Abstract
The endogenous neurosteroid allopregnanolone has recently been demonstrated to have somnogenic properties that are very similar to those of other agonistic modulators of GABAA receptors, especially of short-acting benzodiazepines. Short-acting benzodiazepines are established to rapidly lose their hypnotic effect upon repeated administration. To investigate the tolerance potential of allopregnanolone, we assessed sleep-wake behavior in rats during subchronic treatment (once daily for five days) with placebo or 15 mg/kg allopregnanolone (n = 8 each). The sleep patterns of the placebo and allopregnanolone group did not differ significantly before and after treatment. Throughout the entire treatment period the allopregnanolone group exhibited shorter non-rapid eye movement sleep (non-REMS) latencies, prolonged REMS latencies, longer non-REMS episodes, more pre-REMS and less low-frequency, but higher spindle activity in the electroencephalogram (EEG) within non-REMS than the placebo group. The lack of tolerance effects suggests that allopregnanolone may be an efficacious modulator of sleep-wake behavior over longer time periods than most drugs targeting the benzodiazepine binding site of the GABAA receptor.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Ashton H . (1994): Guidelines for the rational use of benzodiazepines. When and what to use. Drugs 48: 25–40
Borbély AA, Neuhaus HU . (1979): Sleep-deprivation: effects on sleep and EEG in the rat. J Comp Physiol 133: 71–87
Crespi F . (1999): Cholecystokinin-B (CCK-B) receptor antagonists improve “aged” sleep: A new class of sleep modulators? Methods Find Exp Clin Pharmacol 21: 31–38
Depoortere H, Decobert M, Perrault G, Françon D, Sanger DJ . (1998): Neuropharmacological profile of zaleplon, a novel BZ1(ω1) hypnotic, in rodents. J Sleep Res 7(Suppl 2):64
Dingemanse J . (1995): Pharmacotherapy of insomnia: Practice and prospects. Pharm World Sci 17: 67–75
Edgar DM, Seidel WF, Gee KW, Lan NC, Field G, Xia H, Hawkinson JE, Wieland S, Carter RB, Wood PL . (1997): CCD-3693: An orally bioavailable analog of the endogenous neuroactive steroid, pregnanolone, demonstrates potent sedative hypnotic actions in the rat. J Pharmacol Exp Ther 282: 420–429
File SE . (1981): Rapid development of tolerance to the sedative effects of lorazepam and triazolam in rats. Psychopharmacology 73: 240–245
Gallo AM, Smith SS . (1993): Progesterone withdrawal decreases latency to and increases duration of electrified prod burial: A possible rat model of PMS anxiety. Pharmacol Biochem Behav 46: 897–904
Gandolfo G, Scherschlicht R, Gottesman C . (1994): Benzodiazepines promote the intermediate stage at the expense of paradoxical sleep in the rat. Pharmacol Biochem Behav 49: 921–927
Hashimoto T, Hamada C, Wada T, Fukuda N . (1992): Comparative study on the behavioral and EEG changes induced by diazepam, buspirone and a novel anxioselective anxiolytic, DN-2327, in the cat. Neuropsychobiology 26: 89–99
Lader M . (1992): Rebound insomnia and newer hypnotics. Psychopharmacology 108: 248–255
Lancel M . (1999): Role of GABAA receptors in the regulation of sleep: Initial sleep responses to peripherally administered modulators and agonists. Sleep 22: 33–42
Lancel M, Crönlein TAM, Faulhaber J . (1996): Role of GABAA receptors in sleep regulation: Differential effects of muscimol and midazolam on sleep in rats. Neuropsychopharmacology 15: 63–74
Lancel M, Faulhaber J, Schiffelholz T, Romeo E, Di Michele F, Holsboer F, Rupprecht R . (1997): Allopregnanolone affects sleep in a benzodiazepine-like fashion. J Pharmacol Exp Ther 282: 1213–1218
Lancel M, Kerkhof GA . (1989): Effects of repeated sleep deprivation in the dark- or light-period on sleep in rats. Physiol Behav 45: 289–297
Lancel M, Langebartels A . (2000): γ-Aminobutyric acidA (GABAA) agonist 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol persistently increases sleep maintenance and intensity during chronic administration to rats. J Pharmacol Exp Ther 293: 1084–1090
Landolt HP, Gillin JC . (2000): GABAA1a receptors: Involvement in sleep regulation and potential of selective agonists in the treatment of insomnia. CNS Drugs 13: 185–199
Majewska MD . (1992): Neurosteroids: Endogenous bimodal modulators of the GABAA receptor. Mechanism of action and physiological significance. Prog Neurobiol 38: 379–395
Mandema JW, Sansom LN, Dios-Vièitez MC, Hollander-Jansen M, Danhof M . (1991): Pharmacokinetic-pharmacodynamic modelling of the EEG effects of benzodiazepines. Correlations with receptor binding and anticonvulsant activity. J Pharmacol Exp Ther 257: 472–478
Marshall FH, Stratton SC, Mullings J, Ford E, Worton SP, Oakley NR, Hagan RM . (1997): Development of tolerance in mice to the sedative effects of the neuroactive steroid minaxolone following chronic exposure. Pharmacol Biochem Behav 58: 1–8
Mendelson WB, Martin JV, Perlis M, Majewska MD, Paul SM . (1987): Sleep induction by an adrenal steroid in the rat. Psychopharmacology 93: 226–229
Reddy DS, Rogawski MA . (2000): Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself. J Pharmacol Exp Ther 295: 1241–1248
Rupprecht R, Holsboer F . (1999): Neuroactive steroids: mechanisms of action and neuropsychopharmacological perspectives. Trends Neurosci 22: 410–416
Schulz H, Jobert M, Gee KW, Ashbrook DW . (1996): Soporific effect of the neurosteroid pregnanolone in relation to the substance's plasma level: A pilot study. Neuropsychobiology 34: 106–112
Smith SS, Gong QH, Hsu FC, Markowitz RS, ffrench-Mullen JMH, Li X . (1998): GABAA receptor α4 subunit suppression prevents withdrawal properties of an endogenous steroid. Nature 392: 926–930
Acknowledgements
We are grateful to Arnold Höhne for his excellent technical assistance. This study was supported by grants of the Deutsche Forschungsgemeinschaft (M.L.) and the Gerhard-Heβ Programm of the Deutsche Forschungsgemeinschaft (R.R.).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Damianisch, K., Rupprecht, R. & Lancel, M. The Influence of Subchronic Administration of the Neurosteroid Allopregnanolone on Sleep in the Rat. Neuropsychopharmacol 25, 576–584 (2001). https://doi.org/10.1016/S0893-133X(01)00242-1
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1016/S0893-133X(01)00242-1
