Involvement of the melanocortin MC4 receptor in stress-related behavior in rodents
Involvement of the melanocortin MC4 receptor in stress-related behavior in rodents
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DOI：
10.1016/s0014-2999(03)02033-8
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发表时间：
2003-08-01
影响因子：
5
通讯作者：
Okuyama, S
中科院分区：
文献类型：
--
作者：
Chaki, S;Ogawa, S;Okuyama, S
黑素皮质素亚型4 （MC4）受体被认为参与应激和应激相关行为。我们利用黑素皮质素MC4受体激动剂和拮抗剂来研究黑素皮质素MC4受体与应激相关疾病的关系。非特异性黑素皮质素受体激动剂-黑素细胞刺激激素（alpha-MSH）和黑素皮质素MC4受体激动剂Ac-[Nle(4),SP5,D-Phe(7),Lys(10)] - α - msh -(4-10)- nh2 （MT II）剂量依赖性地显著减少大鼠Vogel冲突试验中的舔舐次数，提示黑素皮质素MC4受体的刺激引起大鼠的焦虑样活性。我们合成了一种拟肽类黑素皮质素MC4受体选择性拮抗剂Ac-D-2Nal-Arg-2Nal-NH2 (MCL0020)，它对黑素皮质素MC4受体具有高亲和力，IC50值为11.63 +/- 1.48 nM，而对黑素皮质素MC1和MC3受体的亲和力可以忽略不计。此外，MCL0020显著减弱α - msh在表达黑素皮质素MC4受体的COS-1细胞中诱导的cAMP形成，而不影响基础cAMP含量。因此，我们认为MCL0020是黑素皮质素受体中的一种选择性黑素皮质素MC4受体拮抗剂。抑制应激显著降低了大鼠的食物摄取量，体外循环给药mc0020剂量依赖性显著减弱了抑制应激诱导的厌食症，但不影响食物摄取量。在小鼠明暗探索实验中，游泳应激导致小鼠在光区的时间减少，而MCL0020显著阻止了这一现象。综上所述，我们的研究结果表明，黑素皮质素MC4受体可能与应激诱导的行为变化有关，阻断黑素皮质素MC4受体可能预防应激诱导的疾病，如焦虑。(C) 2003 Elsevier B.V.版权所有
The melanocortin subtype 4 (MC4) receptor has been postulated to be involved in stress and stress-related behavior. We made use of melanocortin MC4 receptor agonists and antagonist to investigate the relationship between the melanocortin MC4 receptor and stress related disorders. The nonspecific melanocortin receptor agonist alpha-melanocyte stimulating hormone (alpha-MSH) and the melanocortin MC4 receptor agonist, Ac-[Nle(4),SP5,D-Phe(7),Lys(10)]alpha-MSH-(4-10)-NH2 (MT II) dose-dependently and significantly reduced the number of licking periods in the rat Vogel conflict test, suggesting that stimulation of the melanocortin MC4 receptor causes anxiogenic-like activity in rats. We synthesized a peptidemimetic melanocortin MC4 receptor selective antagonist, Ac-D-2Nal-Arg-2Nal-NH2 (MCL0020), which has high affinity for the melanocortin MC4 receptor with IC50 values of 11.63 +/- 1.48 nM, in contrast, the affinities for melanocortin MC1 and MC3 receptors were negligible. In addition, MCL0020 significantly attenuated the cAMP formation induced by alpha-MSH in COS-1 cells expressing the melanocortin MC4 receptor without affecting basal cAMP contents. Thus, we considered MCL0020 to be a selective melanocrotin MC4 receptor antagonist among melanocortin receptors. Restraint stress significantly reduced food intake in rats, and i.c.v. administration of MCL0020 dose-dependently and significantly attenuated restraint stress-induced anorexia without affecting food intake. Swim stress induced reduction in the time spent in the light area in the mouse light/dark exploration test, and MCL0020 significantly prevented it. Taken together our findings suggest that the melanocortin MC4 receptor might be related to stress-induced changes in behavior, and blockade of the melanocortin MC4 receptor may prevent stress-induced disorders such as anxiety. (C) 2003 Elsevier B.V. All rights reserved.