Research reportThe promnesic neurosteroid pregnenolone sulfate increases paradoxical sleep in rats
Introduction
Pregnenolone sulfate (PREG-S), as other steroids synthesized in the brain, belongs to the `neurosteroid class' [2]. Numerous studies using different paradigms, demonstrated that PREG-S is a powerful promnesic compound. PREG-S infused intracerebroventricularly or into limbic structures (amygdala, hippocampus) enhances retention in active avoidance paradigm at very low dose 6, 7. PREG-S has also been shown to have promnesic properties in an appetitive learning task [24]and in spatial memory tasks 10, 23. These data have provided evidence that PREG-S acts specifically on the consolidation processes. Indeed, in a two trial memory task, administration of PREG-S after the acquisition induces memory enhancement, whereas administration before acquisition trial has no effect on memory performance [23]. PREG-S has also been implicated in the modulation of memory processes during aging, and in old rats, we have recently observed that hippocampal levels of PREG-S are positively correlated with spatial memory performance [34].
Several studies have reported a positive correlation between cognitive performance in aged animals and amounts of paradoxical sleep [21]. Moreover, sleep stages, particularly paradoxical sleep, have been involved in memory consolidation processes 5, 12, 27, 28, 30. Thus, it can be hypothesized that PREG-S modulates paradoxical sleep. The possible PREG-S action on sleep–wakefulness parameters is reinforced by the recent observations that PREG-S stimulates central cholinergic transmission [34]. Cholinergic mechanisms have been implicated in the modulation of sleep–wake states [13]. Cortical and hippocampal ACh release increase during REM sleep compared to non-REM sleep [22]and PREG-S administration increases hippocampal and cortical ACh release 4, 34. Finally, lesion of the NBM—the main source of cortical ACh innervation—results both in paradoxical sleep alterations and memory deficits [32]and injection of PREG-S into this structure enhance spatial memory 23, 25.
The aim of this study was to investigate the effect of the promnesic neurosteroid PREG-S on sleep–wakefulness parameters. In the first part of the present work, we have investigated the effects of PREG-S administrations on wakefulness, slow-wave sleep and paradoxical sleep measured by 24 h EEG recording. We have chosen two doses including one dose (47.5 mg/kg, i.p.) that has previously been found effective in increasing memory in aged rats [34]and one dose (4.75 mg kg, i.p.) that has been demonstrated to be behaviorally active in some paradigms, but not in memory task 16, 18. In a second experiment, the effects of the administration of similar doses of PREG-S were investigated on the performance in a two trial spatial memory task in young rats.
Section snippets
Animals and housing conditions
Fifty-four male Sprague–Dawley rats (Iffa-Credo, France), weighing 280–300 g upon arrival were used in this study. Animals had ad libitum access to food and water. The light–dark cycle (lights were on from 8 AM to 8 PM), temperature (22°C) and humidity (60%) were kept constant in the animal house. All experiments were carried out in accordance with the European Communities Council Directive (96/609/EEC) on animal welfare.
Drug
Pregnenolone sulfate (5-pregnen-3β-ol-20-one sulfate; Sigma) was dissolved
Experiment 1: PREG-S effects on sleep–wakefulness cycle
PREG-S administration did not affect wakefulness and slow wave sleep. The 24 h mean wakefulness and slow wave sleep were unchanged before and after drug administration (pre-post effect: wakefulness, F(1,24)=3.82, ns; slow wave sleep, F(1,24)=1.54, ns) whatever the treatment group (treatment×pre-post: wakefulness, F(2,24)=1.16, ns; slow wave sleep, F(2,24)=0.62, ns). The time course of wakefulness (Fig. 1) and slow wave sleep (Fig. 2) before and after drug administration were similar between
Discussion
The present report shows that systemically administered, the promnesic neurosteroid PREG-S induces an increase of paradoxical sleep, without significant modification of wakefulness and slow wave sleep. The increase of paradoxical sleep was observed 4 h after 47.5 mg/kg PREG-S administration and lasted for 10 h. In addition, our results show that 47.5 mg/kg PREG-S administration improved performance in a spatial memory task after 24 h of retention. That corroborates previous experiments carried
Conclusions
Our results demonstrate that the promnesic neurosteroid PREG-S increases paradoxical sleep without affecting slow wave sleep or wakefulness and that only the dose effective on paradoxical sleep also enhances memory performance. Taken together, these results suggest that paradoxical sleep increase induced by PREG-S could play a role in the memory consolidation processes and partly explain the promnesic action of this neurosteroid. Finally, given that brain PREG-S levels and basal paradoxical
Acknowledgements
We thank M. Kharouby for technical assistance and M. Dobrossy for English revision and helpful comments on the manuscript. Supported by Ministerio de Educacion y Cultura (Spain), INSERM, Université de Bordeaux II, Conseil Régional d'Aquitaine and Fondation de France, and BIOMED 2, BMH4CT 97-2359.
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