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 [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.

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Volume117, Issue4

February 1996

Pages 647-652

Lack of anticonvulsant tolerance and benzodiazepine receptor down regulation with imidazenil in rats

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Lack of anticonvulsant tolerance and benzodiazepine receptor down regulation with imidazenil in rats

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