title: Neuronal phenotype dependency of agonist-induced internalization of the 5-HT(1A) serotonin receptor.
abstract: Selective serotonin reuptake inhibitors (SSRI) are aimed at increasing brain 5-HT tone; however, this expected effect has a slow onset after starting SSRI treatment because of initial activation of 5-HT(1A) autoreceptor-mediated negative feedback of 5-HT release. After chronic SSRI treatment, 5-HT(1A) autoreceptors desensitize, which allows 5-HT tone elevation. Because 5-HT(1A) receptor (5-HT(1A)R) internalization has been proposed as a possible mechanism underlying 5-HT(1A) autoreceptor desensitization, we examined whether this receptor could internalize under well controlled in vitro conditions in the LLC-CPK1 cell line and in raphe or hippocampal neurons from rat embryos. To this goal, cells were transfected with recombinant lentiviral vectors encoding N-terminal tagged 5-HT(1A)R, and exposed to various pharmacological conditions. Constitutive endocytosis and plasma membrane recycling of tagged-5-HT(1A)R was observed in LLC-PK1 cells as well as in neurons. Acute exposure (for 1 h) to the full 5-HT(1A)R agonists, 5-HT and 5-carboxamido-tryptamine, but not the partial agonist 8-OH-DPAT, triggered internalization of tagged 5-HT(1A)R in serotonergic neurons only. In contrast, sustained exposure (for 24 h) to all agonists induced tagged-5-HT(1A)R endocytosis in raphe serotonergic neurons and a portion of hippocampal neurons, but not LLC-PK1 cells and partial agonist displayed an effect only in serotonergic neurons. In all cases, agonist-induced tagged 5-HT(1A)R endocytosis was prevented by the 5-HT(1A)R antagonist, WAY-100635, which was inactive on its own. These data showed that agonist-induced 5-HT(1A)R internalization does exist in neurons and depends on agonist efficacy and neuronal phenotype. Its differential occurrence in serotonergic neurons supports the idea that 5-HT(1A)R internalization might underlie 5-HT(1A) autoreceptor desensitization under SSRI antidepressant therapy.
authors.affiliation: Centre de Psychiatrie et Neurosciences, INSERM UMR 894, Paris F-75014, France, Université Paris Descartes, Sorbonne Paris Cité, Paris 75270, France, Université Pierre et Marie Curie, Paris F-75013, France, and Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, CNRS UMR-7225, INSERM UMR-975, Paris F-75013, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Bouaziz
authors.forename: Michel Boris
authors.initials: MB
authors.lastname: Emerit
authors.forename: Guilan
authors.initials: G
authors.lastname: Vodjdani
authors.forename: Vanessa
authors.initials: V
authors.lastname: Gautheron
authors.forename: Michel
authors.initials: M
authors.lastname: Hamon
authors.forename: Michèle
authors.initials: M
authors.lastname: Darmon
authors.forename: Justine
authors.initials: J
authors.lastname: Masson
mesh_terms: D000818:Animals; D017660:Autoreceptors / Q000819:agonists* / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology; D005260:Female; D018374:LLC-PK1 Cells; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000378:metabolism* / Q000494:pharmacology; D013552:Swine
chemical_list: D017660:Autoreceptors; D058825:Serotonin 5-HT1 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A
keywords: 5-HT1A receptor; constitutive and drug-induced internalization; hippocampus; neuron; raphe; recycling