Functional role of 5-HT2 receptors in the regulation of sleep and wakefulness in the rat

Abstract

Recently developed agents specifically acting on different 5-hydroxytryptamine (5-HT) receptor populations were used to analyze the functional role of 5-HT2 receptor subtypes in the sleep-wakefulness cycle of the rat. The 5-HT2 receptor antagonist ritanserin injected intraperitoneally (IP) (0.04-2.5 mg/kg) induced an increase in deep slow wave sleep (SWS2) duration at the expense of wakefulness (W), light slow wave sleep (SWS1) and paradoxical sleep (PS). The stimulation of 5-HT2 receptors by 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) produced a dose-related increase in W and a dose-dependent decrease in both SWS2 and PS. Pretreatment with ritanserin (0.16-2.5 mg/kg) or with cinanserin (2.5-5 mg/kg), another 5-HT2 receptor antagonist, dose-dependently reversed the W enhancement and the SWS2 deficit produced by DOM, but not the PS deficit. Sleep-wakefulness alterations (increase in W and SWS1 combined with a suppression of SWS2 and PS) observed after IP injection of two putative 5-HT1 receptor agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (2.5 mg/kg) and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969) (0.63 mg/kg), were not modified by ritanserin pretreatment (0.16-2.5 mg/kg). These results further support the hypothesis that the serotonergic system plays an active role in the regulation of the sleep-wakefulness cycle in the rat and that 5-HT2 receptors are involved in this action. In addition, it is suggested that 5-HT1 receptor subtypes are unlikely to interact with 5-HT2 receptors in the sleep-wakefulness modulation mediated through 5-HT2 receptors.

Contribution of 5-HT2Receptor Subtypes to Sleep–Wakefulness and Respiratory Control, and Functional Adaptations in Knock-Out Mice Lacking 5-HT2AReceptors

“…In the present work, we found that the selective blockade of 5-HT 2A receptors by MDL 100907 induced a dose-dependent increase in NREMS in 5-HT 2A ϩ/ϩ mice. Thus, this 5-HT 2A receptor antagonist mimicked the NREMS-promoting action of wide-spectrum 5-HT 2 antagonists, as reported previously in rats and in humans (Dugovic et al, 1989;Idzikowski et al, 1991;Stutzmann et al, 1992).…”

“…Similar results have been obtained in the rat after administration of various 5-HT 2 ligands, whether agonists or antagonists (Dugovic et al, 1989;Kantor et al, 2004) [but see Benington andHeller (1995), in rats, andIdzikowski et al (1991), in human]. These data suggest that the effects of 5-HT 2 ligands on REMS are mediated by complex mechanisms.…”

“…Reciprocally, activation of 5-HT 2B receptors by BW 723C86 induced an increase in NREMS. These effects of antagonist and agonist aimed at 5-HT 2B receptors are opposite the respective effects of the wide-spectrum 5-HT 2 receptor antagonists, such as ritanserin or RP 62203, and agonists, such as DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane] (Dugovic et al, 1989). This apparent discrepancy might be caused by the relatively low affinity of the latter compounds for 5-HT 2B versus 5-HT 2A and 5-HT 2C receptors (Leysen, 2004).…”

“…In contrast, it has been reported that 5-HT 2 receptors play an inhibitory role in non-REMS (NREMS) expression. Indeed, the wide-spectrum antagonist at 5-HT 2 receptors, ritanserin (Leysen et al, 1985), substantially increases NREMS in humans (Idzikowski et al, 1991) and in rats (Dugovic et al, 1989). 5-HT 2 receptors belong to the superfamily of G-protein-coupled receptors and comprise three subtypes: 5-HT 2A and 5-HT 2C receptors, which have a widespread distribution in the CNS, and 5-HT 2B receptors, which have a restricted expression pattern (Leysen, 2004).…”

Serotonergic Regulation of the Orexin/Hypocretin Neurons through the 5-HT1AReceptor

“…In regard to the present study, 5-HT 1A receptors are located on the soma and dendrites of 5-HT neurons (somatodentritic autoreceptors), as well as postsynaptically on 5-HT target neurons (Kia et al, 1996;Riad et al, 2000). It has been proposed that 5-HT 1A receptors are involved in the regulation of REM sleep and wakefulness (Dzoljic et al, 1992;Tissier et al, 1993;Portas et al, 1996;Thakkar et al, 1998), whereas 5-HT 2A receptors participate in the control of SWS (Idzikowski et al, 1986;Dugovic et al, 1989). The observation that 5-HT 1A null mutant mice have higher amounts of REM sleep than wild-type mice during both the light and dark phases (Boutrel et al, 2002) is consistent with this idea.…”