INCREASED SENSITIVITY TO THE ANTICONVULSANT EFFECT OF VALPROATE IN AGING BN BIRIJ RATS

The aim of the present investigations was to study the influence of in creasing age on the pharmacodynamics of valproate in BN/BiRij rats, ap plying a threshold for electrically induced localized seizure activity as a measure of the anticonvulsant effect. Seven groups of healthy ma le BN/BiRij rats were used, aged 3, 6, 12, 19, 25, 31, and 37 months. Individual plasma concentration versus anticonvulsant effect relations hips were determined during a continuous intravenous infusion of sodiu m valproate at a rate of 5.5 mg/min/kg. The infusion was terminated wh en the anticonvulsant effect intensity had reached the maximum attaina ble level or at a total infusion time of three hours. A nonlinear rela tionship between valproate concentration and anticonvulsant effect int ensity was observed with no maximal effect in the concentration range up to 1200 mg.L-1. With increasing age a parallel shift in the concent ration versus anticonvulsant effect relationships toward lower concent rations occurred. Thus increasing age appears to be associated with an increased sensitivity to the anticonvulsant effect of valproate.