A novel neuropeptide system involved in drug abuse

描述(申请人提供)：黑色素浓缩激素(MCH)是一种生物活性多肽，发现于1980年，作为鱼类和两栖动物皮肤颜色的调节剂。直到1995年，它才引起了研究人员的广泛关注，当时它被证明在遗传性肥胖的小鼠中被诱导，并能够在脑室内注射时增加食物摄入量。这使得MCH系统成为抗肥胖药物设计的目标，但由于缺乏对MCH受体的了解，这一目标是不可行的。随着我们和其他人发现了MCH1受体(MCH1R)的分子结构，这种情况发生了变化，这推动了MCH系统处于抗肥胖药物研究的前沿。然而，我们对MCH1R表达谱的研究得出的结论是，MCH系统不仅仅在摄食行为中发挥作用。最有趣的是，我们发现MCH系统主要是一个中枢神经系统，MCH1R在伏隔核壳中的表达水平最高。因此，我们假设妇幼保健系统可能在奖励中发挥作用。首先，我们发现MCH1R KO小鼠在条件性位置偏爱实验中表现出减少的可卡因诱导反应，这表明MCH系统可能调节可卡因的动机。这促使我们分离了一种MCH1R拮抗剂，以测试阻断MCH系统可能对奖赏反应产生的急性影响。我们发现，封锁妇幼保健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，但表明MCH系统是一种新的神经肽系统，参与调节药物滥用相关的反应。由于奖赏依赖于从腹被盖区延伸到伏核的多巴胺能系统，我们假设MCH系统通过与伏核外壳中的多巴胺受体阳性细胞相互作用来发挥其调节作用，并建议分析MCH系统在增强行为中的作用。

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.