Effects of repeated seizure induction on seizure activity, post-ictal and interictal behavior.
Individual variability and numerous interactions between pharmacokinetics, pharmacodynamics, and homeostatic factors complicate the study of the anticonvulsant effect in animal models of seizure activity. In theory, both individual variability and the contribution of these factors to the anticonvulsant effect can be determined by following the time course of the pharmacological response and the corresponding plasma concentrations in individual animals. Currently, there are several formal pharmacokinetic-pharmacodynamic models available for the analysis of such data, which yield accurate estimates of drug intrinsic activity and potency. However, most models of seizure activity are not suited for such an approach, either because they can be applied only once, or because the expression of seizures is not constant over time. In addition, the induction of seizures constitutes repeated jeopardy to the animals, which may profoundly change behavior and interfere in the anticonvulsant response as well as in different physiological processes. In this paper, we compare ictal, post-ictal, and interictal behavior in three different models of seizure activity in rats, namely, the electroconvulsive shock, amygdala kindling and the cortical stimulation model (CSM). The methods were compared in the same way as they are currently in use for the assessment of antiepileptic drug effect. Our results show that repeated seizure activity induced by cortical stimulation does not exacerbate ictal activity (eye closure, jerk, gasp, forelimb clonus, and hind-limb tonus) nor post-ictal behavior (chewing and freezing), while producing less serious changes in interictal behavior (walk, lean, upright rearing, exploratory, grooming, and rest) than kindling or electroconvulsive shock. We conclude that seizures induced by cortical stimulation are reproducible and qualitatively similar to kindling seizures. Our results also suggest that the electroconvulsive shock model is not suited for pharmacokinetic-pharmacodynamic studies and that the assessment of interictal behavior may contribute to the evaluation of overall antiepileptic drug effect in seizure disorders.
Della Paschoa
O E
OE
Sylvius Laboratory, Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, University of Leiden, P.O. Box 9503, 2300 RA, Leiden, Netherlands.
Kruk
M R
MR
Voskuyl
R A
RA
Danhof
M
M
D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004597:Electroshock; D007696:Kindling, Neurologic; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000188:drug therapy / Q000209:etiology*; D014741:Video Recording
D000927:Anticonvulsants