了前进的准确性并增加了不前进的准确性，限制食物的老鼠.HcrtR1拮抗作用在过早反应中也显示出不同的作用，在自由喂养的情况下，对拮抗剂的反应增加了，少冲动的动物，食物限制减少，更冲动的动物在任务期间，BI001对HcrtR1受体的占有率估计为约66％。
结论：这些数据表明，降血糖素信号传导在目标导向行为和抑制控制中具有动机状态依赖性。虽然可能不是在所有设置中都有用，HcrtR1拮抗作用可能有利于改善脉冲亚群的抑制控制。
目的：在小鼠中使用go/no-go任务来确定HcrtR1拮抗作用和动机状态在抑制对照中的作用。
方法:n=23只雄性C57Bl/6JArc小鼠在进行/不进行任务中进行训练。对训练数据的决策树树状图分析识别出越来越少的脉冲动物簇。HcrtR1拮抗剂（BI001，12.5mg/kg，然后在进行/不进行测试之前30分钟给予每个操作系统)或载体，每天一次，持续5天，在拉丁方交叉设计中处于高（食物限制）和低（自由喂养）动机状态。在动物的卫星组中评估化合物暴露水平。
结果：HcrtR1拮抗作用提高了自由饲养动物的围棋准确性，降低了围棋准确性，而它仅在更冲动的情况下降低了前进的准确性并增加了不前进的准确性，限制食物的老鼠.HcrtR1拮抗作用在过早反应中也显示出不同的作用，在自由喂养的情况下，对拮抗剂的反应增加了，少冲动的动物，食物限制减少，更冲动的动物在任务期间，BI001对HcrtR1受体的占有率估计为约66％。
结论：这些数据表明，降血糖素信号传导在目标导向行为和抑制控制中具有动机状态依赖性。虽然可能不是在所有设置中都有用，HcrtR1拮抗作用可能有利于改善脉冲亚群的抑制控制。
