Lancel M, Faulhaber J, Holsboer F, Rupprecht R
Max Planck Institute of Psychiatry, Clinical Institute, Munich, Germany.
Am J Physiol. 1996 Oct;271(4 Pt 1):E763-72. doi: 10.1152/ajpendo.1996.271.4.E763.
There is much evidence that progesterone has hypnotic anesthetic properties. In this vehicle-controlled study, we examined the effects of three doses of progesterone (30, 90, and 180 mg/kg) administered intraperitoneally at light onset on sleep in rats. Progesterone dose dependently shortened non-rapid eye movement sleep (NREMS) latency, lengthened rapid eye movement sleep (REMS) latency, decreased the amount of wakefulness and REMS, and markedly increased pre-REMS, an intermediate state between NREMS and REMS. Progesterone also elicited dose-related changes in sleep state-specific electroencephalogram (EEG) power densities. Within NREMS, EEG activity was reduced in the lower frequencies (< or = 7 Hz) and was enhanced in the higher frequencies. Within REMS, EEG activity was markedly enhanced in the higher frequencies. The effects were maximal during the first postinjection hours. The concentrations of progesterone and the progesterone metabolites 3 alpha-hydroxy-5 alpha-pregnan-20-one and 3 alpha-hydroxy-5 beta-pregnan-20-one, both positive allosteric modulators of gamma-aminobutyric acid A (GABAA) receptors, were determined at different time intervals after vehicle and 30 or 90 mg/kg progesterone. Progesterone administration resulted in dose-dependent initially supraphysiological elevations of progesterone and its metabolites in the plasma and brain, which were most prominent during the first hour postinjection. The effects of progesterone on sleep closely resemble those of agonistic modulators of GABAA receptors such as benzodiazepines and correlate well with the increases in the levels of its GABAA agonistic metabolites. These observations suggest that the hypnotic effects of progesterone are mediated by the facilitating action of its neuroactive metabolites on GABAA receptor functioning.
有大量证据表明孕酮具有催眠麻醉特性。在这项载体对照研究中，我们检测了在大鼠轻度清醒时腹腔注射三种剂量（30、90和180mg/kg）孕酮对睡眠的影响。孕酮剂量依赖性地缩短了非快速眼动睡眠（NREMS）潜伏期，延长了快速眼动睡眠（REMS）潜伏期，减少了觉醒量和快速眼动睡眠量，并显著增加了NREMS和REMS之间的中间状态——快速眼动睡眠前状态（pre-REMS）。孕酮还引起了睡眠状态特异性脑电图（EEG）功率密度的剂量相关变化。在NREMS期间，较低频率（≤7Hz）的EEG活动减少，较高频率的EEG活动增强。在REMS期间，较高频率的EEG活动显著增强。这些影响在注射后的最初几个小时内最为明显。在给予载体以及30或90mg/kg孕酮后的不同时间间隔，测定了孕酮及其代谢产物3α-羟基-5α-孕烷-20-酮和3α-羟基-5β-孕烷-20-酮的浓度，这两种物质都是γ-氨基丁酸A（GABAA）受体的正变构调节剂。给予孕酮导致血浆和脑中孕酮及其代谢产物最初呈剂量依赖性的超生理水平升高，在注射后第一小时最为显著。孕酮对睡眠的影响与GABAA受体激动剂调节剂（如苯二氮䓬类药物）的影响非常相似，并且与其GABAA激动性代谢产物水平的升高密切相关。这些观察结果表明，孕酮的催眠作用是由其神经活性代谢产物对GABAA受体功能的促进作用介导的。
