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1.
Pharmaceuticals (Basel) ; 17(2)2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38399409

RESUMEN

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.

2.
Int J Neuropsychopharmacol ; 26(9): 618-626, 2023 09 25.
Artículo en Inglés | MEDLINE | ID: mdl-37578355

RESUMEN

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.


Asunto(s)
Trastorno Depresivo Mayor , Ketamina , Ratas , Animales , Ketamina/farmacología , Ketamina/uso terapéutico , Depresión/tratamiento farmacológico , Trastorno Depresivo Mayor/tratamiento farmacológico , Sueño , Antidepresivos/farmacología , Antidepresivos/uso terapéutico
3.
Pharmaceuticals (Basel) ; 14(5)2021 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-34064349

RESUMEN

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.

4.
Front Cell Neurosci ; 13: 138, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31024264

RESUMEN

Environmental stress and its interaction with genetic variation are key contributors in the development of depression and anxiety, yet there is a failure to identify replicable genetic variants and gene-interaction effects in the background of these psychiatric symptoms. Recently it has been reported that 5-HTTLPR and NOSI interact with financial but not other types of recent stressors in the development of depression. In the present study we investigated the interaction of GABRA6 rs3219151 and CNR1 rs7766029 in interaction with different types of recent life events on the presence of depression and anxiety in a large general population sample. 2191 participants completed the List of Threatening Experiences questionnaire which covers four categories of stressful life events (financial problems, illness/personal problems, intimate relationships, and social network) experienced over the previous year and the Brief Symptom Inventory for depression and anxiety symptoms. Participants were genotyped for rs3219151 and rs7766029. Data were analyzed with linear regression models with age and gender as covariates. Results indicated that CNR1 rs7766029 interacted significantly with financial but not other types of life events both in case of depression and anxiety symptoms. In contrast, GABRA6 rs3219151 showed a significant interaction with social network related life events in case of anxiety and with illness/personal problem-related life events in case of depression. Our results suggest that the psychological impact of different types of recent stress may be differentially modulated by distinct molecular genetic pathways. Furthermore, in case of certain genetic variants, the occurring psychiatric symptom may depend on the type of stress experienced.

5.
Front Pharmacol ; 10: 1636, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-32063851

RESUMEN

Serotonin 2C receptors (5-HT2CRs) are implicated in the pathomechanism and treatment of anxiety and depression. Recently, as a new biomarker of depression, alterations in the gamma power of the electroencephalogram (EEG) have been suggested. Chronic treatment with the selective serotonin reuptake inhibitor (SSRI) antidepressant escitalopram has been shown to cause sleep-wake stage-dependent alterations in gamma power. However, despite the antidepressant potency of 5-HT2CR-antagonists, there is no data available regarding the effects of selective 5-HT2CR-antagonists on gamma activity. Therefore, we investigate the acute effect of the 5-HT2CR-antagonist SB-242084 on gamma power in different vigilance stages when given in monotherapy, or in combination with chronic escitalopram treatment. We administered SB-242084 (1 mg/kg, intraperitoneally) or vehicle to EEG-equipped rats after a 21-day-long pretreatment with escitalopram (10 mg/kg/day, via osmotic minipumps) or vehicle. Frontoparietal EEG, electromyogram, and motor activity were recorded during the first 3 h of passive phase, after the administration of SB-242084. Quantitative EEG analysis revealed that acute SB-242084 increased gamma power (30-60 Hz) in light and deep slow-wave sleep, and passive wakefulness. However, in active wakefulness, rapid eye movement sleep, and intermediate stage, no change was observed in gamma power. The profile of the effect of SB-242084 on gamma power was similar to that produced by chronic escitalopram. Moreover, SB-242084 did not alter chronic escitalopram-induced effects on gamma. In conclusion, the similarity in the effect of the 5-HT2CR-antagonist and chronic SSRI on gamma power provides further evidence for the therapeutic potential of 5-HT2CR-antagonists in the treatment of depression and/or anxiety.

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