Related Experiment Videos
Decrease in [3H]flunitrazepam receptor binding in rats tolerant to the effects of nitrazepam
K Szczawińska1, D Cenajek-Musiał, E Nowakowska
1Department of Pharmacology, Academy of Medicine, Poznań, Poland.
Abstract:
Studies were performed to evaluate the binding of [3H]flunitrazepam to cell membranes from the brain cortex of rats that were made tolerant, by the i.p. administration of nitrazepam once daily, to the anxiolytic and sedative effects (after 14 days) and the anticonvulsant action (electroshock, after 28 days) of nitrazepam. A significant decrease in the number of specific [3H]flunitrazepam binding sites was found only in the group that was tolerant to the anticonvulsant effect. The same experiments were also carried out with oxazepam. Since there were no signs of tolerance, the administration of the drug, 10 mg/kg once daily i.p., was continued for 6 weeks. No tolerance occurred and there were no changes in [3H]flunitrazepam binding site density. We conclude that tolerance to the anticonvulsant effect of nitrazepam could be related to the down-regulation of the benzodiazepine receptors.
Insights
Tolerance to nitrazepam's anticonvulsant effects in rats may stem from a reduction in benzodiazepine receptors. This study observed decreased [3H]flunitrazepam binding sites only in rats tolerant to this specific effect.
Area of Science:
- Neuropharmacology
- Molecular Biology
Background:
- Benzodiazepines, like nitrazepam, are widely used for their anxiolytic, sedative, and anticonvulsant properties.
- Tolerance to these effects can develop with chronic administration, impacting therapeutic efficacy.
- Understanding the molecular mechanisms underlying tolerance is crucial for optimizing treatment strategies.
Purpose of the Study:
- To investigate the relationship between tolerance to nitrazepam's effects and changes in benzodiazepine receptor binding.
- To determine if tolerance to anticonvulsant effects is associated with alterations in specific [3H]flunitrazepam binding sites.
Main Methods:
- Rats were administered nitrazepam daily to induce tolerance to anxiolytic, sedative, and anticonvulsant effects.
- Brain cortex cell membranes were isolated to assess specific [3H]flunitrazepam binding.
- Binding assays were performed to quantify the number of benzodiazepine receptors.
Main Results:
- A significant decrease in specific [3H]flunitrazepam binding sites was observed in rats tolerant to nitrazepam's anticonvulsant effects.
- No changes in binding site density were found in rats tolerant to anxiolytic/sedative effects.
- Oxazepam administration did not induce tolerance or alter binding site density, even after prolonged treatment.
Conclusions:
- Tolerance to the anticonvulsant effect of nitrazepam in rats is associated with a reduction in benzodiazepine receptor binding.
- This suggests that down-regulation of benzodiazepine receptors may underlie tolerance to nitrazepam's anticonvulsant action.