慢性间歇性乙醇暴露青春期雌性大鼠中食欲素-2 受体拮抗剂对睡眠和事件相关振荡的影响。
Effects of an Orexin-2 Receptor Antagonist on Sleep and Event-Related Oscillations in Female Rats Exposed to Chronic Intermittent Ethanol During Adolescence.
机构信息
From the, Department of Psychology, (LRA), California State University San Bernardino, San Bernardino, California.
Department of Neuroscience, (DNW, MS-A, CLE), The Scripps Research Institute, La Jolla, California.
出版信息
Alcohol Clin Exp Res. 2020 Jul;44(7):1378-1388. doi: 10.1111/acer.14361. Epub 2020 Jun 12.
BACKGROUND
Alcohol use is on the rise among women in the United States which is especially concerning since women who drink have a higher risk of alcohol-related problems. Orexin (hypocretin) receptor antagonists may have some therapeutic value for alcohol-induced insomnia; however, the use of this class of drugs following female adolescent binge drinking is limited. The current study will address whether adolescent intermittent ethanol (AIE) in female rats can result in lasting changes in sleep pathology and whether orexin-targeted treatment can alleviate these deficits.
METHODS
Following a 5-week AIE vapor model, young adult rats were evaluated on waking event-related oscillations (EROs) and EEG sleep. Subsequently, AIE rats were treated with orexin receptor 2 (OX R) antagonist (MK-1064; 10, 20mg/kg) to test for modifications in sleep pathology and waking ERO.
RESULTS
Female AIE rats exhibited lasting changes in sleep compared to controls. This was demonstrated by increased fragmentation of slow wave sleep (SWS) and rapid eye movement sleep, as well as reductions in delta and theta power during SWS. There was no impact of AIE on waking EROs. Acute MK-1064 hastened SWS onset and increased the number of SWS episodes, without increasing sleep fragmentation in AIE and controls. While treatment with MK-1064 did not impact sleep EEG spectra, waking ERO energy was increased in delta, theta, and beta frequency bands.
CONCLUSIONS
These results demonstrate that AIE can produce lasting changes in sleep in female rats, highly similar to what we previously found in males. Additionally, while the OX R antagonist promoted sleep in both alcohol-exposed and unexposed rats, it did not reverse most of the alcohol-induced disruptions in sleep. Thus, OX R antagonism may serve as a potential therapeutic strategy for the treatment of insomnia, but not the specific signs of alcohol-induced insomnia.
背景
在美国，女性饮酒人数呈上升趋势，这尤其令人担忧，因为女性饮酒者酗酒相关问题的风险更高。食欲素（下丘脑分泌素）受体拮抗剂可能对治疗酒精引起的失眠具有一定的治疗价值；然而，这类药物在女性青少年 binge drinking 后使用的情况有限。目前的研究将探讨雌性大鼠青少年间歇性乙醇（AIE）是否会导致睡眠病理的持久变化，以及食欲素靶向治疗是否可以减轻这些缺陷。
方法
在为期 5 周的 AIE 蒸气模型之后，对年轻成年大鼠进行清醒事件相关振荡（EROs）和 EEG 睡眠评估。随后，用食欲素受体 2（OX R）拮抗剂（MK-1064；10、20mg/kg）对 AIE 大鼠进行治疗，以测试睡眠病理和清醒 ERO 的变化。
结果
与对照组相比，雌性 AIE 大鼠的睡眠出现持久变化。这表现为慢波睡眠（SWS）和快速眼动睡眠（REM）的碎片化增加，以及 SWS 期间 delta 和 theta 功率的降低。AIE 对清醒 EROs 没有影响。急性 MK-1064 加速了 SWS 的起始并增加了 SWS 发作的次数，而在 AIE 和对照组中并没有增加睡眠碎片化。虽然 MK-1064 治疗并没有影响睡眠 EEG 谱，但在 delta、theta 和 beta 频带中增加了清醒 ERO 能量。
结论
这些结果表明，AIE 可以在雌性大鼠中产生持久的睡眠变化，与我们之前在雄性大鼠中发现的情况非常相似。此外，尽管 OXR 拮抗剂促进了暴露和未暴露于酒精的大鼠的睡眠，但它并没有逆转大多数由酒精引起的睡眠中断。因此，OX R 拮抗作用可能是治疗失眠的潜在治疗策略，但不是治疗酒精引起的失眠的特定症状。
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