Rapid and Chronic: Two Distinct Forms of Ethanol Tolerance in Drosophila

Authors

  • Karen H. Berger,

    Corresponding author
    1. Ernest Gallo Clinic and Research Center, Emeryville, California
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  • Ulrike Heberlein,

    1. Ernest Gallo Clinic and Research Center, Emeryville, California
    2. Department of Anatomy, University of California at San Francisco, California.
    3. Program in Neuroscience, University of California at San Francisco, California.
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  • Monica S. Moore

    1. Ernest Gallo Clinic and Research Center, Emeryville, California
    2. Department of Neurology, University of California at San Francisco, California.
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  • Supported by funds provided by the State of California for medical research on alcohol and substance abuse through the University of California, San Francisco (KHB, MSM), by the Department of the Army Grant DAMD 17-01-1-0798 (MSM), and by Grants RO1 AA10035 and AA13105 from the NIH/NIAAA (UH).

Reprint requests: Karen H. Berger, PhD, Ernest Gallo Clinic and Research Center, 5858 Horton St., Ste. 200, Emeryville, CA 94608; Fax: 510-985-3101; E-mail: karenb@egcrc.net.

Abstract

Background: Ethanol tolerance, defined as a reduction in the intensity of the effects of ethanol upon continuous or repeated exposure, is a hallmark of alcoholism. Tolerance may develop at the cellular or neural systems levels. The molecular changes underlying ethanol tolerance are not well understood. We therefore explored the utility of Drosophila, with its accessibility to genetic, molecular, and behavioral analyses, as a model organism to study tolerance development in response to different ethanol-exposure regimens.

Methods: We describe a new assay that quantifies recovery from ethanol intoxication in Drosophila. Using this recovery assay, we define ethanol pre-exposure paradigms that lead to the development of tolerance. We also use the inebriometer, an assay that measures the onset of intoxication, to study the effects of pharmacological and genetic manipulations on tolerance development.

Results: We show that flies develop different forms of ethanol tolerance: rapid tolerance, induced by a single short exposure to a high concentration of ethanol, and chronic tolerance, elicited by prolonged exposure to a low concentration of the drug. Neither rapid nor chronic tolerance involves changes in ethanol pharmacokinetics, implying that they represent functional rather than dispositional tolerance. Chronic and rapid tolerance can be distinguished mechanistically: chronic tolerance is disrupted by treatment with the protein synthesis inhibitor cycloheximide, whereas rapid tolerance is resistant to this treatment. Furthermore, rapid and chronic tolerance rely on distinct genetic pathways: a mutant defective for octopamine biosynthesis shows reduced rapid tolerance but normal chronic tolerance.

Conclusions: Flies, like mammals, develop tolerance in response to different ethanol-exposure regimens, and this tolerance affects both the onset of and the recovery from acute intoxication. Two forms of tolerance, rapid and chronic, are mechanistically distinct, because they can be dissociated genetically and pharmacologically.

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