Long-term treatment of rats with full (
triazolam) or selective (
diazepam) allosteric modulators of
gamma-aminobutyric acid type A (GABAA) receptors rapidly induced tolerance to the protective effect of these drugs against
bicuculline-induced convulsion. In contrast, long-term administration of partial allosteric modulators (
imidazenil and
bretazenil) of GABAA receptors, in doses equipotent to those of
diazepam and
triazolam that induce
anticonvulsant tolerance, failed to elicit such a tolerance. Furthermore, no cross-tolerance was observed between
diazepam and
imidazenil. Discontinuation of long-term treatment with
diazepam or
triazolam, but not of long-term treatment with
imidazenil or
bretazenil, sensitized rats to behavioral inhibition by punishment (electric
shock) in a manner that was potentiated by
flumazenil. Administration of a single oral dose of [14C]
diazepam or [3H]
imidazenil to rats treated repeatedly with the corresponding unlabeled
drug or vehicle revealed that the brain concentrations of drugs and their metabolites were similar in both groups of animals. This suggests that tolerance to the full or selective allosteric modulators of GABAA receptors may be associated with changes in the efficacy of the allosteric modulation rather than with changes in
drug metabolism.
Imidazenil has a longer half-life than an equipotent dose of
diazepam and protects rats against
bicuculline-induced convulsions for a significantly longer time than
diazepam or
bretazenil.(ABSTRACT TRUNCATED AT 250 WORDS)