IMIDAZENIL, A PARTIAL POSITIVE ALLOSTERIC MODULATOR OF GABA(A) RECEPTORS, EXHIBITS LOW TOLERANCE AND DEPENDENCE LIABILITIES IN THE RAT

Long-term treatment of rats with full (triazolam) or selective (diazep am) allosteric modulators of gamma-aminobutyric acid type A (GABAA) re ceptors rapidly induced tolerance to the protective effect of these dr ugs against bicuculline-induced convulsions. In contrast, long-term ad ministration of partial allosteric modulators (imidazenil and bretazen il) of GABA(A) 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 dia zepam and imidazenil. Discontinuation of long-term treatment with diaz epam or triazolam, but not of long-term treatment with imidazenil or b retazenil, sensitized rats to behavioral inhibition by punishment (ele ctric shock) in a manner that was potentiated by flumazenil. Administr ation of a single oral dose of [C-14]diazepam or [H-3] imidazenil to r ats treated repeatedly with the corresponding unlabeled drug or vehicl e revealed that the brain concentrations of drugs and their metabolite s 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 modulati on rather than with changes in drug metabolism. Imidazenil has a longe r half-life than an equipotent dose of diazepam and protects rats agai nst bicuculline-induced convulsions for a significantly longer time th an diazepam or bretazenil. The low tolerance and physical-dependence l iabilities of imidazenil, together with the long duration of its antic onvulsant action, suggest that this drug should be tested clinically t o verify the hypothesis that partial allosteric modulators of GABA act ion at GABA, receptors endowed with low tolerance liability may prove effective in the treatment of epileptic symptoms in humans.