Benzodiazepine Receptor Agonists Cause Drug-Specific and State-Specific Alterations in EEG Power and Acetylcholine Release in Rat Pontine Reticular Formation
Benzodiazepine Receptor Agonists Cause Drug-Specific and State-Specific Alterations in EEG Power and Acetylcholine Release in Rat Pontine Reticular Formation
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DOI：
10.1093/sleep/33.7.909
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发表时间：
2010-07-01
期刊：
影响因子：
5.6
通讯作者：
Lydic, Ralph
中科院分区：
文献类型：
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作者：
Hambrecht-Wiedbusch, Viviane S.;Gauthier, Elizabeth A.;Lydic, Ralph
研究目的：苯二氮卓类（BDZ）和非苯二氮卓类（NBDZ）催眠药可增强GABA能传递，广泛用于治疗失眠。在脑桥网状结构（PRF）中，GABA抑制快速眼动（REM）睡眠和乙酰胆碱（ACh）释放。以前没有研究表征BDZ和NBDZ催眠药对PRF中ACh释放的影响。本研究测试了2个假设：（1）将唑吡坦、右佐匹克隆和地西泮微透析递送至大鼠PRF会改变PRF中的ACh释放和脑电（EEG）增量功率，以及（2）静脉（IV）给予右佐匹克隆对非麻醉大鼠会改变PRF、睡眠和EEG增量功率中的ACh释放。设计：组内和组间实验设计。设置：密歇根大学。患者或参与者：成年雄性Crl：CD*（SD）（Sprague-Dawley）大鼠（n = 57）。干预：使用异氟烷麻醉大鼠的PRF体内微透析来推导唑吡坦、右佐匹克隆和地西泮对ACh释放的浓度-反应效应。慢性仪表大鼠被用来量化的影响，右佐匹克隆（3毫克/公斤，IV）ACh释放的PRF，睡眠-觉醒状态，和皮层EEG power.Measurements和结果：ACh释放显着增加微透析交付的PRF的唑吡坦和右佐匹克隆，但不是地西泮。唑吡坦和地西泮增加了EEG δ功率，但右佐匹克隆未增加PRF。右佐匹克隆（IV）降低了麻醉和非麻醉大鼠PRF中的ACh释放。右佐匹克隆（IV）阻止REM睡眠和增加EEG δ功率。结论：浓度-反应数据提供了第一个功能证据，多种GABA（A）受体亚型存在于大鼠PRF。静脉注射右佐匹克隆可预防REM睡眠，减少PRF中的ACh释放，并增加EEG δ功率。右佐匹克隆的作用与NREM睡眠期间PRF中ACh释放低于REM睡眠期间的证据一致，并且数据显示PRF的胆碱能刺激会激活皮质EEG。
Study Objectives: Benzodiazepine (BDZ) and non-benzodiazepine (NBDZ) hypnotics enhance GABAergic transmission and are widely used for the treatment of insomnia. In the pontine reticular formation (PRF), GABA inhibits rapid eye movement (REM) sleep and acetylcholine (ACh) release. No previous studies have characterized the effects of BDZ and NBDZ hypnotics on ACh release in the PRF. This study tested 2 hypotheses: (1) that microdialysis delivery of zolpidem, eszopiclone, and diazepam to rat PRF alters ACh release in PRF and electroencephalographic (EEG) delta power and (2) that intravenous (IV) administration of eszopiclone to non-anesthetized rat alters ACh release in the PRF, sleep, and EEG delta power.Design: A within- and between-groups experimental design.Setting: University of Michigan.Patients or Participants: Adult male Crl:CD*(SD) (Sprague-Dawley) rats (n = 57).Interventions: In vivo microdialysis of the PRF in rats anesthetized with isoflurane was used to derive the concentration-response effects of zolpidem, eszopiclone, and diazepam on ACh release. Chronically instrumented rats were used to quantify the effects of eszopiclone (3 mg/kg, IV) on ACh release in the PRF, sleep-wake states, and cortical EEG power.Measurements and Results: ACh release was significantly increased by microdialysis delivery to the PRF of zolpidem and eszopiclone but not diazepam. EEG delta power was increased by zolpidem and diazepam but not by eszopiclone administered to the PRF. Eszopiclone (IV) decreased ACh release in the PRF of both anesthetized and non-anesthetized rats. Eszopiclone (IV) prevented REM sleep and increased EEG delta power.Conclusion: The concentration-response data provide the first functional evidence that multiple GABA(A) receptor subtypes are present in rat PRF. Intravenously administered eszopiclone prevented REM sleep, decreased ACh release in the PRF, and increased EEG delta power. The effects of eszopiclone are consistent with evidence that ACh release in the PRF is lower during NREM sleep than during REM sleep, and with data showing that cholinergic stimulation of the PRF activates the cortical EEG.