Withdrawal precipitation by benzodiazepine receptor antagonists in dogs chronically treated with diazepam or the novel anxiolytic and anticonvulsant beta-carboline abecarnil

Abstract

The effects of the benzodiazepine (BZ) receptor antagonists flumazenil (Ro 15-1788) and the beta-carboline ZK 93426 were compared in dogs before and after chronic treatment with diazepam or the novel BZ receptor ligand abecarnil (ZK 112119). Abecarnil, a beta-carboline, is thought to act as partial (low efficacy) and/or subtype selective agonist at central BZ receptors. Diazepam and abecarnil were administered at doses which, based on previous experiments on anticonvulsant activity, resulted in about equieffective drug concentrations during treatment. In dogs treated with diazepam, 6 mg/kg/day p.o., for 2 weeks, severe abstinence symptoms, including seizures, were precipitated in all animals by i.v. infusion of the BZ receptor antagonists, differences being found in the type of symptoms caused by flumazenil and ZK 93426. In dogs treated with abecarnil, 4 mg/kg/d s.c., for 6 weeks, only relatively mild abstinence symptoms were precipitated by infusion of flumazenil or ZK 93426, although pharmacologically active plasma concentrations of abecarnil had been maintained throughout the period of treatment. This suggests that BZ receptor ligands which act as partial and/or selective agonists might be more favourable than traditional agonists, such as diazepam, regarding the induction of physical dependence.