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Development of tolerance to anxiolytic effects of chlordiazepoxide in elevated plus-maze test and decrease of GABAA
S Ishihara1, M Hiramatsu, T Kameyama
1Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University, Japan.
Journal of Neural Transmission. General Section
|January 1, 1993
Summary
Repeated chlordiazepoxide (a benzodiazepine) use caused tolerance to its anxiety-reducing effects. This tolerance may stem from a decrease in GABA-A receptors, not benzodiazepine receptors.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- Benzodiazepines are commonly prescribed for anxiety.
- Tolerance to benzodiazepines can develop with repeated use.
- The precise mechanisms underlying benzodiazepine tolerance are not fully understood.
Purpose of the Study:
- To investigate if repeated chlordiazepoxide administration induces tolerance to its anxiolytic effects.
- To determine if chronic chlordiazepoxide alters benzodiazepine and GABA-A receptor expression.
- To explore the relationship between receptor changes and behavioral tolerance.
Main Methods:
- Utilized an elevated plus-maze test to assess anxiety-like behavior in rodents.
- Employed quantitative autoradiography to measure receptor binding.
- Administered chlordiazepoxide (30 mg/kg, i.p.) daily for 10-14 days.
Main Results:
- Chlordiazepoxide administration for 10 and 14 days resulted in tolerance to its anxiolytic effects.
- No significant changes were observed in benzodiazepine receptor binding ([3H]flunitrazepam, [3H]Ro 15-4513).
- A significant reduction in GABA-A receptor binding ([3H]muscimol) was found in the cortex, caudate putamen, and hippocampus.
Conclusions:
- Repeated chlordiazepoxide administration leads to tolerance to its anxiolytic properties.
- This tolerance is associated with a down-regulation of GABA-A receptors.
- Benzodiazepine receptor density appears unaffected by chronic chlordiazepoxide treatment, suggesting a specific role for GABA-A receptor changes in tolerance development.