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.

Ketamine, a fast-acting antidepressant, is a racemic mixture, composed of equal amounts of R- and S-ketamine. Preclinical studies are comparing them to better understand their role in therapeutic and undesirable effects. An important research gap is that studies do not use long clinically relevant protocols to compare the desired and undesired effects of ketamine enantiomers in modeled and control animals. In our preclinical study, we explored the behavioral effects of R- and S-ketamine at 10 mg/kg in clinically relevant treatment protocol using Wistar-Kyoto rats as a depression model and Wistar rats as a control. Undesirable psychomotor effects were evaluated with locomotor stimulation and sensitization, ataxia, and stereotypy. Persistent effects associated with therapeutic outcomes were evaluated by measuring working memory, anxiety, and behavioral despair. We found that S-ketamine has stronger acute psychomotor effects compared to R-ketamine and that Wistar-Kyoto rats are more sensitive to these effects compared to Wistar rats. After repeated treatment, sensitization to locomotor stimulating effects, and tolerance to ataxic effects of S-ketamine develops. We found no persistent changes due to ketamine treatments. Taken together, our results may indicate that depressed patients would be more prone to negative side effects of ketamine, compared to healthy controls. However, after repeated treatment, tolerance to side effects may develop and make the treatment more tolerable. Future preclinical and clinical studies are needed to address neurobiological mechanisms and clinical relevance of higher sensitivity to the psychomotor effects of ketamine, and the development of tolerance to psychomotor effects of ketamine in depressed individuals.