ANTICONVULSANT TOLERANCE AND WITHDRAWAL CHARACTERISTICS OF BENZODIAZEPINE RECEPTOR LIGANDS IN DIFFERENT SEIZURE MODELS IN MICE - COMPARISONOF DIAZEPAM, BRETAZENIL AND ABECARNIL

The use of benzodiazepines (BDZs) in the long-term treatment of epilep sy is greatly restricted by their capacity to induce tolerance and dep endence. Thus, the development of new BDZ-related therapeutic agents s hould be directed by strategies that minimize tolerance- and dependenc e-inducing properties. Experimental procedures used to determine the s uccess of such strategies often rely on a single assay procedure (e.g. , one seizure model), which might lead to false predictions. Furthermo re, the different types of tolerance, i.e., ''pharmacological'' (metab olic or functional) and ''behavioral'' (''learned'' or ''contingent'') , are often not dealt with in such studies. This prompted us to compar e the chronic anticonvulsant efficacy and withdrawal characteristics o f diazepam and two novel BDZ receptor ligands, i.e., the partial agoni st bretazenil and the subtype-selective agonist abecarnil, in differen t seizure models in mice. Myoclonic, clonic and tonic seizures were in duced by i.v. infusion of pentylenetetrazol and by transcorneal or tra nsauricular application of electrical stimuli. Prolonged administratio n of diazepam (5 mg/kg twice daily for 6 days) resulted in marked anti convulsant effects on myoclonic, clonic and tonic seizure thresholds a t the onset of treatment, but pronounced tolerance developed rapidly d uring subsequent treatment. The time course and extent of tolerance wa s similar with most seizure models. Tolerance characteristics were not affected by study design, i.e., use of separate or the same animals f or each seizure induction, indicating that learned or contingent toler ance was not significantly involved under these experimental condition s. After termination of treatment with diazepam, significant seizure t hreshold decreases were determined, indicating withdrawal hyperexcitab ility in response to physical dependence. During prolonged administrat ion of abecarnil (10 mg/kg twice daily for 6 days), some anticonvulsan t tolerance was seen with electroshock seizures, but not with pentylen etetrazol seizures; no withdrawal hyperexcitability was determined upo n termination of treatment. Bretazenil (10 mg/kg twice daily for 6 day s) produced no tolerance in any of the seizure models, but a significa nt decrease in electroshock seizure threshold was seen in the withdraw al period. The data indicate that tolerance and withdrawal characteris tics of BDZ receptor partial and subtype-selective agonists in mice de pend on the experimental model used, whereas the influence of the expe rimental protocol is less critical in the case of a full BDZ receptor agonist such as diazepam.