title: Long-term treatment with abecarnil does not induce diazepam-like dependence in mice.
abstract: 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 Mice withdrawn from chronic treatment with diazepam (15 mg/kg/day for 12 days) showed a time-related evolution of anxiety, muscle rigidity and seizures between days 4 and 21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 Mice withdrawn from chronic administration of abecarnil (6 mg/kg/day for 12 days) showed no anxiety and no changes in seizure susceptibility and muscle tone.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.
authors.affiliation: Research Laboratories of Schering AG, Berlin, Germany.
authors.forename: K G
authors.initials: KG
authors.lastname: Steppuhn
authors.forename: H H
authors.initials: HH
authors.lastname: Schneider
authors.forename: L
authors.initials: L
authors.lastname: Turski
authors.forename: D N
authors.initials: DN
authors.lastname: Stephens
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000378:metabolism / Q000633:toxicity; D001007:Anxiety / Q000188:drug therapy; D002243:Carbolines / Q000378:metabolism / Q000633:toxicity; D003975:Diazepam / Q000633:toxicity; D004576:Electromyography; D008297:Male; D051379:Mice; D011963:Receptors, GABA-A / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced; D013375:Substance Withdrawal Syndrome; D019966:Substance-Related Disorders
chemical_list: D014151:Anti-Anxiety Agents; D002243:Carbolines; D011963:Receptors, GABA-A; C062769:abecarnil; D003975:Diazepam