PhD Scientific Days 2023

Pharmaceutical Sciences I.

Effects of Ketamine Enantiomers on Sleep-Wake Parameters in Rats

Text of the abstract

Introduction: Recently, S-ketamine (S-enantiomer of ketamine, S-KET) has been approved as an adjunct therapy for major depression, while R-ketamine’s (R-enantiomer of ketamine, R-KET) efficacy is still under investigation. Clinical features of depression include altered sleep parameters, such as disinhibition of rapid eye movement (REM) sleep and disruption of non-REM (NREM) sleep. Conventional (e.g. reuptake inhibitors) and novel (e.g. racemic ketamine) antidepressants characteristically affect these parameters. However, it remains largely unknown how S-KET and R-KET affect these sleep-wake parameters.
Aims: Our aim was to investigate the effects of ketamine enantiomers on different sleep-wake stages.
Method: Electroencephalogram (EEG) equipped Male Wistar rats were treated with S-KET (15 mg/kg i.p.) or R-KET (15 mg/kg i.p.) or vehicle (VEH) at the beginning of the passive phase, and EEG, electromyogram (EMG) and motor activity (MOT) were recorded for 23 h, which included the passive phase (0-11 h) and the active phase (12-23 h) of the animals.
Results: Our analysis revealed that S-KET, but not R-KET promoted wakefulness and decreased NREM sleep in the first 2 h of the passive phase. Moreover, S-KET, but not R-KET decreased REM sleep at 2 h and 3 h of the passive phase, which were followed by a rebound during the active phase. Quantitative EEG analysis revealed that S-KET decreased NREM sleep delta power in the 1 h, followed by a rebound in the 3 h, which was also observable at trend level during the passive phase.
Conclusion: S-KET markedly affects sleep-wake architecture, which may be relevant for its antidepressant efficacy and/or its side-effects, as well. The lack of R-KET effects on sleep-wake stages suggests a better side-effect profile relative to S-KET.


Funding:
2017-1.2.1-NKP-2017-00002, NAP2022-I-4/2022, 2020-4.1.1.-TKP2020, TKP2021-EGA-25
The contribution of Szabolcs Koncz was supported by the ÚNKP-22-4-I-SE-26 New National Excellence Program of the Ministry for Culture and Innovation from the source of the National Research, Development and Innovation Fund.
The publication was prepared also with the support of the Richter Gedeon Talentum Foundation established by Richter Gedeon Plc. in concordance with the framework of the Richter Gedeon PhD Scholarship received by Dóra Pothorszki.