Abecarnil, a beta-carboline derivative, does not exhibit anticonvulsant tolerance or withdrawal effects in mice

Development of tolerance and dependence has been reported to occur upon chronic administration of traditional benzodiazepines (BZDs). We compared the effect of chronic treatment with abecarnil, a beta-carboline derivative with high affinity for central BDZ receptors, and diazepam, the BDZ prototype, in mice. After acute administration, abecarnil was as potent and effective as diazepam in protecting from bicuculline-induced convulsion. The time-course analysis of two peak equieffective doses of abecarnil (1.9 mg/kg p.o.) and diazepam (2.7 mg/kg p.o.) showed a similar duration of action. The anticonvulsant potency of diazepam was reduced in mice given chronic diazepam (25 mg/kg p.o., 2 times a day for 17 days). No tolerance to abecarnil was apparent when the drug was administered for the same period using a comparable dose (20 mg/kg p.o.). Severe symptoms of precipitated withdrawal were observed upon administration of the BDZ partial inverse agonist Ro 15-3505 in mice treated chronically with diazepam but not abecarnil. In mice made tolerant to diazepam, maximum [3H]-flumazenil binding sites were reduced in both cerebral cortex (-50%) and cerebellum (-55.2%). No changes in [3H]-flumazenil binding were measured in chronic abecarnil-treated mice. These data indicate that abecarnil possesses a very low tolerance/dependence liability and does not affect BZD receptor density after chronic administration.