The use of
benzodiazepines (BDZs) in the long-term treatment of
epilepsy is greatly restricted by their capacity to induce tolerance and dependence. Thus, the development of new BDZ-related therapeutic agents should be directed by strategies that minimize tolerance- and dependence-inducing properties. Experimental procedures used to determine the success of such strategies often rely on a single assay procedure (e.g., one seizure model), which might lead to false predictions. Furthermore, the different types of tolerance, i.e., "pharmacological" (metabolic or functional) and "behavioral" ("learned" or "contingent"), are often not dealt with in such studies. This prompted us to compare the chronic
anticonvulsant efficacy and withdrawal characteristics of
diazepam and two novel BDZ receptor
ligands, i.e., the partial agonist
bretazenil and the subtype-selective agonist
abecarnil, in different seizure models in mice. Myoclonic, clonic and
tonic seizures were induced by i.v. infusion of
pentylenetetrazol and by transcorneal or transauricular application of electrical stimuli. Prolonged administration of
diazepam (5 mg/kg twice daily for 6 days) resulted in marked
anticonvulsant effects on myoclonic, clonic and tonic seizure thresholds at the onset of treatment, but pronounced tolerance developed rapidly during subsequent treatment. The time course and extent of tolerance was similar with most seizure models. Tolerance characteristics were not affected by study design, i.e., use of separate or the same animals for each seizure induction, indicating that learned or contingent tolerance was not significantly involved under these experimental conditions. After termination of treatment with
diazepam, significant seizure threshold decreases were determined, indicating withdrawal hyperexcitability in response to physical dependence. During prolonged administration of
abecarnil (10 mg/kg twice daily for 6 days), some
anticonvulsant tolerance was seen with electroshock
seizures, but not with
pentylenetetrazol seizures; no withdrawal hyperexcitability was determined upon termination of treatment.
Bretazenil (10 mg/kg twice daily for 6 days) produced no tolerance in any of the seizure models, but a significant decrease in electroshock seizure threshold was seen in the withdrawal period. The data indicate that tolerance and withdrawal characteristics of BDZ receptor partial and subtype-selective agonists in mice depend on the experimental model used, whereas the influence of the experimental protocol is less critical in the case of a full BDZ receptor agonist such as
diazepam.