Lack of rapid antidepressant effects of Kir4.1 channel inhibitors in a chronic social defeat stress model: Comparison with (R)-ketamine.

A recent study demonstrated a key role of astroglial potassium channel Kir4.1 in the lateral habenula in depression. We investigated whether Kir4.1 protein is altered in the brain regions from susceptible mice after a chronic social defeat stress (CSDS). Furthermore, we compared the rapid and sustained antidepressant actions of Kir4.1 inhibitors (quinacrine and sertraline) and (R)-ketamine, (R)-enantiomer of rapid-acting antidepressant (R,S)-ketamine, in a CSDS model. Western blot analysis of Kir4.1 protein in the brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from CSDS susceptible mice and control mice (no CSDS) was performed. Quinacrine (15, or 30 mg/kg), sertraline (20 mg/kg), (R)-ketamine (10 mg/kg), or vehicle was administered intraperitoneally to CSDS susceptible mice. Subsequently, locomotion test, tail suspension test (TST), forced swimming test (FST) and 1% sucrose preference test (SPT) were performed. There were no changes of Kir4.1 protein in the all regions between two groups. (R)-ketamine showed rapid and long-lasting antidepressant actions in CSDS susceptible mice. In contrast, quinacrine and sertraline did not attenuate the increased immobility time of TST and FST in CSDS susceptible mice. Furthermore, quinacrine and sertraline did not improve decreased sucrose preference of SPT in CSDS susceptible mice. Unlike (R)-ketamine, quinacrine and sertraline did not show rapid and sustained antidepressant effects in a CSDS model. Therefore, it is unlikely that Kir4.1 channel inhibitors may have ketamine-like robust antidepressant actions although further study using selective and potent Kir4.1 channel inhibitors is needed.