Selective MT2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms
Selective MT2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms
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DOI：
10.1096/fasebj.12.12.1211
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发表时间：
1998-09-01
期刊：
影响因子：
4.8
通讯作者：
Masana, MI
中科院分区：
文献类型：
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作者：
Dubocovich, ML;Yun, K;Masana, MI
本研究证实MT 2（Mel（1b））褪黑素受体参与了褪黑素介导的昼夜节律的时相推进。地高辛标记的寡核苷酸探针原位杂交组织化学首次揭示了MT（1）和MT 2褪黑素受体mRNA在C3 H/HeN小鼠视交叉上核的表达。褪黑激素（0.9至30 μ g/小鼠，s.c.）在主观日结束时（CT 10）的3天内，对保持在恒定暗相的C3 H/HeN小鼠给药，以剂量依赖性方式推进了转轮运行活动的昼夜节律[EC 50 =0.72 μ g/小鼠; 0.98+/-0.08 h（n=15）最大推进，9 μ g/小鼠]，选择性MT 2褪黑激素受体拮抗剂4P-ADOT和4P-PDOT（90 μ g/小鼠，s.c.）去甲卢吲哚（300 μ g/小鼠，s.c.），其对MTS的亲和力比mt（1）亚型高25倍，当在CT 10单独给药时，影响昼夜活动节律的相位。然而，所有三种拮抗剂都使对褪黑激素的剂量-反应曲线向右移动，因为它们显著降低了0.9和3 μ g褪黑激素的相移效应，这是第一个研究表明，褪黑激素阶段通过激活膜结合的褪黑激素受体来推进昼夜节律，并强烈表明这种作用是通过昼夜节律计时系统内的MT 2褪黑激素受体亚型介导的。我们得出结论，MT 2褪黑激素受体亚型是开发用于治疗昼夜节律睡眠和情绪相关疾病的亚型选择性类似物的新治疗靶点。Dubocovich，M. L.，Yun，K.，Al-Ghoul，W. M.，Benloucif，S.，马萨纳岛选择性MT 2褪黑激素受体拮抗剂阻断褪黑激素介导的昼夜节律相位提前。
This study demonstrates the involvement of the MT2 (Mel(1b)) melatonin receptor in mediating phase advances of circadian activity rhythms by melatonin, In situ hybridization histochemistry with digoxigenin-labeled oligonucleotide probes revealed for the first time the expression of mt(1) and MT2 melatonin receptor mRNA within the suprachiasmatic nucleus of the C3H/HeN mouse. Melatonin (0.9 to 30 mu g/mouse, s.c.) administration during 3 days at the end of the subjective day (CT 10) to C3H/HeN mice kept in constant dark phase advanced circadian rhythms of wheel running activity in a dose-dependent manner [EC50=0.72 mu g/mouse; 0.98+/-0.08 h (n=15) maximal advance at 9 mu g/mouse], Neither the selective MT2 melatonin receptor antagonists 4P-ADOT and 4P-PDOT (90 mu/mouse, s.c.) nor luzindole (300 mu g/mouse, s.c.), which shows 25-fold higher affinity for the MTS than the mt(1) subtype, affected the phase of circadian activity rhythms when given alone at CT 10, All three antagonists, however, shifted to the right the dose-response curve to melatonin, as they significantly reduced the phase shifting effects of 0.9 and 3 mu g melatonin, This is the first study to demonstrate that melatonin phase advances circadian rhythms by activation of a membrane-bound melatonin receptor and strongly suggests that this effect is mediated through the MT2 melatonin receptor subtype within the circadian timing system. We conclude that the MT2 melatonin receptor subtype is a novel therapeutic target for the development of subtype-selective analogs for the treatment of circadian sleep and mood-related disorders.-Dubocovich, M. L., Yun, K., Al-Ghoul, W. M., Benloucif, S., Masana, M, I. Selective MT2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms.