Comparison of rapid and long-lasting antidepressant effects of negative modulators of α5-containing GABAA receptors and (R)‑ketamine in a chronic social defeat stress model

Abstract

The negative allosteric modulators (NAMs: L-655,708 and MRK-016) of α5 subunit-containing GABAA receptors are reported to show rapid-acting antidepressant effects in rodents. However, there are no reports comparing these NAMs and (R)‑ketamine, (R)-enantiomer of the rapid-acting antidepressant ketamine, in a chronic social defeat stress (CSDS) model. Here we measured expression of α5 GABAA receptor in the brain regions from CSDS susceptible mice and postmortem brain samples from depressed patients. Expression of α5 GABAA receptor in the prefrontal cortex and hippocampus from CSDS susceptible mice was significantly higher than that of control mice. Furthermore, expression of α5 GABAA receptor in the parietal cortex from depressed patients was also higher than that of control subjects. In the tail suspension and forced swimming tests, (R)‑ketamine and MRK-016 significantly attenuated the increased immobility time in the susceptible mice, compared with the vehicle-treated group. In the sucrose preference test, (R)‑ketamine and MRK-016 significantly enhanced the reduced preference in CSDS susceptible mice two days after a single injection. Unlike (R)‑ketamine, MRK-016 did not attenuate the reduced sucrose preference in susceptible mice 7 days after a single injection. In contrast, L-655,708 did not show antidepressant effects in the same model. In conclusion, this study shows that increased levels of α5 GABAA receptors in the PFC and hippocampus may play a role in depression-like phenotype after CSDS. It is unlikely that MRK-016 has long-lasting antidepressant effects although it elicits rapid-acting antidepressant effects.