The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. II. Maximal electroshock seizure models

Abstract

Although seizure models using electrical stimulation for the induction of generalized tonic-clonic seizures in rodents are widely employed to identify potential anticonvulsants, the important role of various technical, biological and pharmacological factors in the interpretation of results obtained with these models is often not recognized. The aim of this study was to delineate factors other than sex, age, diet, climate and circadian rhythms, which are generally known. For this purpose, experiments with 8 clinically established antiepileptic drugs were undertaken in the following electroshock seizure models: 1. (1) the maximal (tonic extensor) electroshock seizure threshold (MEST) in mice; 2. (2) the traditional maximal electroshock seizure (MES) test with supra-threshold stimulation in mice; and 3. (3) the MES test with suprathreshold stimulation in rats. When drugs were dissolved in vehicles which did not themselves exert effects on seizure susceptibility, the most important factors which influenced drug potencies were 1. (1) marked differences between drugs and species in terms of peak drug effect, duration of action and the formation of active metabolites; 2. (2) differences in drug potencies calculated on the basis of administered doses compared to potency calculations based on active drug concentrations; 3. (3) the equipment used for seizure induction; 4. (4) marked effects of current strength on results obtained in electroshock seizure models; 5. (5) site of application of the electrical stimulus (transcorneal vs. transauricular). In order to reduce the variability among estimates of anticonvulsant activity, the various factors delineated in this study should be rigidly controlled in experimental situations involving assay of anticonvulsant agents.