Effect of age on the pharmacodynamics of phenobarbital and ethanol in rats

The purpose of this investigation was to determine the effect of age on the sensitivity of the central nervous system (CNS) to the depressant action of phenobarbital and ethanol. For this purpose, one or the other of these drugs was administered by slow iv infusion to male rats of various ages until the animals lost their righting reflex. The drug concentrations at that time in serum, brain, and cerebrospinal fluid were determined. The results obtained in studies on 1, 9, and 18-month-old Sprague-Dawley rats and on 7, 16, and 24-month-old Fischer-344 rats showed that phenobarbital concentrations at the pharmacologic end-point decreased with increasing age, indicative of an increased sensitivity of older animals to the CNS depressant effect of the barbiturate. Similar studies with ethanol on Sprague-Dawley rats (only) showed substantially higher drug concentrations at all sampling sites in 5-week-old animals than in 9- and 12-month-old animals at the onset of loss of righting reflex, but no significant differences between the 9- and 12-month-old groups. This investigation, which was designed to exclude or account for pharmacokinetic variables and to avoid confounding secondary effects, such as hypothermia and development of acute functional tolerance, showed a substantial increase in CNS sensitivity to phenobarbital and ethanol with increasing age in rats between the age of 1 and 9 months, and a less pronounced increase (phenobarbital) or no significant change (ethanol) in rats between 9 and 18 months of age.