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

Differences in the pharmacological effects of (S)-ketamine and (R)-ketamine are at the focus of research. Clinical data and our rat studies confirmed the antidepressant effect of (S)- but not (R)-ketamine, with similar differences in quantitative electroencephalogram (EEG) and sleep effects. In contrast, studies mainly on mice showed some stronger, preferable effects of (R)-ketamine. EEG theta (5-9 Hz) rhythm originates from the hippocampus, and its power is associated with cognitive functions, attention, and decreased anxiety. To find a brain parameter that is not associated with the antidepressant effect of drugs and may confirm potent in vivo effects of (R)-ketamine in rats, theta EEG power-inducing effects of the two enantiomers were measured and compared for 23 h. EEG-equipped Wistar rats were treated with (R)-ketamine (7.5, 15, 30 mg/kg i.p.), (S)-ketamine (7.5 and 15 mg/kg i.p.), or vehicle at the beginning of the passive phase. Frontoparietal EEG, electromyogram, and motor activity were recorded. (R)-ketamine but not (S)-ketamine dose-dependently increased EEG theta power during wakefulness and rapid eye movement (REM) sleep for 23 h. These results suggest that (R)-ketamine has an effect on a hippocampal function that was not affected by (S)-ketamine and may be associated with neural plasticity and memory encoding.

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

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.

EEG and Sleep Effects of Tramadol Suggest Potential Antidepressant Effects with Different Mechanisms of Action.

Tramadol is a widely used, centrally acting, opioid analgesic compound, with additional inhibitory effects on the synaptic reuptake of serotonin and noradrenaline, as well as on the 5-HT2 and NMDA receptors. Preclinical and clinical evidence also suggests its therapeutic potential in the treatment of depression and anxiety. The effects of most widely used antidepressants on sleep and quantitative electroencephalogram (qEEG) are well characterized; however, such studies of tramadol are scarce. Our aim was to characterize the effects of tramadol on sleep architecture and qEEG in different sleep-wake stages. EEG-equipped Wistar rats were treated with tramadol (0, 5, 15 and 45 mg/kg) at the beginning of the passive phase, and EEG, electromyogram and motor activity were recorded. Tramadol dose-dependently reduced the time spent in rapid eye movement (REM) sleep and increased the REM onset latency. Lower doses of tramadol had wake-promoting effects in the first hours, while 45 mg/kg of tramadol promoted sleep first, but induced wakefulness thereafter. During non-REM sleep, tramadol (15 and 45 mg/kg) increased delta and decreased alpha power, while all doses increased gamma power. In conclusion, the sleep-related and qEEG effects of tramadol suggest antidepressant-like properties, including specific beneficial effects in selected patient groups, and raise the possibility of a faster acting antidepressant action.