Behavioral sensitization and tolerance induced by repeated treatment with ketamine enantiomers in male Wistar rats

Ketamine has gained significant attention as a treatment for depression. However, it is also associated with undesirable side effects. In our preclinical study, we explored the behavioral effects of ketamine enantiomers, hypothesizing that R-ketamine will have fewer behavioral effects than S-ketamine. During repeated intermittent treatment with doses relevant to antidepressant therapy, we examined behaviors that are regarded as behavioral markers of unwanted effects: locomotor stimulation and sensitization, ataxia, and disruption of natural behaviors (grooming and rearing). Male Wistar rats were subcutaneously treated repeatedly with either 5 mg/kg of R-ketamine or S-ketamine, 15 mg/kg of R-ketamine, S-ketamine or racemic ketamine, 30 mg/kg of racemic ketamine or saline every third day for three weeks (seven treatments overall). We found locomotor stimulation after the first dose of 15 mg/kg of S-ketamine and ataxic behaviors after the first dose of 15 mg/kg of S-ketamine and 30 mg/kg of racemic ketamine. After repeated treatment, 15 mg/kg of R-ketamine, S-ketamine, and racemic ketamine and 30 mg/kg of racemic ketamine resulted in locomotor stimulation. After repeated treatment, we also found locomotor sensitization for 15 mg/kg of R-ketamine, S-ketamine, and racemic ketamine and tolerance to the ataxic effects for 15 mg/kg of S-ketamine. Lastly, 5 mg/kg of S-ketamine, 15 mg/kg of S-ketamine and racemic ketamine, and 30 mg/kg of racemic ketamine decreased the duration of natural behaviors, while R-ketamine at 5 mg/kg and 15 mg/kg did not. Our findings suggest that S-ketamine has stronger behavioral effects than R-ketamine, implying that R-ketamine may be a safer antidepressant option.