Tolerance to Anticonvulsant Effects of Diazepam, Clonazepam, and Clobazam in Amygdala‐Kindled Rats

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Abstract
Summary: Benzodiazepines are effective anticonvulsants, but long-term clinical usefulness is limited by development of tolerance. Tolerance to the actions of three prototype anticonvulsant benzodiazepines (BZDs)– diazepam (DZP), clonazepam (CZP), and clobazam (CLB)–was studied in amygdala-kindled rats. Fully kindled rats were dosed three times daily for 2 or 4 weeks. Amygdala stimulation was given 30 min after drug administration on days 1,2, 3,5, and 7 of chronic treatment and then three times weekly. During treatment, tolerance was observed as a loss of drug effect to suppress behavioral and EEG manifestations of seizure activity. Seizure activity remained stable in rats treated with vehicle. Tolerance to the anticonvulsant effects developed most rapidly during CLB treatment and most slowly during CZP treatment. Tolerance to the motor impairment caused by the drugs developed more rapidly. Assay of the amount of drug in brain extracts, using a BZD receptor assay, showed that tolerance was functional, not metabolic. Doubling the dose did not readily restore full anticonvulsant activity. The response to amygdala stimulation 24 h after treatment was stopped showed no residual BZD effect, but there was a rebound in duration of some seizure measures in rats that had been treated with CLB or DZP. Retesting 48 h after treatment was stopped showed that rats were still tolerant. The amygdala-kindled rat is a reliable and sensitive model for studying long-term actions of anticonvulsant BZDs.