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Lack of anticonvulsant tolerance and benzodiazepine receptor down regulation with imidazenil in rats
Author(s) -
Zanotti Adriano,
Mariot Roberta,
Contarino Angelo,
Lipartiti Maria,
Giusti Pietro
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15239.x
Subject(s) - diazepam , flumazenil , anticonvulsant , benzodiazepine , pharmacology , bicuculline , gabaa receptor , agonist , endocrinology , drug tolerance , medicine , chemistry , receptor , epilepsy , psychiatry
1 Development of anticonvulsant tolerance and benzodiazepine (BZD) receptor down‐regulation has been reported to occur upon chronic administration of conventional BZDs. We compared the effect of chronic treatment with imidazenil, a new BZD partial agonist, and diazepam in rats. 2 After acute administration, imidazenil was more potent though less effective than diazepam in protecting from bicuculline‐induced seizure. The time‐course analysis of two peak equieffective doses of imidazenil (2.5 μmol kg −1 p.o.) and diazepam (35 μmol kg −1 , p.o.) showed a longer lasting action of the former drug. 3 The anticonvulsant efficacy of diazepam (35 μmol kg −1 , p.o.) was reduced in rats given chronic diazepam (35 μmol kg −1 , p.o., 3 times a day for 8–15 days). No tolerance to imidazenil (2.5 μmol kg −1 , p.o.) was apparent after 130‐day administration with imidazenil (2.5 μmol kg −1 , p.o., 3 times a day). 4 Plasma levels of imidazenil and diazepam, assessed 30 min after administration, were not changed in chronically treated animals. 5 In rats made tolerant to diazepam, the maximum number of [ 3 H]‐flumazenil binding sites were reduced in both cerebral cortex (−36%) and cerebellum (−42%). No changes in [ 3 H]‐flumazenil binding were found in chronic imidazenil‐treated rats. 6 Specific [ 3 H]‐flumazenil binding in vivo was decreased in the forebrain of chronic diazepam‐ but not of chronic imidazenil‐treated animals. 7 These data indicate that imidazenil possesses a very low tolerance potential to its anticonvulsant activity and does not affect BZD receptor density even after prolonged administration.