Unchanged density of 5-HT1A autoreceptors on the plasma membrane of nucleus raphe dorsalis neurons in rats chronically treated with fluoxetine
Autor: | Luc Zimmer, Laurent Descarries, Latifa Rbah, Mustapha Riad, Nicolas Aznavour, Mathieu Verdurand |
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Rok vydání: | 2008 |
Předmět: |
Male
Agonist medicine.medical_specialty medicine.drug_class media_common.quotation_subject Models Neurological Biology Hippocampus Rats Sprague-Dawley chemistry.chemical_compound Fluoxetine Internal medicine medicine Animals Drug Interactions Microscopy Immunoelectron Receptor Internalization 5-HT receptor Ultrasonography media_common Neurons 8-Hydroxy-2-(di-n-propylamino)tetralin General Neuroscience Cell Membrane Rats Endocrinology medicine.anatomical_structure chemistry Receptor Serotonin 5-HT1A Autoreceptor Raphe Nuclei Neuron MPPF Raphe nuclei Selective Serotonin Reuptake Inhibitors Protein Binding |
Zdroj: | Neuroscience. 151:692-700 |
ISSN: | 0306-4522 |
DOI: | 10.1016/j.neuroscience.2007.11.024 |
Popis: | 5-HT 1A autoreceptors regulate the firing of 5-HT neurons and their release of 5-HT. In previous immuno-electron microscopic studies, we have demonstrated an internalization of 5-HT 1A autoreceptors in the nucleus raphe dorsalis (NRD) of rats, after the acute administration of a single dose of the specific agonist 8-hydroxy-2-(di-n-propylamine)tetralin (8-OH-DPAT) or of the selective 5-HT reuptake inhibitor, fluoxetine. Twenty-four hours after either treatment, the receptors were back in normal density on the plasma membrane of NRD neurons. Here, we examined the subcellular localization of these receptors and the in vivo binding of the 5-HT 1A radioligand 4,2-(methoxyphenyl)-1-[2-( N -2-pyridinyl)- p -fluorobenzamido]ethylpiperazine labeled with [ 18 F]fluorine ([ 18 F]MPPF) after chronic fluoxetine treatment (10 mg/kg daily for 3 weeks, by minipump). Unexpectedly, after such a treatment, there were no more differences between treated and control rats in either the density of plasma membrane labeling of NRD dendrites, or in the in vivo binding of [ 18 F]MPPF, as measured with β-microprobes. This was in keeping with earlier reports of an unchanged density of 5-HT 1A receptor binding sites after chronic fluoxetine treatment, but quite unexpected from the strong electrophysiological and biochemical evidence for a desensitization of 5-HT 1A autoreceptors under such conditions. Indeed, when the fluoxetine-treated rats were challenged with a single dose of 8-OH-DPAT, there was no internalization of the 5-HT 1A autoreceptors, at variance with the controls. Interestingly, several laboratories have reported an uncoupling of 5-HT 1A autoreceptors from their G protein in the NRD of rats chronically treated with fluoxetine. Therefore, the best explanation for our results is that, after repeated internalization and retargeting, functional 5-HT 1A autoreceptors are replaced by receptors uncoupled from their G protein on the plasma membrane of NRD 5-HT neurons. Thus, the regulatory function of these autoreceptors may depend on a dynamic balance among their production, activation, internalization and recycling to the plasma membrane in inactivated (desensitized) form. |
Databáze: | OpenAIRE |
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