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Abecarnil enhances recovery from diazepam tolerance
A Zanotti1, F Natolino, A Contarino
1Fidia Research Laboratories, Padova, Italy.
Neuropharmacology
|September 2, 1999
Summary
Repeated diazepam (BDZ) treatment causes tolerance to its anticonvulsant effects. Abecarnil, but not clonazepam or imidazenil, reversed this tolerance by facilitating receptor re-adaptation.
Area of Science:
- Neuropharmacology
- Drug Tolerance
- Benzodiazepine Receptor Research
Background:
- Long-term benzodiazepine (BDZ) use, like diazepam, can lead to tolerance, diminishing their anticonvulsant efficacy.
- Understanding the mechanisms of BDZ tolerance is crucial for developing strategies to maintain therapeutic effects.
- Cross-tolerance patterns among different BDZs provide insights into receptor interactions and tolerance development.
Purpose of the Study:
- To investigate the development of tolerance to the anticonvulsant effects of diazepam in mice.
- To examine cross-tolerance patterns between diazepam and other benzodiazepines (clonazepam, imidazenil, abecarnil).
- To evaluate the potential of abecarnil as a replacement therapy to mitigate diazepam tolerance.
Main Methods:
- Mice were treated with diazepam to induce tolerance, followed by testing anticonvulsant effects against bicuculline-induced convulsions.
- Cross-tolerance was assessed using clonazepam, imidazenil, and abecarnil.
- Receptor binding studies using [3H]-flumazenil were performed to analyze changes in benzodiazepine receptor binding potential (Bmax) and affinity (Kd).
Main Results:
- Diazepam treatment induced tolerance to its own anticonvulsant effects and cross-tolerance to clonazepam and imidazenil, but not abecarnil.
- Substitution therapy with imidazenil partially reversed tolerance, while clonazepam had no effect.
- Abecarnil administration, either by suspension or replacement, progressively decreased diazepam tolerance, with full recovery after 8-15 days.
- Diazepam tolerance was associated with a significant decrease in cortical Bmax, which was restored to normal levels by abecarnil or vehicle treatment.
Conclusions:
- Repeated abecarnil administration in diazepam-tolerant mice facilitates receptor re-adaptation to the diazepam-free state.
- Replacement therapy with abecarnil may offer a novel strategy to reduce or overcome tolerance to conventional benzodiazepines.
- This approach could improve long-term anticonvulsant treatment outcomes for patients using benzodiazepines.