Anxiety disorders are prevalent across the United States and result in a large personal and societal burden. Currently, numerous therapeutic and pharmaceutical treatment options exist. However, drugs to classical receptor targets have shown limited efficacy and often come with unpleasant side effects, highlighting the need to identify novel targets involved in the etiology and treatment of anxiety disorders. GPR83, a recently deorphanized receptor activated by the abundant neuropeptide PEN, has also been identified as a glucocorticoid regulated receptor (and named GIR) suggesting that this receptor may be involved in stress-responses that underlie anxiety. Consistent with this, GPR83 null mice have been found to be resistant to stress-induced anxiety. However, studies examining the role of GPR83 within specific brain regions or potential sex differences have been lacking. In this study, we investigate anxiety-related behaviors in male and female mice with global knockout and following local GPR83 knockdown in female mice. We find that a global knockdown of GPR83 has minimal impact on anxiety-like behaviors in female mice and a decrease in anxiety-related behaviors in male mice. In contrast, a local GPR83 knockdown in the basolateral amygdala leads to more anxiety-related behaviors in female mice. Local GPR83 knockdown in the central amygdala or nucleus accumbens showed no significant effect on anxiety-related behaviors. Finally, dexamethasone administration leads to a significant decrease in receptor expression in the amygdala and nucleus accumbens of female mice. Together, our studies uncover a significant, but divergent role for GPR83 in different brain regions in the regulation of anxiety-related behaviors, which is furthermore dependent on sex.

Anxiety disorders, prevalent in our society, represent a burden for those suffering with these disorders. Recent studies have shed light onto the brain circuits involved in generating anxiety and there are pharmaceutical treatments for anxiety‐disorders. Despite this, patients still suffer, highlighting the need to investigate new targets involved in the etiology of anxiety disorders. GPR83, a recently deorphanized receptor activated by the abundant neuropeptide PEN, was first identified due to its regulation by the glucocorticoid agonist dexamethasone, suggesting that GPR83 may be involved in stress‐responses that underlie anxiety. Subsequent studies identified that GPR83 null mice were resistant to stress‐induced anxiety, however, these studies did not investigate sex differences or specific brain regions. In the present studies, global loss of GPR83 in knockout mice resulted in reduced anxiety‐related behaviors which were more evident in male mice. Additionally, our studies identified that GPR83 is expressed on parvalbumin‐positive neurons in the basolateral and central amygdala. Furthermore, dexamethasone induced sex‐ and brain region dependent regulation of GPR83 expression with a consistent decrease in GPR83 expression in the nucleus accumbens and amygdala of female mice. Therefore, we sought to determine the effect of local GPR83 knockdown in the basolateral amygdala, central nucleus of the amygdala, and nucleus accumbens of female mice. We uncovered that female mice with local GPR83 knockdown in the basolateral amygdala displayed more anxiety‐related behaviors. Overall, our studies uncovered a significant role for GPR83 in the regulation of anxiety‐related behaviors.