Effects of the serotonin 5-HT2A/2C receptor agonist DOI and of the selective 5-HT2A or 5-HT2C receptor antagonists EMD 281014 and SB-243213, respectively, on sleep and waking in the rat

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Abstract

The effects of the serotonin 5-HT2A/2C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and of the selective 5-HT2A or 5-HT2C receptor antagonists 7-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazine-1-carbonyl}-1H-indole-3-carbonitrile HCl (EMD 281014) and 5-methyl-1-[[-2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline HCl (SB-243213), respectively, on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. Subcutaneous administration of DOI (0.35–0.7 mmol/kg) significantly increased waking and light sleep and reduced slow wave sleep, rapid-eye-movement (REM) sleep, and the number of REM periods. With subcutaneous EMD 281014 (1.2–4.8 mmol/kg) or SB-243213 (1.2–4.8 mmol/kg) a significant reduction in time spent in REM sleep was also seen. Pretreatment with EMD 281014 prevented the DOI-induced increase of waking and light sleep and the reduction of slow wave sleep. However, REM sleep remained suppressed. SB-243213 failed to reverse the changes of sleep and waking induced by DOI. Thus, on the basis of these results it appears that serotonin 5-HT2A receptor mechanisms might be responsible for the DOI-induced effects on waking and slow wave sleep.

Introduction

The effects of serotonin (5-HT) in the central nervous system are mediated by multiple receptor subtypes that have been classified into seven subfamilies (5-HT1–5-HT7) (Hoyer et al., 1994). The 5-HT2 subfamily comprises three subtypes: 5-HT2A, 5-HT2B, and 5-HT2C. Serotonin 5-HT2A and 5-HT2C receptors have been detected in numerous rat brain regions involved in the regulation of sleep and waking, including the cerebral cortex, hippocampus, hypothalamus, medial pontine reticular formation, locus coeruleus, laterodorsal and pedunculopontine tegmental nuclei, and dorsal raphe nucleus (Pompeiano et al., 1994, Abramowski et al., 1995, Cornea-Hébert et al., 1999, Clemett et al., 2000, Fay and Kubin, 2000, López-Giménez et al., 2001).

Systemic administration of the serotonin 5-HT2A/2C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) has been shown to reduce rapid-eye-movement (REM) sleep and slow wave sleep and to increase waking in the rat. Pretreatment with the serotonin 5-HT2A/2C receptor antagonist ritanserin prevented the waking enhancement and the slow wave sleep deficit induced by DOI but not the REM sleep suppression (Monti et al., 1990). However, to date it has not been established which serotonin receptor subtype is involved in the DOI-induced disruption of sleep variables.

The present experiments were undertaken to test the effect of the highly selective and potent 5-HT2A or 5-HT2C receptor antagonists 7-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazine-1-carbonyl}-1H-indole-3-carbonitrile HCl (EMD 281014) (Bonhaus et al., 1995, Bartoszyk et al., 2003) and 5-methyl-1-[[-2-[(2-methyl-3-pyridil)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline HCl (SB-243213) (Bromidge et al., 2000, Smith et al., 2002), respectively, against the DOI-induced changes of sleep and waking.

Section snippets

Materials and methods

Male Wistar rats weighing 350–400 g were included in the study. All rats were cared for and used in strict accordance with the European Community guidelines for the use of experimental animals. All procedures were approved by the Institutional Animal Care and Use Committee of the Medical School, Montevideo, Uruguay.

The animals were anesthetized with sodium pentobarbital (40.0 mg/kg, i.p.) and implanted with Nichrome® electrodes (200-μm diameter) for sleep recordings of electroencephalogram and

Results

As mentioned earlier, DOI was dissolved in 0.9% saline whereas EMD 281014 and SB-243213 were dissolved in distilled water. Notwithstanding this, there were no significant differences in the values of sleep variables determined using saline or distilled water in the control experiments.

Following subcutaneous administration of 0.35, 0.5 or 0.7 mmol/kg DOI, waking was increased (F(3,15) = 27.08, P < 0.05 and P < 0.01, respectively) and slow wave sleep was reduced (F(3,15) = 33.52, P < 0.01) during the first

Discussion

The present study shows that the subcutaneous injection of DOI increased waking and light sleep and reduced slow wave sleep and REM sleep in the rat. With subcutaneous EMD 281014 or SB-243213 a reduction in time spent in REM sleep was also seen. Pretreatment with EMD 281014 prevented the DOI-induced increase of waking and light sleep and the reduction of slow wave sleep. However, REM sleep suppression was not reverted by the serotonin 5-HT2A receptor antagonist. SB-243213 failed to antagonize

Acknowledgements

The study was supported by Pedeciba, Montevideo, Uruguay.

We thank Dr. Gerd D. Bartoszyk from Merck KGaA, Darmstadt, Germany for the gift of EMD 281014. We acknowledge Dr. Martyn Wood, GlaxoSmithKline, Harlow, United Kingdom, for the generous gift of SB-243213.

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