Studies show that neuropeptide-receptor systems in the basolateral amygdala (BLA) play an important role in the pathology of anxiety and other mood disorders. Since GPR171， a recently deorphanized receptor for the abundant neuropeptide BigLEN， is expressed in the BLA， we investigated its role in fear and anxiety-like behaviors. To carry out these studies we identified small molecule ligands using a homology model of GPR171 to virtually screen a library of compounds. One of the hits， MS0021570_1， was identified as a GPR171 antagonist based on its ability to block (i) BigLEN-mediated activation of GPR171 in heterologous cells， (ii) BigLEN-mediated hyperpolarization of BLA pyramidal neurons， and (iii... More
Studies show that neuropeptide-receptor systems in the basolateral amygdala (BLA) play an important role in the pathology of anxiety and other mood disorders. Since GPR171， a recently deorphanized receptor for the abundant neuropeptide BigLEN， is expressed in the BLA， we investigated its role in fear and anxiety-like behaviors. To carry out these studies we identified small molecule ligands using a homology model of GPR171 to virtually screen a library of compounds. One of the hits， MS0021570_1， was identified as a GPR171 antagonist based on its ability to block (i) BigLEN-mediated activation of GPR171 in heterologous cells， (ii) BigLEN-mediated hyperpolarization of BLA pyramidal neurons， and (iii) feeding induced by DREADD-mediated activation of BigLEN containing AgRP neurons in the arcuate nucleus. The role of GPR171 in anxiety-like behavior or fear conditioning was evaluated following systemic or intra-BLA administration of MS0021570_1， as well as following lentiviral-mediated knockdown of GPR171 in the BLA. We find that systemic administration of MS0021570_1 attenuates anxiety-like behavior while intra-BLA administration or knockdown of GPR171 in the BLA reduces anxiety-like behavior and fear conditioning. These results indicate that the BigLEN-GPR171 system plays an important role in these behaviors and could be a novel target to develop therapeutics to treat psychiatric disorders.
