The use of recombinant inbred strains to study mechanisms of drug action

Long-sleep (LS) and short-sleep (SS) mice which were selectively bred for sensitivity to the sedative-hypnotic effects of ethanol have been used extensively in the examination of sensitivity to ethanol as well as to other CNS depressants. Understanding the relationship between sensitivity to ethanol and other depressants using LS and SS mice has been limited to a two mouse line comparison because these mice do not exist as replicate lines. To circumvent this problem, DeFries et al. have bred LSXSS recombinant inbred strains (LSXSS RIs) from a cross of LS and SS mice. These mice are being characterized on their responses to a variety of CNS depressants and agents that interact with the GABAergic system. Preliminary results are presented here on the sensitivity of these LSXSS RIs to pentobarbital, phenobarbital, and flurazepam as measured by sleep times. Additionally, analyses of seizure susceptibility to the GABAergic antagonist, bicuculline, in 24 LSXSS RIs indicate that there is no significant relationship between this measure of GABAergic function and sensitivity to ethanol as measured by the sleep-time response. These results are presented in the context of questions that can be resolved using RIs in drug-abuse research.