Related Experiment Videos
Changes in histamine H3 receptor responsiveness in mouse brain.
S Morisset1, E Traiffort, J M Arrang
1Unité de Neurobiologie et Pharmacologie Moléculaire, U.109, de l'INSERM, Centre Paul Broca, Paris, France. morisset@broca.inserm.fr
Journal of Neurochemistry
|January 5, 2000
Summary
Ciproxifan, an H3 receptor antagonist, causes autoreceptor hypersensitivity after repeated use, altering histamine levels and receptor binding in the brain. This suggests adaptive changes in histamine (HA) signaling pathways.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Histamine (HA) H3 receptors act as autoreceptors and heteroreceptors, modulating neurotransmitter release.
- Ciproxifan is a selective H3 receptor antagonist that penetrates the brain.
Purpose of the Study:
- To investigate the effects of single and repeated ciproxifan administration on H3 receptor-mediated responses and binding in mouse brain.
- To explore the development of H3 autoreceptor hypersensitivity.
Main Methods:
- Mice received single or repeated doses of ciproxifan.
- Tele-methylhistamine (t-MeHA) levels, a major HA metabolite, were measured in brain areas.
- H3 receptor binding assays using [125I]iodoproxyfan were performed.
- K+-induced [3H]HA release from synaptosomes was assessed.
Main Results:
- Single ciproxifan dose effectively enhanced t-MeHA levels, with a transient decrease possibly indicating rapid autoreceptor hypersensitivity.
- Repeated ciproxifan administration (5 days) led to decreased basal t-MeHA levels and increased ED50 for t-MeHA enhancement, confirming H3 autoreceptor hypersensitivity.
- Subchronic ciproxifan (10 days) increased [125I]iodoproxyfan binding to H3 receptors in striatal and hypothalamic membranes.
- H3 receptor-mediated inhibition of HA release was not significantly altered in cortical synaptosomes.
Conclusions:
- Repeated ciproxifan administration induces H3 autoreceptor and heteroreceptor hypersensitivity.
- Increased HA binding sites may contribute to the observed hypersensitivity.
- These adaptive changes highlight the complex regulation of histamine neurotransmission.