Tolerance to anticonvulsant effects of some benzodiazepines in genetically epilepsy prone rats

The development of tolerance to the anticonvulsant effects of clonazepam, clobazam, and diazepam were studied in genetically epilepsy-prone rats following intraperitoneal (IP) or oral administration. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz). All compounds showed 60 min after IP injection antiseizure activity with ED(50) against clonus of 0.24 mu mol kg(-1) for clonazepam, 0.72 mu mol kg(-1) for diazepam, and 3.9 mu mol kg(-1) for clobazam. After 120 min of oral administration the ED(50) against clonus of 2.37 mu mol kg(-1) for clonazepam, 15.8 mu mol kg(-1) for diazepam, and 30 mu mol kg(-1) for clobazam. The dose chosen for the chronic treatment were 2.5 mu mol kg(-1) for clonazepam, 15 mu mol kg(-1) for diazepam, and 30 mu mol kg(-1) for clobazam. The animals were treated three times daily for 4 or 6 weeks. Auditory stimulation was administered 60 min after drug IP injection on various days. During treatment, tolerance was observed as a loss of drug anticonvulsant effects. No changes of occurrence of audiogenic seizures was observed in rats treated with vehicle. Tolerance to the anticonvulsant activity developed most rapidly during clobazam treatment, less rapidly following diazepam treatment, and most slowly during clonazepam treatment. Sixty minutes after IP injection on various days of chronic treatment the motor impairment induced by these benzodiazepines was also studied by means of a rotarod apparatus. The tolerance to the motor impairment developed more rapidly than the anticonvulsant effects. The response to auditory stimulation to beniodiazepines was stopped 24 and 48 h after chronic treatment with these compounds, showing no residual drug effects and that rats were still tolerant. The genetically epilepsy-prone rats is a reliable and sensitive model for studying long-term effects of anticonvulsant drugs.