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Mouse lines selected for genetic differences in diazepam sensitivity

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Abstract

Selective breeding techniques were used to alter allelic frequencies responsible for diazepam sensitivity and resistance. We used the rotarod test to determine the duration of diazepam-induced neurologic deficit in genetically heterogeneous mice. Males were more sensitive than females in the initial population. We then selectively bred for diazepam resistance and sensitivity. A significant difference between the lines was apparent in both sexes after two generations, and divergence has continued over seven generations. Brain benzodiazepine assays indicated that absorption and distribution of diazepam do not differ in the two lines. Differences in brain benzodiazepine concentrations at recovery from ataxia indicated that the two lines differ in central nervous system sensitivity. We found diazepam-induced rotarod impairment to be blocked in a dose-dependent manner by the specific benzodiazepine antagonist Ro 15-1788, indicating that this effect is mediated through BZ receptors. A dose-response curve obtained from generations 6 and 7 indicates a 9- to 14-fold difference in dose required to obtain similar effects in the two lines. These mice are expected to be useful experimental subjects in studies of benzodiazepine mechanisms.

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Authors and Affiliations

  1. Veterans Administration Medical Center, 94304, Palo Alto, CA, USA

    E. J. Gallaher, L. E. Hollister & S. E. Gionet

  2. Departments of Medicine, Psychiatry, and Pharmacology, Stanford University, 94305, Palo Alto, CA, USA

    L. E. Hollister

  3. Veterans Administration Medical Center and Departments of Medical Psychology and Pharmacology, Oregon Health Sciences University, 97207, Portland, OR, USA

    J. C. Crabbe

Authors
  1. E. J. Gallaher
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  2. L. E. Hollister
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  3. S. E. Gionet
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  4. J. C. Crabbe
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Permanent address: VA Medical Center (151P) Portland OR 97207 USA

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Gallaher, E.J., Hollister, L.E., Gionet, S.E. et al. Mouse lines selected for genetic differences in diazepam sensitivity. Psychopharmacology 93, 25–30 (1987). https://doi.org/10.1007/BF02439582

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  • DOI: https://doi.org/10.1007/BF02439582

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