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 upo n chronic administration of traditional benzodiazepines (BZDs). We com pared 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 wa s as potent and effective as diazepam in protecting from bicuculline-i nduced 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.) show ed a similar duration of action. The anticonvulsant potency of diazepa m 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 dru g was administered for the same period using a comparable dose (20 mg/ kg p.o.). Severe symptoms of precipitated withdrawal were observed upo n administration of the BDZ partial inverse agonist Ro 15-3505 in mice treated chronically with diazepam but not abecarnil. In mice made tol erant to diazepam, maximum [H-3]-flumazenil binding sites were reduced in both cerebral cortex (-50%) and cerebellum (-55.2%). No changes in [H-3]-flumazenil binding were measured in chronic abecarnil-treated m ice. These data indicate that abecarnil possesses a very low tolerance /dependence liability and does not affect BZD receptor density after c hronic administration.