Lack of anticonvulsant tolerance and benzodiazepine receptor down regulation with imidazenil in rats.
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 mumol kg-1 p.o.) and diazepam (35 mumol kg-1, p.o.) showed a longer lasting action of the former drug. 3. The anticonvulsant efficacy of diazepam (35 mumol kg-1, p.o.) was reduced in rats given chronic diazepam (35 mumol kg-1 p.o., 3 times a day for 8-15 days). No tolerance to imidazenil (2.5 mumol kg-1, p.o.) was apparent after 130-day administration with imidazenil (2.5 mumol 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 [3H]-flumazenil binding sites were reduced in both cerebral cortex (-36%) and cerebellum (-42%). No changes in [3H]-flumazenil binding were found in chronic imidazenil-treated rats. 6. Specific [3H]-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.
Zanotti
A
A
Fidia Research Laboratories, Abano, Italy.
Mariot
R
R
Contarino
A
A
Lipartiti
M
M
Giusti
P
P
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001569:Benzodiazepines / Q000097:blood / Q000494:pharmacology*; D001640:Bicuculline / Q000633:toxicity; D003975:Diazepam / Q000097:blood / Q000494:pharmacology; D015536:Down-Regulation; D004361:Drug Tolerance; D005442:Flumazenil / Q000378:metabolism; D018757:GABA Modulators / Q000097:blood / Q000494:pharmacology*; D007093:Imidazoles / Q000097:blood / Q000494:pharmacology*; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced; D014316:Tritium
D000927:Anticonvulsants; D018757:GABA Modulators; D007093:Imidazoles; D011963:Receptors, GABA-A; D014316:Tritium; D001569:Benzodiazepines; D005442:Flumazenil; C082661:imidazenil; D003975:Diazepam; D001640:Bicuculline