Failure of flumazenil to precipitate a withdrawal syndrome in cats chronically treated with the new anxioselective beta-carboline derivative abecarnil.

The effect of chronic administration of the novel anxiolytic beta-carboline derivative, abecarnil (isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate), was examined and compared with the capability of diazepam to induce physical dependence in cats. The acute administration of the benzodiazepine receptor antagonist, flumazenil (20mg/kg i.p.), to cats treated for 2 weeks with diazepam (7mg/kg i.p., three times daily), induced a severe withdrawal syndrome characterized by the appearance of severe physical signs. Within minutes all cats displayed tremors, increased muscle tone, fear response, repeated vocalization and salivation. On the contrary, in all cats treated chronically (2 weeks) with abecarnil (7mg/kg i.p. three times daily) the challenge dose of flumazenil failed to precipitate a clear abstinence syndrome. In fact, a pupillary dilatation and a mild fear response were the only signs present 15-30min after flumazenil administration. This finding indicates that abecarnil, a new potential therapeutic agent for anxiety disorders and seizures, might have advantages over classical benzodiazepines with regard to development of physical dependence.