A novel neuropeptide system involved in drug abuse

一种与药物滥用有关的新型神经肽系统

• 批准号: 8416263
• 负责人: OLIVIER CIVELLI
• 金额: $ 34.91万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416263
• 关键词: Acute; Affect; Amphibia; Anti-Anxiety Agents; Anti-Obesity Agents; Area; Attention; Behavior; Biological Assay; Brain; Cells; Cocaine; Cocaine Dependence; Cues; Data; Dopamine Receptor; Drug Design; Drug abuse; Eating; Exhibits; Feeding behaviors; Fishes; Food; Hypothalamic structure; In Situ Hybridization; Knowledge; Lateral; Mammals; Molecular Profiling; Molecular Structure; Motivation; Mouse Strains; Mus; Neurons; Neuropeptides; Nucleus Accumbens; Obese Mice; Peptides; Physiological; Property; Psychological reinforcement; Research; Rewards; Rodent; Role; Self Administration; Site; Skin; System; Testing; addiction; base; brain tissue; dopamine melanin; dopamine system; drug of abuse; drug relapse; fighting; interest; melanin-concentrating hormone; melanin-concentrating hormone receptor; novel; preference; public health relevance; receptor; receptor expression; reinforced behavior; response; teleost fish; zona incerta

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.

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，可作为鱼类和两栖动物肤色的调节剂。直到 1995 年，它才在研究中引起太多关注，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，但由于缺乏对 MCH 受体的了解，这一目标并不可行。随着我们和其他人发现 MCH1 受体 (MCH1R) 的分子结构，这种情况发生了变化，推动 MCH 系统走在抗肥胖药物研究的前沿。然而，我们对 MCH1R 表达谱的研究得出这样的结论：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 CNS 系统，并且 MCH1R 表达水平最高的是伏隔核壳。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 KO 小鼠在条件位置偏好测定中表现出可卡因诱导的反应减少，这表明 MCH 系统可能调节可卡因的动机。这促使我们分离出一种 MCH1R 拮抗剂，以测试 MCH 系统阻断可能对奖赏反应产生的急性影响。我们发现，封锁 MCH 系统对食物奖励没有影响，但对可卡因强化和恢复有深远影响。这些结果虽然是初步的，但表明 MCH 系统是一种参与调节药物滥用相关反应的新型神经肽系统。由于奖励依赖于从腹被区延伸到伏隔核的多巴胺能系统，我们假设 MCH 系统通过与伏隔核壳中的多巴胺受体阳性细胞相互作用来激发其调节作用，并建议分析其作用MCH 系统在强化行为方面的作用。

项目成果

Histamine inhibits the melanin-concentrating hormone system: implications for sleep and arousal.

组胺抑制黑色素浓缩激素系统：对睡眠和唤醒的影响。

• DOI: 10.1113/jphysiol.2013.268771
• 发表时间: 2014
• 期刊: The Journal of physiology
• 作者: Parks,GregoryS;Olivas,NicholasD;Ikrar,Taruna;Sanathara,NaynaM;Wang,Lien;Wang,Zhiwei;Civelli,Olivier;Xu,Xiangmin
• 通讯作者: Xu,Xiangmin

The Antinociceptive Properties of the Corydalis yanhusuo Extract.

延胡索提取物的镇痛特性

• DOI: 10.1371/journal.pone.0162875
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Wang L;Zhang Y;Wang Z;Gong N;Kweon TD;Vo B;Wang C;Zhang X;Chung JY;Alachkar A;Liang X;Luo DZ;Civelli O
• 通讯作者: Civelli O