Acute and Subchronic GPR171 Agonism Affects Anxiety and Depression in Female Mice

Abstract

<b>Abstract ID 26904</b> <b>Poster Board 546</b> G-protein coupled receptors (GPCRs) are one of the most promising targets for pharmaceutical intervention in psychiatric disorders. GPR171, a newly deorphanized GPCR, is of particular interest as a novel therapeutic as it is highly expressed in areas directly involved in anxiety and depression. In males, acute treatment with a GPR171 antagonist decreased anxiety-like behavior compared to vehicle-treated mice but did not affect depressive or fear behaviors. This research has not been extended to females despite females representing approximately two-thirds of those afflicted with anxiety and/or depression. To address the need to develop and test treatments in the larger clinical population, the aim of our research was to determine the role of GPR171 in depression and anxiety in females. We also sought to determine whether the effects of GPR171 were dependent on treatment length, as the long-term effects of treatments are generally neglected in studies exploring depression and anxiety in mice. To explore acute treatment effects, female mice were subjected to a single injection of a GPR171 agonist, antagonist, or vehicle and immediately tested for depressive symptoms in the forced swim test (FST). A separate cohort of females were injected with either a GPR171 agonist, antagonist, or vehicle for 6 days, followed by testing in the elevated plus maze (EPM), and FST to assess anxiety and depression. Time spent in the closed arms vs. open arms in the EPM was automatically recorded using ANYmaze software and immobility time in the FST was manually recorded by a blind reviewer. Results indicate that acute agonist treatment reduced immobility time in the FST in females, while the antagonist did not have any measurable effect compared to the vehicle. Subchronic treatment with the agonist also reduced immobility time in the FST as compared to the vehicle treated mice, indicating that the agonist had an antidepressant effect that was consistent regardless of treatment length. Interestingly, results indicate that subchronic agonist-treated mice had a higher ratio of time spent in the closed vs. open arms in the EPM when compared to vehicle treated mice, suggesting that subchronic treatment of the agonist increased anxiety compared to the vehicle treated mice while the antagonist had no effect. These effects are unlikely to be attributed to any differences in movement seeing as mice did not differ significantly in total distance traveled in the open field test, regardless of treatment group. Together, these findings identify a GPR171 agonist as a potential antidepressant target in females, but future studies are needed to elucidate on the mechanisms underlying the increase of anxiety behaviors under subchronic agonist treatment.