(S)-Ketamine but Not (R)-Ketamine Shows Acute Effects on Depression-Like Behavior and Sleep-Wake Architecture in Rats

Racemic ketamine contains two mirror-image molecules, (R)-ketamine and (S)-ketamine, which have different effects. (S)-ketamine is approved for treating major depression, but (R)-ketamine failed in recent clinical trials. In rats, a single dose of (S)-ketamine, but not (R)-ketamine, delayed the onset of rapid eye movement (REM) sleep, reduced total REM sleep time, and increased slow-wave activity during non-REM sleep. (S)-ketamine also increased wakefulness and decreased non-REM sleep in the first two hours. In chronically stressed rats, only (S)-ketamine reduced immobility in the forced swimming test, indicating antidepressant-like activity. The two enantiomers produce markedly different effects on sleep-wake patterns and behavior at the same dose.

Study at a glance

Abstract

Abstract 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, whereas (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 non-REM (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 sleep-wake stages in freely moving, EEG-equipped 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 2 and 3 hours, and increased electroencephalogram 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 sleep-wake architecture and behavior are markedly different when administered in the same dose. (S)-ketamine remarkably affects the sleep-wake cycle and very likely sleep-related 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 recent clinical studies.