Background
Racemic ketamine consists of two enantiomers, namely (R)ketamine and (S)ketamine, with distinguishable pharmacological properties. Both enantiomers have been reported to show rapid antidepressant effects in rodents. Currently, the (S)enantiomer has been approved for the treatment of major depression, while (R)ketamine failed to show antidepressant effect in recent clinical studies. Major depressive disorder is frequently characterized by disinhibition of rapid eye movement (REM) sleep and disruption of nonREM (NREM) sleep. Racemic ketamine and most conventional antidepressants affect these parameters. However, it remains largely unknown which enantiomer is responsible for these effects.
Methods
Here, we compared acute effects of the two ketamine enantiomers (15 mg/kg i.p.) on different sleepwake stages in freely moving, EEGequipped rats. We also evaluated the antidepressant-like activity of the enantiomers in a chronic restraint stress model of depression.
Results
(S)ketamine, but not (R)ketamine increased REM sleep latency and decreased REM sleep time at 2h and 3h, and increased EEG delta power during NREM sleep. In addition, only (S)-ketamine increased wakefulness and decreased NREM sleep in the first 2 hours. In the forced swimming test only (S)-ketamine decreased the immobility time of chronically stressed rats.
Conclusion
Effects of the two ketamine enantiomers on rat sleepwake architecture and behavior are markedly different when administered in the same dose. (S)ketamine remarkably affects sleepwake cycle and very likely sleeprelated neuroplasticity, which may be relevant for its antidepressant efficacy. Our results regarding (R)-ketamine’s lack of effect on vigilance and behavior are in line with the recent clinical studies.