Neuromedin U as a Novel Mechanism Underlying Cocaine Addiction

描述（由申请人提供）：需要安全有效的可卡因成瘾治疗方法来解决药物滥用障碍的巨大负担。需要对奖赏的分子、神经和行为基础进行扩展的机制性评价，以确定成瘾的整体药物靶点。有趣的是，超过40万美国人是活跃的可卡因使用者，但不被认为是可卡因依赖者。这些人具有潜在的弹性神经生物学，使他们对可卡因成瘾的发展具有抵抗力。研究这种“复原力的神经生物学”可能会深入了解成瘾的分子，神经和行为基础，并导致可卡因成瘾的新药物靶点。在这方面的一个创新的前景是神经介肽U（NMU），它是一种高度保守的神经肽，已被证明可以抑制食物的摄入，这是一种自然的奖励。NMU的这些作用可能是由于腹侧被盖区（VTA）的作用，腹侧被盖区是中脑系统的起源。很少有人知道NMU在mesoebens电路的参与，虽然最近的数据表明，NMU管理增加神经元的活动，在该电路的终端区域，核神经元。初步数据表明，在VTA中的表达增加，以响应急性或慢性可卡因，这种响应显示出高水平的个体差异，一些动物在对照范围内，而另一些动物比对照高五倍。此外，我们发现外周注射NMU可以阻断对可卡因的行为敏化。本提案的目标是探索VTA中的NMU信号传导作为对可卡因的行为反应的关键机制。为此，将确定VTA中NMU表达的变化是否可以预测对可卡因的行为反应的程度。此外，我们试图证明NMU在可卡因的行为效应中的作用，通过使用RNAi介导的敲低VTA中的NMU，然后评估可卡因的运动敏感性。总的来说，将VTA中的NMU信号传导与可卡因的行为效应联系起来将促进NMU信号传导是对滥用药物的行为反应的基础的想法，并支持其作为治疗成瘾的新治疗靶点的潜力。

DESCRIPTION (provided by applicant): Safe and effective approaches for the treatment of cocaine addiction are needed to address the tremendous burden of substance abuse disorders. An expanded mechanistic appreciation of the molecular, neural, and behavioral bases of reward is needed to identify integral pharmacotherapeutic targets for addiction. Interestingly, over 400,000 Americans are active cocaine users but are not considered cocaine dependent. These individuals have an underlying resilient neurobiology which makes them resistant to the development of addiction to cocaine. Studying this "neurobiology of resilience" may provide insight into the molecular, neural, and behavioral basis of addiction and lead to novel pharmacotherapeutic targets for cocaine addiction. An innovative prospect in this regard is neuromedin U (NMU), a highly conserved neuropeptide which has been shown to inhibit intake of food, a natural reward. These effects of NMU may be due to actions in the ventral tegmental area (VTA), the origin of the mesoaccumbens system. Little is known about the involvement of NMU in mesoaccumbens circuit, although recent data demonstrate that NMU administration increases neuronal activity in a terminal area of this circuit, the nucleus accumbens. Preliminary data indicates that expression is increased in the VTA in response to acute or chronic cocaine, a response which shows high levels of individual differences, with some animals in the range of controls while others are fivefold higher than controls. Also, we found that peripheral injection o NMU can block behavioral sensitization to cocaine. The goal of the present proposal is to explore NMU signaling in the VTA as a key mechanism that underlies behavioral responses to cocaine. To this end, it will be determined if changes in expression of NMU in the VTA can predict the magnitude of behavioral responses to cocaine. In addition, we seek to demonstrate a role for NMU in the behavioral effects of cocaine via use of RNAi-mediated knockdown of NMU in the VTA followed by assessment of locomotor sensitization to cocaine. Overall, linking NMU signaling in the VTA with the behavioral effects of cocaine will promote the idea that NMU signaling underlies behavioral responses to drugs of abuse, and support its potential as a novel therapeutic target to treat addiction.