A novel neuropeptide system involved in drug abuse

描述（由申请人提供）：黑色素浓缩激素（MCH）是1980年发现的一种生物活性肽，可调节鱼类和两栖动物的皮肤颜色。直到1995年，它才在研究中引起了很大的关注，当时它被证明可以在遗传性肥胖小鼠中诱导，并且在脑室内注射时能够增加食物摄入量。这使得MCH系统成为抗肥胖药物设计的目标，然而由于缺乏对MCH受体的了解，这一目标是不可行的。这一点随着我们和其他人发现MCH 1受体（MCH 1R）的分子结构而改变，这将MCH系统推向了抗肥胖药物研究的前沿。然而，我们对MCH 1R表达谱的研究得出的结论是，MCH系统不仅仅在摄食行为中起作用。最感兴趣的是，我们发现MCH系统主要是CNS系统，并且最高水平的MCH1R表达在丘脑核的壳中。因此，我们假设MCH系统可能在奖励中发挥作用。首先，我们发现，MCH1R基因敲除小鼠表现出减少可卡因诱导的反应，在条件性位置偏爱试验，表明MCH系统可能调节可卡因的动机。这促使我们分离MCH1R拮抗剂，以测试MCH系统的阻断可能对奖励反应产生的急性影响。我们发现，阻断MCH系统对食物奖励没有影响，但对可卡因的强化和恢复有深远的影响。这些结果，虽然是初步的，指向MCH系统作为一种新的神经肽系统参与调节药物滥用相关的反应。由于奖励是已知的依赖于多巴胺能系统从腹侧被盖区延伸到核丘脑，我们假设，MCH系统唤起其调节作用的相互作用与多巴胺受体阳性细胞的壳丘脑，并建议分析MCH系统在加强行为的作用。 公共卫生相关性：如果我们能够证明MCH系统可以调节滥用药物的动机方面，我们将发现一种与成瘾有关的新型递质系统。由于我们可能表明妇幼保健系统可以阻止药物复吸，我们的数据可以作为使用妇幼保健系统作为帮助打击药物滥用的可能目标的基础。

DESCRIPTION (provided by applicant): Melanin-concentrating hormone (MCH) is a bioactive peptide found in 1980 as a modulator of skin coloration in fishes and amphibians. It had not attracted much attention in research until 1995, when it was shown to be induced in genetically obese mice and to be able to increase food intake when injected intracerebroventrically. This made the MCH system a target for anti-obesity drug design, an aim however not feasible for lack of knowledge of the MCH receptor. This changed with our and others discovery of the molecular structure of MCH1 receptor (MCH1R), which propelled the MCH system at the forefront of anti obesity drug research. Our study on the expression profile of the MCH1R however had led to the conclusion that there was much more to the MCH system than only a role in feeding behavior. Of most interest, we had found that the MCH system is predominantly a CNS system and that the highest level of MCH1R expression is in the shell of the nucleus accumbens. We therefore hypothesized that the MCH system may have a role in reward. First, we found that MCH1R KO mice exhibit a reduced cocaine-induced response in the conditioned place preference assay, an indication that the MCH system may regulate motivation for cocaine. This incited us to isolate a MCH1R antagonist to test the acute effects that blockade of the MCH system may have on reward responses. We found that blockade of the MCH system has no effect on food reward but has a profound effect on cocaine reinforcement and reinstatement. These results, although preliminary, point at the MCH system as a novel neuropeptide system involved in modulating drug of abuse related responses. Since reward is known to rely on the dopaminergic system extending from the ventrotegmental area to the nucleus accumbens, we hypothesize that the MCH system evokes its modulatory role by interacting with dopamine receptor positive cells in the shell of the nucleus accumbens and propose to analyze the role of the MCH system in reinforcing behaviors. PUBLIC HEALTH RELEVANCE: If we can demonstrate that the MCH system can regulate the motivational aspect of drugs of abuse, we will have discovered a novel transmitter system involved in addiction. Since we may show that the MCH system may block drug relapse, our data may serve as a basis to use the MCH system as a possible target for helping fight drugs of abuse.