Further evidence for the sleep-promoting effects of 5-HT2A receptor antagonists and demonstration of synergistic effects with the hypnotic, zolpidem in rats

Autor: R. Alonso, Patrick Avenet, Agnès Jacquet, Dominique Françon, Sandra Beeské, Guy Griebel, Christian Laufrais, Michel Decobert
Rok vydání: 2013
Předmět:
Zdroj: Neuropharmacology. 70:19-26
ISSN: 0028-3908
Popis: 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.
Databáze: OpenAIRE
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