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Tolerance to anticonvulsant effects of some benzodiazepines in genetically epilepsy prone rats
G De Sarro1, E D Di Paola, U Aguglia
1Department of Experimental Medicine, School of Medicine, Catanzaro, Italy.
Abstract:
The development of tolerance to the anticonvulsant effects of clonazepam, clobazam, and diazepam were studied in genetically epilepsy-prone rats following intraperitoneal (IP) or oral administration. The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz). All compounds showed 60 min after IP injection antiseizure activity with ED50 against clonus of 0.24 mumol kg-1 for clonazepam, 0.72 mumol kg-1 for diazepam, and 3.9 mumol kg-1 for clobazam. After 120 min of oral administration the ED50 against clonus of 2.37 mumol kg-1 for clonazepam, 15.8 mumol kg-1 for diazepam, and 30 mumol kg-1 for clobazam. The dose chosen for the chronic treatment were 2.5 mumol kg-1 for clonazepam, 15 mumol kg-1 for diazepam, and 30 mumol kg-1 for clobazam. The animals were treated three times daily for 4 or 6 weeks. Auditory stimulation was administered 60 min after drug IP injection on various days. During treatment, tolerance was observed as a loss of drug anticonvulsant effects. No changes of occurrence of audiogenic seizures was observed in rats treated with vehicle. Tolerance to the anticonvulsant activity developed most rapidly during clobazam treatment, less rapidly following diazepam treatment, and most slowly during clonazepam treatment. Sixty minutes after IP injection on various days of chronic treatment the motor impairment induced by these benzodiazepines was also studied by means of a rotarod apparatus. The tolerance to the motor impairment developed more rapidly than the anticonvulsant effects. The response to auditory stimulation to benzodiazepines was stopped 24 and 48 h after chronic treatment with these compounds, showing no residual drug effects and that rats were still tolerant. The genetically epilepsy-prone rats is a reliable and sensitive model for studying long-term effects of anticonvulsant drugs.
Insights
Tolerance to anticonvulsant drugs like clonazepam, clobazam, and diazepam developed at different rates in epilepsy-prone rats. Clobazam showed the fastest tolerance, while clonazepam showed the slowest, impacting long-term effectiveness.
Area of Science:
- Neuroscience
- Pharmacology
- Epilepsy Research
Background:
- Benzodiazepines such as clonazepam, clobazam, and diazepam are commonly used for their anticonvulsant properties.
- The development of tolerance to the therapeutic effects of these drugs can limit their long-term efficacy.
- Genetically epilepsy-prone rats serve as a valuable model for investigating chronic drug effects.
Purpose of the Study:
- To investigate and compare the development of tolerance to the anticonvulsant effects of clonazepam, clobazam, and diazepam.
- To evaluate the time course of tolerance development to both anticonvulsant and motor impairment effects.
- To assess the utility of genetically epilepsy-prone rats in modeling long-term anticonvulsant drug effects.
Main Methods:
- Genetically epilepsy-prone rats were administered clonazepam, clobazam, or diazepam via intraperitoneal or oral routes.
- Anticonvulsant activity was assessed using sound-evoked seizures (audiogenic seizures).
- Motor impairment was evaluated using a rotarod apparatus; tolerance was assessed over 4-6 weeks of chronic treatment.
Main Results:
- All tested benzodiazepines demonstrated acute anticonvulsant activity.
- Tolerance to anticonvulsant effects developed at varying rates: fastest with clobazam, intermediate with diazepam, and slowest with clonazepam.
- Tolerance to motor impairment developed more rapidly than tolerance to anticonvulsant effects.
Conclusions:
- The rate of tolerance development varies significantly among different benzodiazepines.
- Genetically epilepsy-prone rats provide a reliable model for studying the long-term effects and tolerance development of anticonvulsant medications.
- Understanding differential tolerance rates is crucial for optimizing long-term benzodiazepine therapy in epilepsy.