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

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, 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.

Unique Effects of (R)-Ketamine Compared to (S)-Ketamine on EEG Theta Power in Rats

“…Recently, we have shown that 15 mg/kg i.p. (S)-ketamine but not (R)-ketamine has acute effects on depression-like behavior and sleep–wake architecture, which is in line with the clinical data [ 6 ]. To elaborate, (S)-ketamine decreased REM sleep time at two and three hours following administration, while it decreased NREM sleep and increased wakefulness in the first two hours.…”

“…Standard rodent food and tap water were available ad libitum for the animals during the whole study. The sample size (6–8 rats/group) was determined based on previous research investigating the sleep effect of conventional antidepressants and ketamine enantiomers [ 6 , 14 , 15 , 28 ]. Before surgery, the rats were acclimatized to the housing conditions for 7 days and were handled for 2 min each day for 5 days during this period.…”

“…Rats (9 weeks old), weighing between 290–325 g at surgery, were implanted with EEG and electromyographic (EMG) electrodes under 2% isoflurane anesthesia, using a Kopf stereotaxic instrument, as described earlier [ 6 , 27 , 28 , 29 ]. Briefly, for frontoparietal EEG recordings, stainless steel screw electrodes were placed epidurally over the left frontal cortex (1.5 mm lateral and 2.0 mm anterior to bregma) and over the left parietal cortex (1.5 mm lateral and 2.0 mm anterior to lambda), and a ground electrode was equipped over the cerebellum.…”

“…The determination of the doses was based on our recent publication, in which we showed that the 15 mg/kg i.p. dose is relevant to show antidepressant effects of (S)-ketamine [ 6 ]. Therefore, in this study, we applied the same dose (15 mg/kg i.p.…”

Esketamine Inhibits Cocaine-Seeking Behaviour Subsequent to Various Abstinence Conditions in Rats

“…However, some limitations existed here, as long-term cocaine exposure, despite no effects on “inactive” lever presses, might have affected the baseline activity of the rats. The inhibitory action of esketamine in a lower (5 mg/kg), but not higher (10 mg/kg), dose was unexpected, even more so that some locomotor inhibitory effects were noticed for esketamine doses (15 mg/kg) in the vehicle-pretreated rats, but not repeatedly adrenocorticotropic-hormone (ACTH)-treated rats [ 23 ], while other authors recently demonstrated a lack of motor effects of esketamine in a dose range of 15–20 mg/kg in rats [ 30 , 31 ]. Although a significant effect, the number of inactive lever presses following the 5 mg of esketamine was similar to the response during the cocaine self-administration or vehicle-pretreated rats during the cocaine reinstatement test in rats forwarded to abstinence with social isolation.…”