Despite Similar Anxiolytic Potential, the 5-Hydroxytryptamine 2C Receptor Antagonist SB-242084 [6-Chloro-5-methyl-1-[2-(2-methylpyrid-3-yloxy)-pyrid-5-yl Carbamoyl] Indoline] and Chlordiazepoxide Produced Differential Effects on Electroencephalogram Power Spectra

Abstract

Serious efforts have been made to develop anxiolytics with improved clinical utility and reduced side effects. 5-Hydroxytryptamine (5-HT) 2C receptor antagonists are potential anxiolytics; however, their effects on vigilance are not well characterized. To compare the effects of benzodiazepines and subtype-selective 5-HT 2C receptor antagonists on anxiety, vigilance, and electroencephalogram (EEG) power density, social interaction test and polygraphic recordings were performed in male Sprague-Dawley rats after chlordiazepoxide (CDP; 4.0 mg/kg i.p.) and SB-242084 (6-chloro-5-methyl-1-[2-(2-methylpyrid-3-yloxy)-pyrid-5-yl carbamoyl] indoline) (0.1, 0.3, and 1.0 mg/kg i.p.) treatment. CDP and SB-242084 (0.3 and 1.0 mg/kg) had similar anxiolytic effects. Spectral analysis of EEG in wakefulness (W) and paradoxical sleep (PS) showed an opposite effect on activity (5-9 Hz); it decreased after CDP, whereas it increased after SB-242084 (even at 0.1 mg/kg). In addition, CDP significantly decreased slow-wave activity (0.5-4 Hz) in deep slow-wave sleep (SWS-2) and increased power at frequencies above 12 Hz mainly in W and PS. A markedly increased intermediate stage of sleep was also found after CDP treatment. At the highest dose, SB-242084 increased W and decreased SWS-2. In summary, low but potent anxiolytic doses of the subtype-selective 5-HT 2C receptor antagonist SB-242084 did not affect vigilance states but caused an increased activity in W, raising the possibility of a cognitive-enhancing effect of the drug. In contrast, acute CDP administration, based on spectral analysis of the EEG, produced a more superficial sleep along with a decreased activity.Efforts to improve the clinical utility and reduce the side effects of classic benzodiazepines have a long history (Haefely et al., 1992). Although the anxiolytic properties of these drugs are well established both clinically and experimentally (Argyropoulos and Nutt, 1999;File and Seth, 2003), the side effects like impaired short-term memory, vigilance, or psychomotor performance limit their clinical applicability (Kunsman et al., 1992;van Laar et al., 2001;Buffett-Jerrott and Stewart, 2002). On the other hand, these effects are often subtle when low doses are involved (Kunsman et al., 1992), and tolerance develops to the sedative and psychomotor effects with their continued use as anxiolytics (Lucki et al., 1986).Pharmacological characterization of the effects of the

S32006, a novel 5-HT2C receptor antagonist displaying broad-based antidepressant and anxiolytic properties in rodent models

“…Similarly, 5-HT 2C antagonists consistently enhance active social interaction in rats, and S32006 was likewise effective in this procedure (Kennett et al 1996b(Kennett et al , 1997Wood et al 2001;Martin et al 2002;Kantor et al 2005;Harada et al 2006;Millan et al 2005). The "ceiling" effect in the social interaction procedure was not unexpected inasmuch as 5-HT 2C antagonists-and other anxiolytics-generally display biphasic dose-response curves in this model File and Seth 2003).…”

“…Inasmuch as activation of 5-HT 2B receptors in the amygdala enhances social interaction, their blockade is unlikely to participate in the anxiolytic properties of S32006 (Kennett et al 1996a;Millan 2003). Nonetheless, 5-HT 2B receptors modulate sleep-wake cycle architecture (Smith et al 2002;Kantor et al 2004Kantor et al , 2005Cespuglio et al 2005;Millan 2006), so a possible role of their blockade in the influence of S32006 upon sleep (Descamps-Lefebvre et al 2008) should not be discounted.…”

Decrease in REM latency and changes in sleep quality parallel serotonergic damage and recovery after MDMA: a longitudinal study over 180 days

“…The polygraphic recordings were classified by sleep analysis software for the 24-h recordings (SleepSign for Animal, Kissei Comtec America Inc.). EEG power spectra were computed for consecutive 4-s epochs at the frequency range of 0.25-30 Hz (fast Fourier transformation routine, Hanning window ; frequency resolution, 0.25 Hz) (Kantor et al, 2002(Kantor et al, , 2005.…”

The Serotonin 2C Receptor Antagonist SB 242084 Exhibits Abuse-Related Effects Typical of Stimulants in Squirrel Monkeys

“…For example, in preclinical rodent studies, 5-HT 2C R-selective antagonists have demonstrated antidepressant-like effects (Dekeyne et al, 2008), enhanced the antidepressant-like effects of selective serotonin reuptake inhibitors (Cremers et al, 2004), and displayed an anxiolytic-like spectrum of behaviors (Kantor et al, 2005;Harada et al, 2006;Burghardt et al, 2007;Dekeyne et al, 2008). Although the precise neurobiological mechanism of action underlying these effects remains unclear, studies have consistently demonstrated that 5-HT 2C Rs exert a modulatory role on dopamine (DA) activity.…”