title: Further evidence for the sleep-promoting effects of 5-HT₂A receptor antagonists and demonstration of synergistic effects with the hypnotic, zolpidem in rats.
abstract: 5-Hydroxytryptamine (5-HT)2A antagonists are promising therapeutic agents for the treatment of sleep maintenance insomnias, but unlike hypnotics, they have limited effects on sleep initiation. This study evaluated the effects of several 5-HT₂A antagonists (eplivanserin, volinanserin and AVE8488) alone and/or in combination with the short-acting hypnotic, zolpidem, on the rat sleep profile. A repeated-measures design was used in which rats were treated with eplivanserin (3 and 10 mg/kg, i.p. or p.o.), volinanserin (0.3-3 mg/kg, i.p.), AVE8488 (0.1-3 mg/kg, i.p.) and zolpidem (3 and 10 mg/kg, p.o.). In addition, animals received a combination of eplivanserin (3 mg/kg, p.o.) and zolpidem (3 mg/kg, p.o.). Electroencephalogram was analyzed for 6 h after administration. Eplivanserin did not modify wakefulness and non-rapid eye movement sleep (NREMS), while zolpidem (10 mg/kg po) induced a marked increase in NREMS duration. Volinanserin (1 and 3 mg/kg) and AVE8488 (0.3 mg/kg) similarly increased NREMS, while reducing wakefulness. Moreover, the 5-HT₂A antagonists and, to a lesser extent, zolpidem, increased duration of NREMS episodes, while decreasing their frequency. When eplivanserin was co-administered with zolpidem, a synergistic effect was observed as the combination produced an increase in NREMS time and bouts duration. These findings confirm further that 5-HT₂A antagonists promote the maintenance of sleep, and suggest that combining a 5-HT₂A antagonist with a short-acting hypnotic may be a useful strategy for the treatment of insomnia.
authors: Sanofi, Exploratory Unit, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France. guy.griebel@sanofi.com
authors: Guy
authors: G
authors: Griebel
authors: Sandra
authors: S
authors: Beeské
authors: Agnès
authors: A
authors: Jacquet
authors: Christian
authors: C
authors: Laufrais
authors: Richard
authors: R
authors: Alonso
authors: Michel
authors: M
authors: Decobert
authors: Patrick
authors: P
authors: Avenet
authors: Dominique
authors: D
authors: Françon
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005464:Fluorobenzenes / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D008297:Male; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D012702:Serotonin Antagonists / Q000494:pharmacology*; D012894:Sleep Stages / Q000187:drug effects*; D014851:Wakefulness / Q000187:drug effects; D000077334:Zolpidem
chemical_list: D005464:Fluorobenzenes; D006993:Hypnotics and Sedatives; D010636:Phenols; D010880:Piperidines; D011725:Pyridines; D012702:Serotonin Antagonists; C076033:SR 46349B; D000077334:Zolpidem; C079049:volinanserin