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 Martin, Vincent S.ca
  • 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 2016-12-15T08:14:27Z
  • dc.date.available 2016-12-15T08:14:27Z
  • dc.date.issued 2015ca
  • 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. Dr Trigo was supported by Fundacion Alicia Koplowitz. Dr Fink (DA07287, DA034488) and Dr Cunningham (DA024157, DA020087) were supported by the National Institute on Drug Abuse grants
  • 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):[12 p.]. DOI: 10.1093/ijnp/pyu056ca
  • dc.identifier.doi http://dx.doi.org/10.1093/ijnp/pyu056
  • dc.identifier.issn 1461-1457ca
  • dc.identifier.uri http://hdl.handle.net/10230/27769
  • dc.language.iso engca
  • dc.publisher Oxford University Pressca
  • dc.relation.ispartof International Journal of Neuropsychopharmacology. 2015 Oct 31;18(3):[12 p.].
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/201714ca
  • dc.rights © Cédric BP Martin [et al.] 2014. Published by Oxford University Press. This is an Open Access article distributed under the terms of a Creative Commons Attribution Licenseca
  • dc.rights.accessRights info:eu-repo/semantics/openAccessca
  • dc.rights.uri http://creativecommons.org/licenses/by-nc/4.0/
  • dc.subject.other Angoixa
  • dc.subject.other Cervell -- Metabolisme
  • dc.subject.other Serotonina
  • dc.title 5-HT2C receptor desensitization moderates anxiety in 5-HTT deficient mice: from behavioral to cellular evidenceca
  • dc.type info:eu-repo/semantics/articleca
  • dc.type.version info:eu-repo/semantics/publishedVersionca

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