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BEHAVIORAL PHARMACOLOGY

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

Laboratory of Neurochemistry and Experimental Medicine, National Institute of Psychiatry and Neurology, Budapest, Hungary (S.K., R.J., E.M., N.G., G.B.); Group of Neuropsychopharmacology, Hungarian Academy of Sciences, Budapest, Hungary (G.B.); Department of Vascular Neurology, Semmelweis University, Budapest, Hungary (G.B.); and Department of Physiology and Neurobiology, Eotvos Lorand University, Budapest, Hungary (A.T., L.D.)

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.

Address correspondence to: Dr. Gyorgy Bagdy, Laboratory of Neurochemistry and Experimental Medicine, National Institute of Psychiatry and Neurology, Budapest, Huvosvolgyi ut 116, H-1021, Hungary. E-mail: bag13638{at}mail.iif.hu