Mouse lines selected for genetic differences in diazepam sensitivity

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.

Cerebellar granule‐cell‐specific GABAA receptors attenuate benzodiazepine‐induced ataxia: evidence from α6‐subunit‐deficient mice

“…In the Δα6lacZ –/– mutant mice, a major contribution can be assigned to the cerebellar receptors. A pharmacodynamic action has been demonstrated to be responsible for differential ataxic sensitivity between diazepam‐sensitive and diazepam‐resistant mouse lines (Gallaher et al . 1987), which indicates that pharmacokinetic differences are not needed to produce wide sensitivity differences to diazepam between mouse lines.…”

Selective breeding for differential saccharin intake as an animal model of drug abuse

“…For example, selectively bred lines have been developed for ethanolrelated hypnotic (McClearn and Kakihana, 1981), hypothermic (Crabbe et al, 1987a), locomotor (Crabbe et al, 1987b), and withdrawal effects (Wilson et al, 1984;Crabbe et al, 1986) as well as ethanol preference (Eriksson, 1968a, b;Li and Lumeng, 1977). Selective breeding in rodents has also been extended to the ataxic effects of diazepam (Gallaher et al, 1987), analgesic effects of opiates (Belknap et al, 1987), sensitivity to psychostimulants (Smolen and Marks, 1991;Marley et al, 1998), and to the locomotor effects of nicotine (Smolen and Marks, 1991;Smolen et al, 1994). The selective breeding process invariably reveals accompanying phenotypic changes that, when properly controlled for, can be attributed to the pleiotropic effects of the genes underlying the selected phenotype.…”

Sensitivity to cocaine and amphetamine among mice selectively bred for differential cocaine sensitivity

“…Selective breeding techniques have more recently begun to be applied to other psychoactive agents, including the ataxic effects of diazepam (Gallaher et al 1987), the analgesic effects of opiates (Belknap et al 1987), and the locomotor effects of nicotine (Smolen and Marks 1991;Smolen et al 1994). To date, however, only a limited attempt has been made selectively to breed for differential sensitivity to psychostimulants (Smolen and Marks 1991).…”