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Research ArticleArticle

Response-Rate Suppression in Operant Paradigm as Predictor of Soporific Potency in Rats and Identification of Three Novel Sedative-Hypnotic Neuroactive Steroids

Kimberly E. Vanover, Dale M. Edgar, Wesley F. Seidel, Derk J. Hogenkamp, David B. Fick, Nancy C. Lan, Kelvin W. Gee and Richard B. Carter
Journal of Pharmacology and Experimental Therapeutics December 1999, 291 (3) 1317-1323;
Kimberly E. Vanover
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Dale M. Edgar
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Wesley F. Seidel
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Derk J. Hogenkamp
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David B. Fick
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Nancy C. Lan
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Kelvin W. Gee
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Richard B. Carter
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Abstract

Novel neuroactive steroids were evaluated for their effects on operant responding, rotorod motor performance, and electroencephalogram recording in rats. Co 134444, Co 177843, and Co 127501 were compared with the prototypical γ-aminobutyric acidA-positive allosteric modulators triazolam, zolpidem, pentobarbital, pregnanolone, and CCD 3693. Each of the compounds produced a dose-related decrease in response rates under a variable-interval 2-min schedule of positive reinforcement in an operant paradigm. In addition, all compounds produced a dose-related increase in ataxia and significant increases in nonrapid eye movement sleep in this experiment or have been previously reported to do so. Co 134444, Co 177843, and Co 127501 increased nonrapid eye movement sleep at doses that had no effect on rapid eye movement sleep. All of the compounds were more potent at decreasing operant responding than they were at increasing ataxia. Furthermore, the potency of compounds to produce response-rate suppression in an operant paradigm appeared to be a better predictor of soporific potency than did potency in the rotorod assay. The screening for sedative-hypnotic activity resulted in the identification of the novel orally active neuroactive steroids Co 134444, Co 177843, and Co 127501.

Footnotes

  • Send reprint requests to: Kimberly E. Vanover, Ph.D., CoCensys, Inc., 213 Technology Dr., Irvine, CA 92618. E-mail:kvanover{at}cocensys.com

  • ↵1 Current address: Sleep Research Center, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94304.

  • ↵2 Current address: Dept. of Pharmacology, College of Medicine, University of California, Irvine, CA 92697-4625.

  • Abbreviations:
    NREM
    nonrapid eye movement
    REM
    rapid eye movement
    CT
    circadian time
    EEG
    electroencephalogram
    GABA
    γ-aminobutyric acid
    MSD
    minimum significant dose
    SD50
    suppressive dose
    TD50
    toxic dose
    VI
    variable interval
    • Received July 13, 1999.
    • Accepted August 31, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 291 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 291, Issue 3
1 Dec 1999
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Research ArticleArticle

Response-Rate Suppression in Operant Paradigm as Predictor of Soporific Potency in Rats and Identification of Three Novel Sedative-Hypnotic Neuroactive Steroids

Kimberly E. Vanover, Dale M. Edgar, Wesley F. Seidel, Derk J. Hogenkamp, David B. Fick, Nancy C. Lan, Kelvin W. Gee and Richard B. Carter
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1317-1323;

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Research ArticleArticle

Response-Rate Suppression in Operant Paradigm as Predictor of Soporific Potency in Rats and Identification of Three Novel Sedative-Hypnotic Neuroactive Steroids

Kimberly E. Vanover, Dale M. Edgar, Wesley F. Seidel, Derk J. Hogenkamp, David B. Fick, Nancy C. Lan, Kelvin W. Gee and Richard B. Carter
Journal of Pharmacology and Experimental Therapeutics December 1, 1999, 291 (3) 1317-1323;
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