Dopamine D1 receptor in the NAc shell is involved in delayed emergence from isoflurane anesthesia in aged mice.
Dopamine D1 receptor in the NAc shell is involved in delayed emergence from isoflurane anesthesia in aged mice.
复制标题
NAc 壳中的多巴胺 D1 受体与老年小鼠异氟烷麻醉苏醒延迟有关。
DOI：
10.1002/brb3.1913
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发表时间：
2021-01
影响因子：
3.1
通讯作者：
Liang X
中科院分区：
文献类型：
--
作者：
Zhang Y;Gui H;Hu L;Li C;Zhang J;Liang X
全身麻醉后延迟苏醒倾向于发生在老年人群中，但其机制尚不清楚。除了年龄相关的药代动力学变化外，还应考虑促觉醒神经基质中老化诱导的结构和功能变化。延髓核（NAc）是一个重要的觉醒相关核团，激活其中表达多巴胺D1受体（D1 R）的中型棘神经元（MSNs）可以促进自然睡眠的觉醒。与此同时，多巴胺能系统在多个脑区随着年龄的增长而下降。然而，NAc壳中D1 R的年龄相关性下降是否会减弱其全身麻醉的唤醒促进能力仍有待阐明。本研究首次证实了异氟醚麻醉对老年小鼠的苏醒延迟，并观察了相应的脑电功率变化。反过来，通过将D1 R激动剂/拮抗剂微量注射到NAc壳中，在年轻和老年队列中表征D1 R的唤醒调节能力。此外，为了解决老年NAc的唤醒调节能力减弱的可能机制，测量了NAc壳中D1 R的表达，并在年轻和老年小鼠之间进行了比较。我们的数据表明，与年轻小鼠相比，老年小鼠的出现时间显著延长，而δ频段（1 - 4 Hz）的EEG功率显著增加，β频段（12 - 25 Hz）的功率降低。通过微量注射D1 R激动剂/拮抗剂激活或抑制NAc壳中的D1 R，可促进或延迟幼鼠的羽化过程。然而，这种调节能力的D1 R在NAc壳下降，分别在老年小鼠。同时，在老年脑中检测到NAc壳中D1 R表达下调。总之，这些结果表明，衰老可能通过下调NAc壳中D1 R的表达来减弱NAc壳中D1 R的唤醒调节能力，这可能为老年患者对麻醉剂的敏感性增加提供了潜在的解释和治疗靶点。异氟醚麻醉后的苏醒时间延迟，老年小鼠苏醒过程中皮层脑电功率发生改变。激活或抑制NAc壳中的D1 R促进或延迟行为和EEG功率方面的出现过程。然而，NAc壳中D1 R的调节能力随着年龄的增长而下降，可能是由于NAc壳中D1 R的年龄相关下调。这些数据可能提供了一个潜在的药效学解释和治疗目标，延迟从全身麻醉和麻醉药敏感性增加的老年患者。
Delayed emergence after general anesthesia tends to occur in the elderly population, but the mechanism remains unclear. Apart from age‐related pharmacokinetic changes, the aging‐induced structural and functional alterations in the arousal‐promoting neural substrates should be considered. The nucleus accumbens (NAc) is a crucial arousal‐related nucleus, in which activating medium spiny neurons (MSNs) expressing dopamine D1 receptor (D1R) could facilitate the arousal from natural sleep. Meanwhile, the dopaminergic systems decline with aging in multiple brain regions. However, whether the age‐related decline in D1R in the NAc shell attenuates its arousal‐promoting capacity from general anesthesia remains to be elucidated. We first verified the delayed emergence from isoflurane anesthesia and examined the corresponding changes of electroencephalogram (EEG) power in aged mice. In turn, the arousal‐modulating capacity of D1R was characterized in the young and aged cohorts by microinjection of D1R agonist/antagonist into the NAc shell. Furthermore, to address the possible mechanism responsible for the attenuated arousal‐modulating capacity of the aged NAc, the expression of D1R in the NAc shell was measured and compared between young and aged mice. Our data indicated that compared with young mice, the emergence time in aged mice was notably longer, while EEG power in δ band (1‐4Hz) was significantly higher and power in β band (12‐25Hz) was lower. Activating or inhibiting D1R in the NAc shell by microinjection D1R agonist/antagonist promoted or delayed the emergence process in young mice. Nevertheless, this modulation capacity of D1R in the NAc shell declined in aged mice, respectively. Meanwhile, downregulation of D1R expression in the NAc shell was detected in the aged brain. Together, these results suggest that aging attenuates the arousal‐modulating capacity of D1R in the NAc shell probably through downregulation of D1R expression therein, which may provide a potential explanation and a therapeutic target for increased sensitivity to anesthetics in the elderly patients. Emergence time from isoflurane anesthesia was delayed and cortical EEG power was altered during the emergence process in aged mice. Activating or inhibiting D1R in the NAc shell promoted or delayed the emergence process in terms of behavior and EEG power. Nevertheless, the modulation capacity of D1R in the NAc shell declined with age, probably due to the age‐related downregulation of D1R in the NAc shell. These data may provide a potential pharmacodynamical explanation and a therapeutic target for delayed emergence from general anesthesia and increased sensitivity to anesthetics in elderly patients.
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DOI：
10.1073/pnas.1614340113
发表时间：
2016-11-08
影响因子：
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通讯作者：
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