Blocking melanin-concentrating hormone MCH1 receptor affects rat sleep-wake architecture
Blocking melanin-concentrating hormone MCH1 receptor affects rat sleep-wake architecture
复制标题
DOI：
10.1016/j.ejphar.2007.10.017
复制
发表时间：
2008-01-28
影响因子：
5
通讯作者：
Dautzenberg, Frank M.
中科院分区：
文献类型：
--
作者：
Ahnaou, Abdellah;Drinkenburg, Wilhelmus H. I. M.;Dautzenberg, Frank M.
黑色素浓缩激素（MCH）是一种下丘脑肽，集中调节食物摄入，能量平衡和情绪。有趣的是，MCH和黑色素浓缩激素MCH 1受体分布在已知调节警惕状态的大脑区域。研究了皮下注射两种选择性黑色素浓集激素MCH 1受体拮抗剂（标记为A和B）在宽剂量范围（1、3、10、20、40 mg/kg）内对大鼠睡眠-觉醒结构的影响。两种化合物对重组人黑色素浓集激素MCH 1受体具有纳摩尔拮抗剂活性（IC 50分别为44.1 +/- 6.1 nM和26.6 +/- 5.4 nM），并有效抑制MCH诱导的[Ca 2 +]动员（IC 50分别为29.1 +/- 8.1 nM和10.5 +/- 4.1 nM）。两种化合物的选择性在一组受体、转运蛋白和通道上得到进一步证实。在体内，这两种化合物主要通过减少给药后前4小时内发作的平均持续时间来剂量依赖性地减少深度睡眠。与此同时，REM睡眠和中间阶段睡眠减少，而主动和被动觉醒增加。在较高剂量下，深度睡眠和REM睡眠开始时间显著延长。没有观察到深睡眠的自我平衡反弹，而REM睡眠的恢复趋势被发现在随后的黑暗阶段。总之，这些结果支持黑色素浓缩激素MCH 1受体在调节深慢波睡眠-REM睡眠周期中的作用。黑色素浓集激素MCH 1受体抑制剂的治疗应用应考虑深度睡眠的显著减少而不恢复，因为这些可能干扰睡眠依赖性记忆巩固。(C)2007 Elsevier B. V.保留所有权利。
Melanin-concentrating hormone (MCH) is a hypothalamic peptide that centrally regulates food intake, energy balance and emotion. Interestingly, MCH and melanin-concentrating hormone MCH1 receptors are distributed in brain areas known to regulate vigilance states. Effects of subcutaneous administration of two selective melanin-concentrating hormone MCH1 receptor antagonists, labeled A and B were examined over a broad dose range (1, 3, 10, 20, 40 mg/kg) on rat sleep-wake architecture. Both compounds have a nanomolar antagonist activity at recombinant human melanin-concentrating hormone MCH1 receptor (IC50=44.1 +/- 6.1 nM and 26.6 +/- 5.4 nM, respectively) and potently inhibited the MCH-induced mobilization of [Ca2+] (IC50 29.1 +/- 8.1 nM and 10.5 +/- 4.1 nM, respectively). The selectivity of both compounds was further confirmed on a panel of receptors, transporters and channels. In vivo, both compounds dose-dependently decreased deep sleep primarily by decreasing the mean duration of episodes during the first 4 h post-administration. In parallel, REM sleep and intermediate stage sleep were decreased while active and passive waking increased. Deep sleep and REM sleep onset latencies were significantly prolonged at higher doses. No homeostatic rebound of deep sleep was observed, while a tendency for recovery of REM sleep was found during subsequent dark phase. Together, the results support a role of the melanin-concentrating hormone MCH1 receptor in the regulation of deep slow-wave sleep-REM sleep cycle. Therapeutic application of melanin-concentrating hormone MCH1 receptor-inhibiting agents should take into account the significant decreases in deep sleep without recovery as these may interfere with sleep dependent memory consolidation. (C) 2007 Elsevier B.V. All rights reserved.