The effect of interstimulation interval on the assessment of anticonvulsant drug potency in fully kindled rats

Abstract

Multiple stimulation regimes with interstimulation intervals of 0.25–2 h were investigated in fully kindled rats as methods of testing the time course and potency of anticonvulsant drugs after a single administration. Protocols with conventional interstimulation intervals of 1–3 days were used for comparison. Prior to the drug experiments, the different stimulation regimes were examined in drug-naive, kindled rats in order to determine the extent of postseizure inhibition occurring with such protocols. All stimulations were carried out with a suprathreshold current of 500 μA. Using protocols with 3–9 stimulations within 8 h, seizure severity was relatively stable, but motor seizure duration was reduced in most experiments. Both decreases and increases were observed with respect to afterdischarge duration (ADD). The increases in ADD were primarily due to the appearance of ‘secondary’ afterdischarges with small amplitude, which were associated with immobility, intermittent facial clonus and head nodding. After a series of stimulations at short intervals, reduced seizure severity was observed after this series for at least 1 week, so that an interval of at least 2 weeks had to be interposed between multistimulation experiments in the same group of rats. When the effects of carbamazepine, 15 mg/kg, were determined with 4 different stimulation regimes, it was found that the anticonvulsant potency of the drug was higher in experiments with short interstimulation intervals compared to conventional protocols with interstimulation intervals of 1–3 days, indicating synergistic effects between the drug and postictal inhibition. Indication for such synergism was also found when the animals were only stimulated once daily durine the drug experiments. With higher doses of carbamazepine or phenobarbital, 30 mg/kg, the difference between the stimulation protocols was less marked. Furthermore, the time course of anticonvulsant action determined with different stimulation regimes was similar. The data indicate that multistimulation regimes can be used in kindled rats to determine the time course following single administration of anticonvulsant drugs, but such protocols may lead to an overestimation of anticonvulsant potency.