The Role of 5-HT2A/2C Receptors in Sleep and Waking

Abstract

AbstractThe 5-HT2A and 5-HT2C receptors are located within postsynaptic structures, and their actions are mediated by the activation of phospholipase C (PLC) with a resulting depolarization of the host cell. 5-HT2A- and 5-HT2C-receptor knockout mice show a significant increase of waking (W) and a reduction of nonrapid eye movement (NREM) sleep. In contrast, rapid eye movement (REM) sleep values remain unchanged. The limited available evidence tends to suggest that the increment of W and reduction of NREM sleep is related to the increased release of noradrenaline (NA) and dopamine (DA). Systemic administration of selective 5-HT2C agonists (RO 60-0175, RO-60-0332) and nonselective 5-HT2A/2C agonists (DOI, DOM) has been shown to reduce slow wave sleep (SWS) and REM sleep and to augment W in laboratory animals. The increased availability of acetylcholine (ACh) at central sites has been proposed to be responsible, at least in part, for the greater incidence of W.The injection of nonselective 5-HT2A/2C receptor antagonists (ketanserin, ritanserin, ICI 170,809, sertindole) significantly increased SWS and reduced REM sleep in the rat. Similar effects have been reported following the administration of selective 5-HT2A (MDL 100907) and 5-HT2C (SB 243213) receptor antagonists. Microinjection of DOI into the dorsal raphe nucleus (DRN) resulted in the suppression of REM sleep in the rat. Similar results have been obtained following the local administration of DOI into the laterodorsal tegmental nuclei (LDT). Rapid-eye-movement (REM) sleep suppression following microinjection of the 5-HT2A/2C agonist into the DRN or the LDT would depend on the γ-aminobutyric acid (GABA) inhibition of cholinergic cells involved in the induction of the behavioral state. Oral administration of the 5-HT2A/2C receptor antagonists ritanserin, ketanserin, seganserin, ICI 169,369, and SR 46349B increased SWS for subjects with normal sleep. In addition, ritanserin was shown to augment SWS for poor sleepers, chronic insomniacs, and patients with a generalized anxiety disorder (GAD) or a mood disorder. The atypical antipsychotic drugs olanzapine and risperidone increase SWS for schizophrenia patients, which could be related to their affinity for the 5-HT2A and the 5-HT2C receptors.KeywordsSlow Wave SleepDorsal Raphe NucleusNREM SleepOrexin NeuronMedial Pontine Reticular FormationThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.