GPR171 is necessary for normal physiological functions and mood-related behaviors in males, but not females.

GPR171 is a recently deorphanized G protein-coupled receptor that has been implicated in feeding, mood regulation, and pain. However, the role of this receptor in other physiological functions and in female mice is largely unexplored. Using a novel genetic GPR171 knockout mouse model, we examined general physiological behaviors and mood-related behaviors in both sexes. In male GPR171 knockout mice, we observed increased feeding, reduced water intake, heightened ataxia, and decreased anxiety-like behaviors. Male GPR171 knockout mice showed greater depressive-like behaviors compared to female knockout mice, but this did not correspond to a change in cFos activity in the basolateral amygdala. No significant changes were detected in female GPR171 knockout mice in other behaviors measured. These findings corroborate previous studies linking GPR171 to feeding and mood regulation in males, but highlight notable sex differences that were previously unknown. These sex differences indicate that future studies should focus on elucidating the behavioral effects of GPR171 in females to provide a more comprehensive understanding of its physiological roles.