CART Peptide Modulation of Stimulant Reward

描述(申请人提供)：药物滥用是一种慢性复发性精神障碍，影响数百万人。然而，由于对成瘾原因的了解很少，有效的治疗方法很少，新的治疗方法的前景也不乐观。 近年来，一些新的基因和蛋白质被描述出来，它们可能在药物成瘾中起作用，值得考虑进行研究。CART(可卡因和苯丙胺调节转录物)多肽是一类神经肽，其在大脑中的功能尚不清楚，但被认为对可卡因和苯丙胺等兴奋剂的动机和成瘾特性具有重要作用。 这项提议将检验CART多肽调节可卡因和安非他明等兴奋剂的奖赏特性的假设。CART多肽被认为增强了与刺激剂相关的奖励的神经编码。尽管卡特多肽最为人所知的是它们抑制食物摄取的能力--这是兴奋剂的一个经典特征，但我们最初发现它们是因为可卡因和苯丙胺增加了它在大鼠伏隔核中的基因表达，这是大脑中与动机相关的区域。CART和CART肽在动机神经回路中的分布在化学递质和受体中是独一无二的。我们最近的研究表明，与野生型小鼠相比，Cart基因敲除(KO)小鼠对苯丙胺的运动反应减弱。最近的一份报告显示，CART多肽在大鼠中产生条件性位置偏爱。这些和其他数据表明，刺激剂的奖赏特性受CART多肽的调节。 CART多肽在兴奋剂奖励特性中的作用将通过三个方面进行测试。首先，将通过在异源细胞中表达产生一系列CART多肽，其中一些是新的。其次，将通过测量它们对大鼠的运动活动和条件性位置偏爱的影响来测试这些CART多肽以及内源性多肽的刺激和条件反射特性。第三，将从行为、细胞和分子水平研究可卡因、苯丙胺以及CART多肽对CART KO小鼠的影响。 这些研究将确定CART多肽是否调节刺激剂的奖赏特性。CART多肽可能是兴奋剂成瘾的底物，因此，它们代表了一个新的治疗靶点。选择性CART多肽治疗兴奋剂成瘾可能是成功的，因为这些多肽在大脑中的分布有限，而且作为神经肽，它们在化学信号中具有调节功能。这些药物也可能用于治疗肥胖症和与饮食相关的疾病。因此，这项工作对药物成瘾的生物学和治疗有意义，也对食物相关的疾病有意义。

DESCRIPTION (provided by applicant): Drug abuse is a chronic relapse mental disorder that affects millions of people. However, there are few effective treatments and the outlook for new ones is not promising because of the poor understanding of the causes of addiction. In recent years, several novel genes and proteins have been described that may have a role in drug addiction and merit consideration for study. CART (Cocaine and Amphetamine-Regulated Transcript) peptides are a family of neuropeptides whose function in the brain is poorly understood but are thought to be important to the motivation and in the addictive properties of stimulants such as cocaine and amphetamine. This proposal will test the hypothesis that CART peptides modulate the rewarding properties of stimulants such as cocaine and amphetamine. CART peptides are thought to enhance the neural coding for reward associated with stimulants. Although CART peptides are best known for their ability to suppress food intake -- a classic feature of stimulants, they were initially identified by us because cocaine and amphetamine increase its expression of its gene in the rat nucleus accumbens, a brain area associated with motivation. The distribution of CART and CART peptides in neural circuitry of motivation is unique among chemical transmitters and receptors. Our recent studies show that CART knockout (KO) mice exhibit decreased locomotor responses to amphetamine compared to wild-type mice. A recent report shows that CART peptides produce conditioned place preference in rats. These and other data suggest that the rewarding property of stimulants is regulated by CART peptides. The role of CART peptides in the rewarding properties of stimulants will be tested three ways. First, a series of CART peptides, some of which are novel, will be produced by expression in heterologous cells. Second, the stimulatory and conditioning properties of these CART peptides as well as endogenous ones will be tested by measuring their effects on locomotor activity and conditioned place preference in rats. Third, the effects of cocaine and amphetamine as well as CART peptides on CART KO mice will be investigated at a behavioral, cellular and molecular level. These studies will determine whether CART peptides modulate the rewarding properties of stimulants. CART peptides may be possible substrates of stimulant addiction, and as such, they represent a novel therapeutic target. Selective CART peptide pharmacotherapies for stimulant addiction may be successful because these peptides show a restricted distribution in brain, and as neuropeptides, they have modulatory functions in chemical signaling. These medications may also find use in the treatment of obesity and eating related disorders. Hence, this work has implications for the biology and treatment of drug addiction, but also for food related disorders.