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

Ketamine's antidepressant potential is limited by side effects such as motor impairment. In rats, repeated low doses of ketamine enantiomers produced distinct behavioral changes. S-ketamine at 15 mg/kg caused initial locomotor stimulation and ataxia, while repeated administration led to locomotor sensitization and tolerance to ataxia. R-ketamine at 15 mg/kg also stimulated locomotion and caused sensitization but did not induce ataxia or reduce natural behaviors like grooming and rearing. Higher doses of racemic ketamine (30 mg/kg) produced both stimulation and ataxia. Overall, S-ketamine had stronger behavioral effects than R-ketamine, suggesting R-ketamine may have a more favorable side-effect profile.

Study at a glance

Abstract

Ketamine has gained significant attention as a fast-acting antidepressant. However, ketamine is also associated with undesirable side effects. In our preclinical study, we explored the behavioral effects of ketamine enantiomers at subanesthetic doses. During repeated intermittent treatment, we examined locomotor stimulation and sensitization, ataxia, and expression 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). After the first treatment, only 15 mg/kg of S-ketamine induced locomotor stimulation, and both 15 mg/kg of S-ketamine and 30 mg/kg of racemic ketamine induced ataxia. Upon repeated administration, doses of 15 mg/kg of R-ketamine, S-ketamine, and racemic ketamine, as well as 30 mg/kg of racemic ketamine, stimulated locomotion. 15 mg/kg of R-ketamine, S-ketamine, and racemic ketamine additionally resulted in locomotor sensitization. The last administration of 15 mg/kg of S-ketamine, 15 mg/kg of racemic ketamine, and 30 mg/kg of racemic ketamine resulted in ataxia. In the case of 15 mg/kg of S-ketamine, ataxic effects were significantly weaker in comparison to the effects from the first administration, indicating tolerance. Natural behaviors were attenuated after 5 and 15 mg/kg of S-ketamine and 15 and 30 mg/kg of racemic ketamine. Neither of the R-ketamine doses produced such an effect. We conclude that S-ketamine has a stronger behavioral effect than R-ketamine.