Effects of ipsapirone, a 5‐HT_1A agonist, on sleep/wakefulness cycles: probable post‐synaptic action

Abstract

The effects of ipsapirone, a ligand of the 5-HT1A receptors and a new potential anxiolytic, on sleep/wakefulness regulation were examined in the rat. Injected i.p. at 1, 3 and 5 mg kg-1, this compound induced a dose-dependent reduction of paradoxical sleep for 2 to 4 hours, followed, at a dose of 5 mg kg-1, by a secondary rebound. The other states of vigilance were not modified, except at the latter dose where the amounts of wakefulness were enhanced initially and decreased secondarily, while those of SWS were enhanced from 2 to 4 hours post-treatment. The effects of ipsapirone (3 mg kg-1) persisted after infusion of the neurotoxin 5,7-dihydroxytryptamine into the dorsal raphe nucleus which induced the sub-total destruction of the serotoninergic system. Thus, the action of the 5-HT1A agonist ipsapirone on sleep/wakefulness cycles probably involves the stimulation of the post-synaptic 5-HT1A receptors.

Homeostatic Regulation of Sleep in a Genetic Model of Depression in the Mouse: Effects of Muscarinic and 5-HT1A Receptor Activation

“…This is in agreement with results obtained in depressed patients vs controls (Gillin et al, 1996;Seifritz et al, 1998), but it contrasts with the augmented hypothermia response to the same agonist found in H mice (El Yacoubi et al, 2003). This apparent discrepancy is due to the fact that the sleep response is mediated by post-synaptic 5-HT 1A receptors (Tissier et al, 1993), possibly at pontine level (Horner et al, 1997), whereas the hypothermic response is mediated by pre-synaptic (auto-) receptors (Goodwin et al, 1985). Indeed, the latter receptors are functionally hypersensitive in H mice (El Yacoubi et al, 2003), whereas the post-synaptic ones are unchanged, as observed under various experimental conditions (Fabre et al, 2000, Hensler, 2003.…”

“…In contrast to muscarinic receptors, activation of 5-HT 1A receptors by 8-OH-DPAT induced a dose-dependent reduction of REM sleep amounts and an increase in REM sleep latency in both mouse lines, as observed in other mouse strains (Boutrel et al, 1999), in rats (Tissier et al, 1993), and also in humans (Driver et al, 1995). This effect is most probably accounted for by an agonist action of 8-OH-DPAT at 5-HT 1A but not 5-HT 7 receptors (Wood et al, 2000).…”

“…In particular, REM sleep is enhanced following treatments with cholinergic agonists in rats (Baghdoyan, 1997), mice (Coleman et al, 2004), and humans (Seifritz et al, 1998;Sitaram and Gillin, 1980). In contrast, REM sleep is inhibited by 5-HT 1A agonists (Boutrel et al, 1999;Driver et al, 1995;Tissier et al, 1993).…”

5-HT1A/1B Receptor-Mediated Effects of the Selective Serotonin Reuptake Inhibitor, Citalopram, on Sleep: Studies in 5-HT1A and 5-HT1B Knockout Mice

“…Among the receptors at which 5-HT in excess could act to induce PS inhibition, the 5-HT 1A and 5-HT 1B types appeared as the most relevant candidates (Dzoljic et al, 1992;Tissier et al, 1993;Bjorvatn and Ursin, 1994;Monti et al, 1995;Bjorvatn et al, 1997;Boutrel et al, 1999Boutrel et al, , 2002. Indeed, we can conclude from the present study that 5-HT 1A receptors are primarily involved in such a PS inhibition because the effect of citalopram on sleep was markedly reduced in 5-HT 1A À/À, but globally unchanged in 5-HT 1B À/À, mutants compared to wild-type mice.…”

“…Indeed, in several species and notably the rat (Pastel and Fernstrom, 1987;Ursin et al, 1989;Lelkes et al, 1994;Maudhuit et al, 1994;Neckelmann et al, 1996b), the hamster (Gao et al, 1992), and also in humans (Van Bemmel et al, 1993;Hendrickse et al, 1994), the most consistent action of SSRIs is a reduction of paradoxical sleep (PS), which is sometimes associated with an enhancement of wakefulness (W) and a secondary increase in slow wave sleep (SWS) (Maudhuit et al, 1994;Ursin, 2002). In the same manner, systemic treatment with selective agonists at 5-HT 1A and 5-HT 1B receptors induces an inhibition of PS and an enhancement of wakefulness, notably in rodents (Dzoljic et al, 1992;Tissier et al, 1993;Bjorvatn and Ursin, 1994;Monti et al, 1995;Bjorvatn et al, 1997;Boutrel et al, 1999Boutrel et al, , 2002. In contrast, inactivation of 5-HT 1A and 5-HT 1B receptors (notably in mice with genetic deletions targeted at these receptors) facilitates the expression of PS (Boutrel et al, 1999(Boutrel et al, , 2002.…”