LACK OF ANTICONVULSANT TOLERANCE AND BENZODIAZEPINE RECEPTOR DOWN-REGULATION WITH IMIDAZENIL IN RATS

1 Development of anticonvulsant tolerance and benzodiazepine (BZD) rec eptor down-regulation has been reported to occur upon chronic administ ration of conventional BZDs. We compared the effect of chronic treatme nt with imidazenil, a new BZD partial agonist, and diazepam in rats. 2 After acute administration, imidazenil was more potent though less ef fective than diazepam in protecting from bicuculline-induced seizure. The time-course analysis of two peak equieffective doses of imidazenil (2.5 mu mol kg(-1) p.o.) and diazepam (35 mu mol kg(-1), p.o.) showed a longer lasting action of the former drug. 3 The anticonvulsant effi cacy of diazepam (35 mu mol kg(-1), p.o.) was reduced in rats given ch ronic diazepam (35 mu mol kg(-1) p.o., 3 times a day for 8-15 days). N o tolerance to imidazenil (2.5 mu mol kg(-1), p.o.) was apparent after 130-day administration with imidazenil (2.5 mu mol kg(-1), p.o., 3 ti mes a day). 4 Plasma levels of imidazenil and diazepam, assessed 30 mi n after administration, were not changed in chronically treated animal s. 5 In rats made tolerant to diazepam, the maximum number of [H-3]-fl umazenil binding sites were reduced in both cerebral cortex (-36%) and cerebellum (-42%). No changes in [H-3]-Aumazenil binding were found i n chronic imidazenil-treated rats. 6 Specific [H-3]-flumazenil binding in vive was decreased in the forebrain of chronic diazepam- but not o f chronic imidazenil-treated animals. 7 These data indicate that imida zenil possesses a very low tolerance potential to its anticonvulsant a ctivity and does not affect BZD receptor density even after prolonged administration.