Abecarnil (isopropyl-6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate) is a metabolically stable
anxiolytic and
anticonvulsant beta-carboline derivative with few
sedative and muscle relaxant effects in rodents. Abecamil binds with high affinity to
benzodiazepine receptors. Because long-term treatment with
benzodiazepines leads to development of dependence, we evaluated in mice whether
abecarnil also possesses a potential for producing dependence, using electroencephalographic and electromyographic monitoring, and behavioral assessment of anxiety to detect withdrawal responses after chronic treatment.
Diazepam was used as a reference. Mice withdrawn from chronic treatment with
diazepam (15 mg/kg/day for 12 days) showed a time-related evolution of anxiety,
muscle rigidity and
seizures between days 4 and 21 after discontinuation of the treatment. A period between withdrawal days 1 and 3 was symptom free. Mice withdrawn from chronic administration of
abecarnil (6 mg/kg/day for 12 days) showed no anxiety and no changes in seizure susceptibility and muscle tone. The doses of
diazepam and
abecarnil used for chronic treatment were equivalent in terms of kinetics and binding to
benzodiazepine receptors. These data indicate that long-term treatment with
abecarnil does not induce
benzodiazepine-like dependence in mice. Thus, it may be predicted that chronic treatment with
abecarnil in humans may offer an important alternative to
benzodiazepines in the treatment of anxiety.