Acute 5-HT2C Receptor Antagonist SB-242084 Treatment Affects EEG Gamma Band Activity Similarly to Chronic Escitalopram.

Noémi Papp,Diána Kostyalik,Tamás Kitka,Szilvia Vas,Szabolcs Koncz,Péter Petschner,György Bagdy

doi:10.3389/fphar.2019.01636

Noémi Papp, Diána Kostyalik + Show 5 more

Open Access

https://doi.org/10.3389/fphar.2019.01636

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Abstract

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.

Highlights

The most prominent effects were observed during slow-wave sleep stages, where the acute SB-242084, the chronic escitalopram, and the combined treatment caused a power elevation
This is the first study investigating the acute effects of the selective 5-HT2CR-antagonist SB-242084 on the gamma frequency band of the EEG spectra in different vigilance stages
Our findings about the additional 21-day-long pretreatment with escitalopram (10 mg/kg/day, osmotic minipumps) demonstrate that SB-242084 did not modify further the gamma power altered by the chronic antidepressant treatment

Summary

Introduction

Serotonin (5-hydroxytryptamine, 5-HT) 2C receptors (5HT2CRs) are widely distributed in the brain, and mediate regulatory effects of 5-HT on anxiety, sleep, hormonal secretion, feeding behavior, locomotor activity, as well as learning and memory processes (Bagdy, 1998; Chagraoui et al, 2016). 5-HT2CR dysfunction has been implicated in pathological conditions, like anxiety and depression (Chagraoui et al, 2016; Di Giovanni and De Deurwaerdere, 2016). Numerous antidepressants, anxiolytics, and antipsychotics have affinities to the 5-HT2CRs, that may be involved in the therapeutic effects of these drugs (Bagdy et al, 2001; Chagraoui et al, 2016; Di Giovanni and De Deurwaerdere, 2016). Stimulation of 5-HT2CRs has been described to produce anxiety, and in turn, subtype-selective 5-HT2CR-antagonists like SB-242084 exerted marked anxiolytic effects (Dekeyne et al, 2000; Bagdy et al, 2001; Kantor et al, 2005). The selective 5-HT2CR-antagonists RS-102221 and SB-242084 produced fast-onset antidepressant-like effects in mice (Opal et al, 2014). 5-HT2CR-antagonism potentiated the anxiolytic and antidepressant effects of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), reduced motor side effects in mice (Demireva et al, 2018). The interaction of 5-HT and dopamine (DA) systems has been suggested to contribute to these effects (De Deurwaerdere and Di Giovanni, 2017)

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