CART Peptide Modulation of Stimulant Reward

描述（由申请人提供）：药物滥用是一种慢性复发性精神障碍，影响数百万人。然而，有效的治疗方法很少，而且由于对成瘾原因的认识不足，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已经被描述，可能在药物成瘾中发挥作用，值得考虑进行研究。CART（可卡因和安非他明调节转录物）肽是一个神经肽家族，其在大脑中的功能知之甚少，但被认为对动机和兴奋剂（如可卡因和安非他明）的成瘾特性很重要。 这项提议将检验CART肽调节可卡因和安非他明等兴奋剂的奖励性质的假设。CART肽被认为增强了与兴奋剂相关的奖励的神经编码。尽管CART肽最出名的是它们抑制食物摄入的能力--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安非他明增加了大鼠延髓核（一个与动机相关的大脑区域）中其基因的表达。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特的。我们最近的研究表明，CART基因敲除（KO）小鼠表现出减少运动反应安非他明相比，野生型小鼠。最近的一份报告显示，CART肽在大鼠中产生条件性位置偏爱。这些和其他数据表明，兴奋剂的奖励性质是由CART肽调节的。 CART肽在兴奋剂的奖励性质中的作用将通过三种方式进行测试。首先，一系列CART肽，其中一些是新的，将通过在异源细胞中表达产生。第二，这些CART肽以及内源性的刺激和调节特性将通过测量它们对大鼠的自发活动和条件性位置偏爱的影响来测试。第三，可卡因和安非他明以及CART肽对CART KO小鼠的影响将在行为、细胞和分子水平上进行研究。 这些研究将确定CART肽是否调节兴奋剂的奖励特性。CART肽可能是兴奋剂成瘾的可能底物，因此，它们代表了一种新的治疗靶点。选择性CART肽药物治疗兴奋剂成瘾可能是成功的，因为这些肽在大脑中显示出有限的分布，并且作为神经肽，它们在化学信号传导中具有调节功能。这些药物也可用于治疗肥胖和饮食相关疾病。因此，这项工作不仅对药物成瘾的生物学和治疗有意义，而且对食物相关疾病也有意义。

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.