Effects of social isolation on pentobarbital activity in mice: Relationship to racemate levels and enantiomer levels in brain

The effects of social isolation on hypnotic actions induced by pentobarbital (PB) were investigated pharmacokinetically in isolated and aggregated mice and rats. Animals were administered i.p. 50 mg/kg of sodium (±)-PB, S(-)-PB or R(+)-PB. Experiments in mice indicated that the duration of sleep induced by sodium (±)-PB was reduced in the isolated mice, while the onset of sleep or the (±)-PB brain levels at the time of awakening did not differ significantly between isolated and aggregated mice. These results suggest that changes in pharmacokinetics of PB may underlie the difference in duration of sleep between isolated and aggregated mice. In additional experiments in mice, brain concentrations of (±)-PB, S(-)-PB or R(+)-PB were determined at predetermined intervals after injection. These experiments demonstrated that the brain concentrations of (±)-PB, as well as those of S(-)-PB, at each predetermined timepoint in mice sacrificed before awakening were significantly lower in the isolated mice. The brain R(+)-PB levels in the isolated mice were also significantly lower as compared with those in the aggregated mice at each timepoint after injection. Experiments in rats indicated that urinary 3'-hydroxypentobarbital (major metabolite) concentrations were higher in the isolated rats at 0 to 6 hr after injection, suggesting an increased rate of hepatic drug metabolism in the isolated rats. Take together, these findings suggest that an increased rate of metabolism of PB, especially that of the S(-)-enantiomer which is responsible for hypnotic action, in isolated rodents may be involved in the shorter duration of sleep time induced by sodium (±)-PB.