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-HT2C 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 θ 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-HT2C receptor antagonist SB-242084 did not affect vigilance states but caused an increased θ 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 θ activity.
Footnotes
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This work was supported by the Sixth Framework Programme of the European Union (LSHM-CT-2004-503474); by the Hungarian Research Fund Grants D 048502, M 27976, and T020500; by Ministry of Welfare Research Grant 058/2003; by Fund Management of Ministry of Education (OMFB 01926/2002); and by the Postdoctoral Ph.D. Fellowship Program of Semmelweis University, Ministry of Culture and Education, Hungary.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.086413.
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ABBREVIATIONS: 5-HT, 5-hydroxytryptamine (serotonin); m-CPP, 1-(3-chlorophenyl)piperazine; SB-242084, 6-chloro-5-methyl-1-[2-(2-methylpyrid-3-yloxy)-pyrid-5-yl carbamoyl] indoline; SWS-2, deep slow-wave sleep; EEG, electroencephalogram; EMG, electromyogram; SB-243213, 5-methyl-1-[[-2[2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoro-methylindoline hydrochloride; CDP, chlordiazepoxide; W, wakefulness; SWS-1, light slow-wave sleep; IS, intermediate stage of sleep; PS, paradoxical sleep; MANOVA, multivariate analysis of variance; MS, medial septum; SWA, slow-wave activity; DBv, vertical limb of the diagonal band nucleus; MDL 100907, R(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol.
- Received March 16, 2005.
- Accepted August 2, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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