GABA transporter-1 inhibitor NO-711 alters the EEG power spectra and enhances non-rapid eye movement sleep during the active phase in mice
GABA transporter-1 inhibitor NO-711 alters the EEG power spectra and enhances non-rapid eye movement sleep during the active phase in mice
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DOI：
10.1016/j.euroneuro.2013.09.002
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发表时间：
2014-04
影响因子：
5.6
通讯作者：
Xin-Hong Xu;M. Qiu;Hui Dong;W. Qu;Y. Urade;Zhi-Li Huang
中科院分区：
文献类型：
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作者：
Xin-Hong Xu;M. Qiu;Hui Dong;W. Qu;Y. Urade;Zhi-Li Huang
GABA转运蛋白亚型1 （GAT1）在中枢神经系统中构建GABA的高亲和力再摄取位点，并调节GABA的能量传递。抑制GAT1的化合物是通常用于治疗癫痫的靶点；然而，镇静已被报道为这些药物的副作用，表明这些化合物的潜在镇静和/或催眠用途。在本研究中，我们观察了选择性GAT1抑制剂NO-711处理后小鼠的睡眠行为，以阐明GAT1在活跃期睡眠-觉醒调节中的作用。结果表明，高剂量（10 mg/kg） NO-711可显著增强清醒和快速眼动（REM）睡眠时3 ~ 25 Hz频率范围内的脑电图活动。在非快速眼动（NREM）睡眠期间，NO-711 （10 mg/kg）在1.5 ~ 6.75 Hz频率范围内升高脑电图活动。在低剂量3 mg/kg的小鼠中也发现了类似的变化。NO-711按1、3、10 mg/kg滴注可显著缩短NREM睡眠潜伏期，增加NREM睡眠时间和NREM睡眠发作次数。NO-711不影响睡眠潜伏期和快速眼动睡眠时间。NO-711剂量依赖性地增加睡眠促进核腹外侧视前区和正中视前区c-Fos表达。然而，c-Fos在促醒核、结节乳头核和外侧下丘脑中的表达减少。这些结果表明NO-711可以增加小鼠NREM睡眠。
GABA transporter subtype 1 (GAT1) constructs high affinity reuptake sites for GABA in the CNS and regulates GABAergictransmission. Compounds that inhibit GAT1 are targets often used for the treatment of epilepsy; however sedation has been reported as a side effect of these agents, indicating potential sedative and/or hypnotic uses for these compounds. In the current study, we observed the sleep behaviors of mice treated with NO-711, a selective GAT1 inhibitor, in order to elucidate the role of GAT1 in sleep–wake regulation during the active phase. The data revealed that NO-711 at a high dose of 10 mg/kg caused a marked enhancement of EEG activity in the frequency ranges of 3–25 Hz during wakefulness as well as rapid eye movement (REM) sleep. During the non-REM (NREM) sleep, NO-711 (10 mg/kg) elevated EEG activity in the frequency ranges of 1.5–6.75 Hz. Similar changes were found in mice treated with a low dose of 3 mg/kg. NO-711 administered i.p. at a dose of 1, 3 or 10 mg/kg significantly shortened the sleep latency of NREM sleep, increased the amount of NREM sleep and the number of NREM sleep episodes. NO-711 did not affect the sleep latency and the amount of REM sleep. NO-711 dose-dependently increased c-Fos expression in sleep-promoting nucleus of the ventrolateral preoptic area and median preoptic area. However, c-Fos expression was decreased in the wake-promoting nuclei, tuberomammillary nucleus and lateral hypothalamus. These results indicate that NO-711 can increase NREM sleep in mice.