Kinetic and dynamic components of increased benzodiazepine sensitivity in aging animals

Male CD-1 mice (age 6 weeks, 6 months, 1 and 2 years) received single 2-mg/kg i.p. doses of clonazepam. Plasma and cortex clonazepam concentrations, rotarod ataxia and in vivo benzodiazepine receptor occupancy were measured at multiple times up to 14 hr after dosage. Elimination of clonazepam from plasma and cortex became slower with age, but cortex concentrations always exceeded those in plasma. The mean ratio was 1.82, and was not influenced by age. Rotarod ataxia was quantitatively greater and of longer duration in aging animals. This was not explained entirely by kinetic changes, as ataxia at any given cortex clonazepam concentration or degree of receptor occupancy was greater in 1-year-old animals than in those age 6 weeks or 6 months. In a second study, 6-week and 1-year-old animals were tested at a fixed time (1 hr) after variable doses of clonazepam (0.01-2.0 mg/kg); findings were consistent with results from the fixed-dose study. In vitro studies evaluated benzodiazepine receptor binding, chloride channel binding and muscimol-stimulated chloride uptake in cortical membrane preparations from animals of the four age groups. Binding affinity and number of binding sites were not influenced by age, or was γ-aminobutyric acid-dependent muscimol-stimulated chloride uptake (either with or without addition of lorazepam) significantly related to age. Thus, increased overall sensitivity of aging animals to the central depressant effects of clonazepam is evident in the described model. The change in sensitivity is explained in part by a slower rate of clonazepam elimination, and in part by an intrinsic increase in the susceptibility of the aging brain, the mechanism of which is not established.