CART Peptides as Targets for CNS Drug Development
CART Peptides as Targets for CNS Drug Development
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DOI：
10.2174/1568007033482896
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发表时间：
2003-01-01
影响因子：
3
通讯作者：
Kuhar, Michael J.
中科院分区：
文献类型：
--
作者：
Hunter, Richard G.;Kuhar, Michael J.
CART肽是一种相对较新的神经肽，与摄食、药物奖励和应激有关。它们是由人类版本的89个氨基酸长度的原cart多肽形成的。片段42-89和片段49-89在摄食和运动以及其他功能方面具有行为活性。这些肽在脑、肠、垂体、肾上腺和胰腺中含量丰富，分布广泛而分散。在下丘脑的特定核中CART免疫反应性的存在导致了对注射icv的CART肽对摄食的影响的检查，这已被证明是显著的厌食。对转基因动物和人类的研究也证明了与肥胖和厌食症的联系。同样，CART定位于中边缘多巴胺系统的子区域，这证明了CART肽在注射到腹侧被盖区（VTA）时对运动活动和条件性位置偏好的影响，这在质量上类似于精神兴奋剂。这些发现还表明CART具有调节中脑边缘多巴胺的能力，这可能不仅对精神兴奋剂滥用的治疗有影响，而且对其他与中脑边缘多巴胺有关的疾病的治疗也有影响，如精神分裂症。其他证据也表明CART肽参与恐惧和惊吓行为，这可能对理解焦虑和压力有影响。开发CART模拟物和相关药物的一个重要部分将是鉴定CART受体。目前这样的受体还没有被识别出来，应该在这个问题上投入更多的努力。尽管如此，CART肽还是为肥胖和其他疾病的新药开发提供了有趣的靶点。
CART peptides are relatively novel neuropeptides involved in feeding, drug reward and stress. They are formed from a proCART polypeptide that is 89 amino acids in length in the human version. Fragments 42-89 and 49-89 are behaviorally active in feeding and locomotion as well and other functions. These peptides are highly abundant and widely but discretely distributed in the brain, gut, pituitary, adrenals and pancreas. The presence of CART immunoreactivity in specific nuclei of the hypothalamus has led to an examination of icv-injected CART peptides' effects on feeding, which have proven to be significantly anorectic. Studies of transgenic animals and humans have also demonstrated a linkage to both obesity and anorexia. Similarly, the localization of CART to sub-regions of the mesolimbic dopamine system has led to demonstration of the effects of CART peptides on locomotor activity and conditioned place preference when injected into the ventral tegmental area (VTA), which are psychostimulant-like in quality. These findings also suggest that CART has the capacity to modulate mesolimbic dopamine, which could have implications for the treatment not only of psychostimulant abuse but also for the treatment of other disorders with mesolimbic dopamine involvement, such as schizophrenia. Other lines of evidence also show that CART peptides are involved in fear and startle behaviors which may have implications for understanding anxiety and stress. An important part of the development of CART mimetics and related drugs would be the identification of CART receptors. At the present time such receptors have not been identified, and much effort should be directed at this problem. Nonetheless, CART peptides offer interesting targets for new drug development for obesity and, potentially, a number of other disorders.