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Development of tolerance to the CNS effects of aminoglutethimide in mice
1Welsh School of Pharmacy, University of Wales College of Cardiff, U.K.
Abstract:
Initially, there is a high incidence of CNS-depressant side-effects when the aromatase inhibitor, aminoglutethimide, is used in the treatment of patients with advanced breast cancer. Tolerance to these effects develops with continued dosing. This study examines the development of tolerance to various indices of CNS depression with the drug in mice. Single doses of aminoglutethimide induced a dose-dependent depression of spontaneous locomotor activity, rotarod performance, righting reflex and body temperature and a dose-related antileptazol activity. On repeated dosing with the drug, tolerance to these various activities occurred. The tolerance was found to be dose-dependent in the rotarod and righting reflex tests and time-dependent in the locomotor and body temperature tests. Although the results do not allow a determination of whether this clearly demonstrated phenomenon in the mouse is primarily functional or dispositional, the slow onset (14 days) for complete tolerance may be indicative of a functional mechanism.
Insights
Aminoglutethimide, an aromatase inhibitor, causes CNS depression in breast cancer patients. Studies in mice show tolerance develops to these effects with continued dosing, suggesting a functional mechanism.
Area of Science:
- Pharmacology
- Neuroscience
- Oncology
Background:
- Aromatase inhibitors like aminoglutethimide are used for advanced breast cancer.
- Central nervous system (CNS) depressant side effects are common with initial aminoglutethimide treatment.
- Tolerance to these side effects develops over time with continued drug administration.
Purpose of the Study:
- To investigate the development of tolerance to CNS depressant effects of aminoglutethimide in a mouse model.
- To characterize the dose- and time-dependency of tolerance to various CNS depression indices.
Main Methods:
- Mice were administered single or repeated doses of aminoglutethimide.
- Assessed CNS depression through measures of spontaneous locomotor activity, rotarod performance, righting reflex, body temperature, and antileptazol activity.
- Analyzed tolerance development in relation to drug dosage and duration of treatment.
Main Results:
- Single doses of aminoglutethimide induced dose-dependent CNS depression.
- Repeated dosing led to the development of tolerance to these effects.
- Tolerance varied: dose-dependent for rotarod and righting reflex, time-dependent for locomotor activity and body temperature.
- Complete tolerance onset was observed around 14 days.
Conclusions:
- Tolerance to aminoglutethimide-induced CNS depression demonstrably occurs in mice.
- The slow onset of tolerance (14 days) suggests a potential functional mechanism, though dispositional mechanisms cannot be excluded.
- Findings contribute to understanding the neuropharmacological adaptations to aromatase inhibitor therapy.