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

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

  1. Jatelka
    British Journal of Pharmacology 1996 Feb;117(4):647-52

    Zanotti A (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Mariot R (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Contarino A (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Lipartiti M (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus), Giusti P (http://www.ncbi.nlm.nih.gov/sites/e...l.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus).

    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.