Prophylactic (R,S)-Ketamine Is Effective Against Stress-Induced Behaviors in Adolescent but Not Aged Mice

Abstract

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.

Dose-Dependent Antidepressant-Like Effects of Cannabidiol in Aged Rats

“…In fact, the prevalence of depression in the population aged over 80 years has been shown to be around 15-20% (Stek et al, 2004), with the corresponding increased prescription of antidepressant drugs (Sonnenberg et al, 2008). Surprisingly, antidepressant-like treatments are known to change their efficacy with age [e.g., reviewed by Felice et al (2015)]; however, not much research is focused on characterizing classical antidepressant-like responses and/or novel therapeutical options for this age group (see some representative recent preclinical studies: Fernández-Guasti et al, 2017;Mastrodonato et al, 2022), posing a health problem for our continuously increasing elderly population. In the clinic, the only approach taken with elderly patients includes lowering the doses to adjust for a slower metabolism.…”