CART Peptides as Targets for CNS Drug Development

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.