In vivo identification and characterization of binding sites for selective serotonin reuptake inhibitors in mouse brain
| Autor: | Yoshiyuki Kagawa, Kazufumi Hirano, Ryohei Kimura, Shizuo Yamada, Syuji Maruyama |
|---|---|
| Rok vydání: | 2004 |
| Předmět: |
Male
Fluvoxamine Pharmacology Tritium General Biochemistry Genetics and Molecular Biology Mice Radioligand Assay In vivo Fluoxetine Sertraline medicine Radioligand Animals General Pharmacology Toxicology and Pharmaceutics Chromatography High Pressure Liquid Serotonin transporter Analysis of Variance Mice Inbred ICR Binding Sites Dose-Response Relationship Drug biology Chemistry Brain General Medicine Paroxetine medicine.anatomical_structure Cerebral cortex Area Under Curve Receptors Serotonin biology.protein Regression Analysis Selective Serotonin Reuptake Inhibitors medicine.drug |
| Zdroj: | Life Sciences. 75:2933-2945 |
| ISSN: | 0024-3205 |
| DOI: | 10.1016/j.lfs.2004.05.030 |
| Popis: | The present study was undertaken to identify and characterize in vivo binding sites of selective serotonin reuptake inhibitors (SSRIs) in the mouse brain by using [ 3 H]paroxetine as radioligand. Relatively higher concentration of [ 3 H]paroxetine was detected in the whole brain (minus cerebellum) than in the plasma of mice after the i.v. injection of the radioligand, and the half-life (t 1/2 ) of elimination was much slower. The in vivo specific [ 3 H]paroxetine binding in the mouse brain after the i.v. injection was defined as the difference of particulate-bound radioactivity between the whole brain and cerebellum, and it was dose-dependently attenuated by oral or intraperitoneal administration of fluoxetine (8.68–116 μmol/kg). Furthermore, oral administration of fluvoxamine, fluoxetine, paroxetine and sertraline at the pharmacologically relevant doses reduced significantly (25–94%) in vivo specific [ 3 H]paroxetine binding in the cerebral cortex, striatum, hippocampus, thalamus and midbrain of mice, and their significant decreases were observed up to at least 8 h (fluvoxamine), 24 h (fluoxetine), and 12 h (paroxetine and sertraline) later. The value of area under the curve (AUC) for decrease in [ 3 H]paroxetine binding vs. time in each brain region was largest for fluoxetine among these SSRIs, due to the relatively longer-lasting occupation of brain serotonin transporter. The AUC value in mouse brain after oral administration of each SSRI was 1.2–3.2 times greater in the thalamus and midbrain than in the cerebral cortex, striatum and hippocampus. Thus, the present study has revealed that [ 3 H]paroxetine may be a suitable radioligand for in vivo characterization of brain binding sites and pharmacological effects of SSRIs. |
| Databáze: | OpenAIRE |
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