AUTHOR=Mastrodonato Alessia , Pavlova Ina , Kee Noelle , McGowan Josephine C. , Mann J. John , Denny Christine A. 

TITLE=Acute (R,S)-Ketamine Administration Induces Sex-Specific Behavioral Effects in Adolescent but Not Aged Mice

JOURNAL=Frontiers in Neuroscience

VOLUME=16

YEAR=2022

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2022.852010

DOI=10.3389/fnins.2022.852010

ISSN=1662-453X

ABSTRACT=<p>(<italic>R</italic>,<italic>S</italic>)-ketamine is an <italic>N</italic>-methyl-D-aspartate (NMDA) receptor antagonist that was originally developed as an anesthetic. Most recently, (<italic>R</italic>,<italic>S</italic>)-ketamine has been used as a rapid-acting antidepressant, and we have reported that (<italic>R</italic>,<italic>S</italic>)-ketamine can also be a prophylactic against stress in adult mice. However, most pre-clinical studies have been performed in adult mice. It is still unknown how an acute (<italic>R</italic>,<italic>S</italic>)-ketamine injection influences behavior across the lifespan (e.g., to adolescent or aged populations). Here, we administered saline or (<italic>R</italic>,<italic>S</italic>)-ketamine at varying doses to adolescent (5-week-old) and aged (24-month-old) 129S6/SvEv mice of both sexes. One hour later, behavioral despair, avoidance, locomotion, perseverative behavior, or contextual fear discrimination (CFD) was assessed. A separate cohort of mice was sacrificed 1 h following saline or (<italic>R</italic>,<italic>S</italic>)-ketamine administration. Brains were processed to quantify the marker of inflammation Cyclooxygenase 2 (Cox-2) expression to determine whether the acute effects of (<italic>R</italic>,<italic>S</italic>)-ketamine were partially mediated by changes in brain inflammation. Our findings show that (<italic>R,S</italic>)-ketamine reduced behavioral despair and perseverative behavior in adolescent female, but not male, mice and facilitated CFD in both sexes at specific doses. (<italic>R,S</italic>)-ketamine reduced Cox-2 expression specifically in ventral CA3 (vCA3) of male mice. Notably, (<italic>R</italic>,<italic>S</italic>)-ketamine was not effective in aged mice. These results underscore the need for sex- and age-specific approaches to test (<italic>R,S</italic>)-ketamine efficacy across the lifespan.</p>