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Mouse lines selected for genetic differences in diazepam sensitivity.

E J Gallaher, L E Hollister, S E Gionet

    Psychopharmacology
    |January 1, 1987
    PubMed
    Summary

    Selective breeding created mice with high or low diazepam sensitivity. These genetically modified mice exhibit significant differences in central nervous system response to benzodiazepines, aiding future research.

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    Area of Science:

    • Neuroscience
    • Pharmacology
    • Genetics

    Background:

    • Diazepam sensitivity varies within populations.
    • Understanding genetic factors influencing drug response is crucial.

    Purpose of the Study:

    • To develop mouse lines with distinct diazepam sensitivities through selective breeding.
    • To investigate the genetic and neurobiological basis of diazepam resistance and sensitivity.

    Main Methods:

    • Selective breeding of genetically heterogeneous mice for diazepam resistance and sensitivity.
    • Rotarod test to assess diazepam-induced neurologic deficit duration.
    • Brain benzodiazepine assays to measure drug absorption, distribution, and concentration.
    • Administration of benzodiazepine antagonist Ro 15-1788.

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    Main Results:

    • Significant divergence in diazepam sensitivity between selected lines observed within two generations and continued over seven generations.
    • No differences in diazepam absorption or distribution between lines.
    • Differences in central nervous system sensitivity to diazepam confirmed by brain benzodiazepine concentrations at recovery.
    • Diazepam-induced motor impairment is mediated by benzodiazepine (BZ) receptors, as shown by blockade with Ro 15-1788.
    • A 9- to 14-fold difference in required dose for similar effects between the lines.

    Conclusions:

    • Selective breeding is effective in creating distinct lines of mice with varying diazepam sensitivity.
    • Differences in diazepam response are primarily due to central nervous system sensitivity, not pharmacokinetics.
    • These selectively bred mice provide a valuable model for studying benzodiazepine mechanisms and drug action.