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Journal of Pharmacology and Experimental Therapeutics

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OtherNEUROPHARMACOLOGY

Allopregnanolone Affects Sleep in a Benzodiazepine-Like Fashion

Marike Lancel, Johannes Faulhaber, Thomas Schiffelholz, Elena Romeo, Flavia Di Michele, Florian Holsboer and Rainer Rupprecht
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1213-1218;
Marike Lancel
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Johannes Faulhaber
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Thomas Schiffelholz
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Elena Romeo
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Flavia Di Michele
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Florian Holsboer
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Rainer Rupprecht
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Abstract

Recent research in rats and humans has shown that exogenous progesterone evokes a sleep profile similar to that induced by agonistic modulators of γ-aminobutyric acidAreceptors, such as benzodiazepines. This finding suggests the involvement of the neuroactive metabolite of progesterone, allopregnanolone. In the vehicle-controlled study reported here, we assessed the sleep effects of two doses of allopregnanolone (7.5 and 15 mg/kg), mixed with oil, administered intraperitoneally at light onset in 8 rats. The electroencephalogram (EEG) and electromyogram were recorded during the first 6 postinjection hr. Compared with vehicle, both doses of allopregnanolone reduced the latency to non-rapid eye movement sleep (non-REMS) and 15 mg/kg allopregnanolone significantly increased the time spent in pre-REMS, an intermediate state between non-REMS and REMS. Furthermore, allopregnanolone dose-dependently influenced EEG activity during non-REMS and REMS. In non-REMS, EEG activity was decreased in the lower frequencies (≤7 Hz) and enhanced in the frequencies of ≥13 Hz. In REMS, allopregnanolone enhanced high-frequency EEG activity (≥17 Hz). The effects were most pronounced during the first postinjection hours and gradually diminished thereafter. Analysis of the plasma and brain concentrations of allopregnanolone in 45 rats revealed long-lasting increases, which reached maximal levels during the first postinjection hour. The sleep effects of allopregnanolone are very similar to those elicited by larger doses of progesterone, which produce comparable brain levels of allopregnanolone. These data indicate that the steroid allopregnanolone has benzodiazepine-like effects on sleep.

Footnotes

  • Send reprint requests to: Dr. Marike Lancel, Max Planck Institute of Psychiatry, Clinical Institute, Kraepelinstrasse 2, 80804 Munich, Germany. E-mail:lancel{at}mpipsykl.mpg.de

  • ↵1 This study was supported by grants from the Deutsche Forschungsgemeinschaft (M.L.) and the Gerhard-Heβ-Programm of the Deutsche Forschungsgemeinschaft (R.R.).

  • Abbreviations:
    GABA
    γ-aminobutyric acid
    EEG
    electroencephalogram
    EMG
    electromyogram
    REMS
    rapid eye movement sleep
    ANOVA
    analysis of variance
    HFBAA
    heptafluorobutyric acid anhydride
    • Received January 21, 1997.
    • Accepted May 14, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherNEUROPHARMACOLOGY

Allopregnanolone Affects Sleep in a Benzodiazepine-Like Fashion

Marike Lancel, Johannes Faulhaber, Thomas Schiffelholz, Elena Romeo, Flavia Di Michele, Florian Holsboer and Rainer Rupprecht
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1213-1218;

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OtherNEUROPHARMACOLOGY

Allopregnanolone Affects Sleep in a Benzodiazepine-Like Fashion

Marike Lancel, Johannes Faulhaber, Thomas Schiffelholz, Elena Romeo, Flavia Di Michele, Florian Holsboer and Rainer Rupprecht
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1213-1218;
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