5-HT2C receptor desensitization moderates anxiety in 5-HTT deficient mice: from behavioral to cellular evidence

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• dc.contributor.author Martin, Cedric B.P.ca
• dc.contributor.author Martín, Vicenteca
• dc.contributor.author Trigo i Rodríguez, Josep M.ca
• dc.contributor.author Chevarin, Carolineca
• dc.contributor.author Maldonado, Rafael, 1961-ca
• dc.contributor.author Fink, Latham H.ca
• dc.contributor.author Cunningham, Kathryn A.ca
• dc.contributor.author Hamon, Michelca
• dc.contributor.author Lanfumey, Laurenceca
• dc.contributor.author Mongeau, Raymondca
• dc.date.accessioned 2017-03-31T10:44:32Z
• dc.date.available 2017-03-31T10:44:32Z
• dc.date.issued 2015
• dc.description.abstract Background: Desensitization and blockade of 5-HT2C receptors (5-HT2CR) have long been thought to be central in the therapeutic action of antidepressant drugs. However, besides behavioral pharmacology studies, there is little in vivo data documenting antidepressant-induced 5-HT2CR desensitization in specific brain areas. Methods: Mice lacking the 5-HT reuptake carrier (5-HTT-/-) were used to model the consequences of chronic 5-HT reuptake inhibition with antidepressant drugs. The effect of this mutation on 5-HT2CR was evaluated at the behavioral (social interaction, novelty-suppressed feeding, and 5-HT2CR–induced hypolocomotion tests), the neurochemical, and the cellular (RT-qPCR, mRNA editing, and c-fos–induced expression) levels. Results: Although 5-HTT-/- mice had an anxiogenic profile in the novelty-suppressed feeding test, they displayed less 5-HT2CR–mediated anxiety in response to the agonist m-chlorophenylpiperazine in the social interaction test. In addition, 5-HT2CR–mediated inhibition of a stress-induced increase in 5-HT turnover, measured in various brain areas, was markedly reduced in 5-HTT-/- mutants. These indices of tolerance to 5-HT2CR stimulation were associated neither with altered levels of 5-HT2CR protein and mRNA nor with changes in pre-mRNA editing in the frontal cortex. However, basal c-fos mRNA production in cells expressing 5-HT2CR was higher in 5-HTT-/- mutants, suggesting an altered basal activity of these cells following sustained 5-HT reuptake carrier inactivation. Furthermore, the increased c-fos mRNA expression in 5-HT2CR–like immune-positive cortical cells observed in wild-type mice treated acutely with the 5-HT2CR agonist RO-60,0175 was absent in 5-HTT-/- mutants. Conclusions: Such blunted responsiveness of the 5-HT2CR system, observed at the cell signaling level, probably contributes to the moderation of the anxiety phenotype in 5-HTT-/- mice.
• dc.description.sponsorship This work was supported by grants from INSERM, UPMC, the European Community (FP7, “Devanx” consortium, F2-2007–201714), and ANR (Sercedit 2008–2010, contract ANR-06-Neuro-045-01). Dr CBP Martin was recipient of a fellowship from the French Ministère de la Recherche during performance of this work.
• dc.format.mimetype application/pdfca
• dc.identifier.citation Martin CB, Martin VS, Trigo JM, Chevarin C, Maldonado R, Fink LH et al. 5-HT2C receptor desensitization moderates anxiety in 5-HTT deficient mice: from behavioral to cellular evidence. Int J Neuropsychopharmacol. 2015 Oct 31;18(3):pyu056. DOI: 10.1093/ijnp/pyu056
• dc.identifier.doi http://dx.doi.org/10.1093/ijnp/pyu056
• dc.identifier.issn 1461-1457
• dc.identifier.uri http://hdl.handle.net/10230/28352
• dc.language.iso eng
• dc.publisher Oxford University Pressca
• dc.relation.ispartof International Journal of Neuropsychopharmacology. 2015 Oct 31;18(3):pyu056
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/201714
• dc.rights © The Author 2015. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
• dc.subject.keyword Antidepressant drugs
• dc.subject.keyword C-fos mRNA
• dc.subject.keyword Editing
• dc.subject.keyword Frontal cortex
• dc.subject.keyword Serotonin2C
• dc.title 5-HT2C receptor desensitization moderates anxiety in 5-HTT deficient mice: from behavioral to cellular evidenceca
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion