Prophylactic (R,S)-ketamine is effective against stress-induced behaviors in adolescent but not aged miceProphylactic (R,S)-ketamine is effective against stress-induced behaviors in adolescent but not aged mice

Background: (R,S)-ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, is frequently used as an anesthetic and as a rapid-acting antidepressant. We and others have reported that (R,S)-ketamine is prophylactic against stress in adult mice, but have yet to test its efficacy in adolescent or aged populations.

Methods: Here, we administered saline or (R,S)-ketamine as a prophylactic at varying doses to adolescent (5-week-old) and aged (24-month-old) 129S6/SvEv mice of both sexes 1 week before a 3-shock contextual fear conditioning (CFC) stressor. Following CFC, we assessed behavioral despair, avoidance, perseverative behavior, locomotion, and contextual fear discrimination (CFD). To assess whether the prophylactic effect could persist into adulthood, adolescent mice were injected with saline or varying doses of (R,S)-ketamine, and administered a 3-shock contextual fear conditioning (CFC) as a stressor 1 month later. Mice were then re-exposed to the aversive context 5 days later and administered behavioral tests as aforementioned. Brains were also processed to quantify Cyclooxygenase 2 (Cox-2) expression as a proxy for inflammation to determine whether the prophylactic effects of (R,S)-ketamine were partially due to changes in brain inflammation.

Results: Our data indicate that (R,S)-ketamine is prophylactic at sex-specific doses in adolescent, but not aged mice. (R,S)-ketamine attenuated learned fear and perseverative behavior in females and reduced behavioral despair in males, and facilitated CFD in both sexes. (R,S)-ketamine reduced Cox-2 expression specifically in ventral CA3 (vCA3) of male mice.

Conclusions: These findings demonstrate that prophylactic (R,S)-ketamine efficacy is sex-, dose-, and age-dependent and will inform future studies investigating (R,S)-ketamine efficacy across the lifespan.