ANTICONVULSANT TOLERANCE TO CLONAZEPAM IN AMYGDALA-KINDLED RATS - CLONAZEPAM CONCENTRATIONS AND BENZODIAZEPINE RECEPTOR-BINDING

The relationship between anticonvulsant tolerance to clonazepam and be nzodiazepine receptor changes was studied in amygdala kindled rats. Fu lly kindled rats were given 1 mg/kg clonazepam (clonazepam treated) or vehicle (kindled control) orally three times per day for 4 weeks. Dur ing chronic treatment, amygdala stimulation was given twice per week, 30 min after a single protective dose of clonazepam (0.5 mg/kg, i.p.) was injected to both groups of rats. As measured by seizure stage, clo nazepam treated rats showed a greater degree of tolerance than kindled control rats; contingent tolerance to the anticonvulsant effects of c lonazepam developed in kindled control rats, while clonazepam treated rats shows contingent plus pharmacologic tolerance. There were no sign ificant differences between clonazepam treated and kindled control rat s in ''peak'' plasma clonazepam concentrations 40 min after clonazepam injections. Benzodiazepine receptor assays showed no significant diff erence in maximal binding capacity (B-max), dissociation constant (K-d ) or gamma-aminobutyric acid (100 mu M) enhancement of benzodiazepine receptor binding between clonazepam treated and kindled control rats. These data suggest that pharmacologic tolerance to anticonvulsant acti on of clonazepam is not related to either plasma clonazepam concentrat ions or benzodiazepine receptor changes.