Brain functions are regulated by the interactions of neurotransmitters and neuropeptides with their specific receptors. Dysfunction in these interactions is the cause of many neurological and psychiatric disorders. Today, over 100 different neurotransmitters and neuropeptides have been identified. However, genomic sequence analyses show that about 50% of the molecules that mediate brain functions are still unknown. Finding and characterizing these molecules should significantly extend our understanding of brain function. We have developed a strategy, called the orphan receptor strategy, which allows us to discover novel neurotransmitters and neuropeptides. This strategy uses orphan G protein-coupled receptors (GPCRs) as """"""""bait"""""""" to isolate their natural ligands. We analyzed two orphan GPCRs and identified the neuropeptides that are their natural ligands: melanin-concentrating hormone (MCH) and urotensin II (UII). We have studied these systems anatomically, pharmacologically and biologically. We have isolated a MCH receptor antagonist and have found that it can inhibit the hedonic aspect of food intake, e now propose to analyze the effects of this antagonist on rewarding responses. We have also studied two recently found equentially-similar neuropeptides, NPB and NPW, that bind to the orphan GPCR, GPR7. Since little is known about the function of this novel neuropeptide system, we propose to help identify its central roles by first study NPB sites of action in the CNS. We have already obtained preliminary anatomical and behavioral data that show that NPB may act as an anxiolytic agent. Because anxiety is a response to stress, this could set the NPB/NPW system as an important medical target. We propose to further study this role by analyzing NPB effect in different anxiety-related assays. We also propose to extend these studies to mice devoid of GPR7 receptor and analyze their innate level of anxiety. Finally we propose to isolate GPR7 antagonists, by applying the methodology that we used to identify MCH antagonists, and use these antagonists to further understand the function of the NPB/NPW system in anxiety and possibly other behaviors.
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