Abstract

The influence of aging on the activity of five anticonvulsant agents was studied in rats and mice. In addition, the relation of aging to the CO₂ content of the cerebral cortex of the rat was investigated.

In the rat, the ED50 values in four of the five agents studied decreased with age. Three of the drugs whose ED50 values fell with age are considered to act through the same mechanism, an increase in the CO₂ content of the central nervous system. These anticonvulsants are C0₂, acetazolamide, and sulfanilamide. The increase in sensitivity of the nervous syste to CO₂ was not related to detectable changes in the amount of CO₂ in the cerebral cortex. In addition, changes in the amount of CO₂ could not be measured in the cortex after administration of anticonvulsant doses of acetazolamide. The marked sensitivity of the central nervous system to CO₂ in old rats indicates that changes in tissue CO₂ below the limits of manometric detection are sufficient to produce anticonvulsant effects.

At present it is not possible to relate any changes in blood-brain barrier, in rates of drug metabolism, in the level of central nervous system excitability, or in carbonic anhydrase activity to the decrease in ED50 observed for acetazolamide and sulfanilamide. It appears that the decrease in ED50 of these agents is the consequence of an increase in sensitivity of the nervous system to CO₂. The ED50 for phenobarbital also decreased with age, and this decrease may be the consequence of a decrease in the rate of metabolism of the barbiturates with age.

The mice data demonstrate some species differences from the rat. The ED50 for both acetazolamide and diphenylhydantoin increased with age. Mice, nevertheless, resemble rats in that the ED50 for CO₂ decreased with age. Therefore, in both species aging is associated with an increase in sensitivity of the nervous system to the anticonvulsant effects of CO₂.