Effect of aging on anticonflict and CNS depressant activity of diazepam in rats

Abstract

Male Fischer 344 rats were examined for an age-dependent sensitivity to the anticonflict and central nervous system (CNS) depressant effects of diazepam. A conflict paradigm was used to measure the ability of single intravenous injections of diazepam to attenuate punishment-induced suppression of behavior and to elicit CNS depression in young, mature, and senescent rats. Senescent rats had the lowest behaviorally active threshold dose. However, diazepam at the behaviorally active threshold dose produced a simultaneous increase in punished and unpunished responding in all three age groups. Punished responding was increased more and over a wider dose range in the young and mature rats than in the senescent rats. Sensitivity to the CNS depressant effects of diazepam was over four times greater in the senescent rats than in the other two age groups. In summary, the results indicate that the behavioral effects of diazepam vary with dosage and age of the rat. The male Fischer 344 rat may be a useful animal model for exploring how diazepam elicits age-related behavioral effects in humans.

Age and anxiety: Increased anxiety, decreased anxiolytic, but enhanced sedative, response to chlordiazepoxide in old rats

“…Thus the results of the present experiment confirm the previous report (Komiskey et al, 1987) that old rats are less sensitive to the anxiolytic effects of a BDZ, although they are more sensitive to its C N S depressant effects. If the same biological changes occur with age in humans, this would suggest that the elderly may well gain less antianxiety benefit from BDZ.…”

“…The failure to find this response in the old rats suggests they are less sensitive to the anxiolytic action of chlordiazepoxide. This is in accord with previous results with diazepam in a conflict test (Komiskey et al, 1987) and thus the finding can at least be generalized to two BDZ and two animal tests of anxiety. The failure to find an anxiolytic response in the old rats is unlikely to be due to the low response level of the undrugged rats, since in the young rats with comparable low scores (Batch 2) the effect of CDP was even greater than it was in Batch 1 young rats.…”

“…The failure to find an anxiolytic response in aged rats is unlikely to be due to pharmacokinetic changes, since the only reports of changes with age indicate increased drug concentrations, not reduced. It is also difficult to see how pharmacokinetic changes can account both for the reduced anxiolytic effect and for the enhanced sedative effect found in both this experiment and in the earlier study (Komiskey et al, 1987). Chlordiazepoxide has equal affinity for type 1 and type 2 benzodiazepine receptors, but the results of one study suggest that there might be an age-related change in the action of diazepam, with an increased action on type 2 receptors in old rats (Reeves and Schweizer, 1983).…”

“…In the 12-month-old rats fewer entries and less time was spent in the open arms. In the strain of rats (Fischer 344) used by Komiskey et al (1987), the age-related changes were found only in rats older than 12 months, but this is likely simply to reflect the different life-spans of the two strains. It was possible to test senescent Fischer 344 rats at 28 months of age, whereas in our housing conditions the hooded Lister rats that we use live for only 18-24 months.…”

“…Both groups showed an increase in the density of benzodiazepine (BDZ) binding sites, but whereas in the normal rats the increase was in the binding of the BDZl receptor subtype, in the aged rats the increase was in the BDZ2 receptor subtype (Reeves and Schweizer, 1983). Interestingly, whilst senescent rats showed enhanced sensitivity to the CNS depressant actions of diazepam, they showed a reduced anti-punishment effect in a conflict test (Komiskey et al, 1987). This suggests that there might be a reduction of the anxiolytic efficacy of the BDZ in elderly subjects.…”