Prophylactic (R,S)-ketamine selectively protects against inflammatory stressors.

Individuals with peripheral inflammation are a particularly vulnerable population for developing depression and are also more resistant towards traditional antidepressants. This signals the need for novel drugs that can effectively treat this patient population. Recently, we have demonstrated that (R,S)-ketamine is a prophylactic against a variety of stressors, but have yet to test if it is protective against inflammatory-induced vulnerability to a stressor. Here, male 129S6/SvEv mice were administered saline or (R,S)-ketamine (30 mg/kg) 6 days before an injection of vehicle (VEH) or lipopolysaccharide (LPS) (0.83 or 1.0 mg/kg, serotypes O111:B4 or O127:B8). Twenty-four hours after LPS administration, mice were administered a contextual fear conditioning (CFC) paradigm, followed by a context re-exposure and the forced swim test (FST). In a separate cohort, we tested if (R,S)-ketamine was effective as a prophylactic against polyinosinic-polycytidylic acid (PIC), a viral mimetic. (R,S)-ketamine was effective as a prophylactic for attenuating learned fear in the O111:B4 and O127:B8 strains of LPS. (R,S)-ketamine was also effective as a prophylactic for decreasing stress-induced depressive-like behavior in the O111:B4 and O127:B8 strains of LPS. Both of these effects were limited to administration of 1.0, but not 0.83 mg/kg of the O111:B4 and O127:B8 strains of LPS. (R,S)-ketamine was not effective against either stress phenotype following PIC administration. These data suggest that prophylactic (R,S)-ketamine may protect against selective inflammation-induced stress phenotypes following an inflammatory challenge. Future studies will be necessary to determine if (R,S)-ketamine can be useful in patient populations with peripheral inflammation.